Closed-chest Dogs Research Articles

The early translational research of radiofrequency catheter ablation

The history of the development of radiofrequency (RF) catheter ablation is a mirror of my life’s work and has been a fulfilling professional and personal journey for me. In 1981, Gonzales and Scheinman first reported His-bundle catheter ablation using direct current (DC) in closed-chest dogs.1 Subsequently, in 1982, Gallagher and Scheinman individually applied the same technique to treat refractory supraventricular tachycardia by ablating the atrioventricular (AV) junction in humans.2,3 When I began my academic career at the University of Arizona Medical Center in 1982, I was intrigued by this nonpharmacologic therapeutic modality.

Serial coronary microembolization induced ischemic cardiomyopathy: Model refinement in the closed-chest Beagle dog

Serial coronary microembolization induced ischemic cardiomyopathy: Model refinement in the closed-chest Beagle dog

A novel technique to predict pulmonary capillary wedge pressure utilizing central venous pressure and tissue Doppler tricuspid/mitral annular velocities.

Assessing left ventricular (LV) filling pressure (pulmonary capillary wedge pressure, PCWP) is an important aspect in the care of patients with heart failure (HF). Physicians rely on right ventricular (RV) filling pressures such as central venous pressure (CVP) to predict PCWP, assuming concordance between CVP and PCWP. However, the use of this method is limited because discordance between CVP and PCWP is observed. We hypothesized that PCWP can be reliably predicted by CVP corrected by the relationship between RV and LV function, provided by the ratio of tissue Doppler peak systolic velocity of tricuspid annulus (S(T)) to that of mitral annulus (S(M)) (corrected CVP:CVP·S(T)/S(M)). In 16 anesthetized closed-chest dogs, S T and S M were measured by transthoracic tissue Doppler echocardiography. PCWP was varied over a wide range (1.8-40.0 mmHg) under normal condition and various types of acute and chronic HF. A significantly stronger linear correlation was observed between CVP·S(T)/S(M) and PCWP (R2 = 0.78) than between CVP and PCWP (R2 = 0.22) (P < 0.01). Receiver-operating characteristic (ROC) analysis indicated that CVP·S(T)/S(M) >10.5 mmHg predicted PCWP >18 mmHg with 85% sensitivity and 88% specificity. Area under ROC curve for CVP·S T/S M to predict PCWP >18 mmHg was 0.93, which was significantly larger than that for CVP (0.66) (P < 0.01). Peripheral venous pressure (PVP) corrected by S T/S M (PVP·S(T)/S(M) also predicted PCWP reasonably well, suggesting that PVP·S(T)/S (M) may be a minimally invasive alternative to CVP·S(T)/S(M) In conclusion, our technique is potentially useful for the reliable prediction of PCWP in HF patients.

Abstract 9413: A Feasibility Study of Non-Invasive Ablation of Ventricular Tachycardia Using High-Intensity Focused Ultrasound

Introduction: Conventional catheter ablation of ventricular tachycardia (VT) is limited in part by its invasiveness and associated complications, particularly when an epicardial approach is needed. This study evaluated the feasibility of targeted ablation of cardiac tissues using high-intensity focused ultrasound (HIFU) as a potential means for non-invasive VT ablation. Methods &amp; Results: Ablation of ventricular myocardium was performed in anesthetized closed-chest dogs using a HIFU therapeutic system that is being used clinically for ablation of human solid tumors. The animal was placed onto the HIFU system with its left chest immersed in a tank filled with specially treated water. Ventricular pacing using a quadripolar catheter via the internal carotid artery was performed at a rate slightly higher than intrinsic sinus rate to mimic VT. The myocardium at the tip of the pacing catheter (Figure 1) was targeted for ablation (400 watts for 2-4 s). Ablation end-point was loss of ventricular capture at twice pacing threshold. In 5 separate preparations, pacing could be terminated successfully (Figure 2). No subsequent capture was seen at 5 times baseline pacing threshold but capture could be obtained at different locations using the same pacing catheter. Both transmural and localized lesions could be created in a controlled fashion without evident injury to the skin, lung, or pericardium on postmortem examination. Conclusion: This pilot study suggests that HIFU is potentially useful for non-invasive ablation of targeted, localized myocardial tissue; and may be applicable for VT ablation, particularly those of intramyocardial / epicardial origin.

A novel minimally-invasive technique to predict pulmonary capillary wedge pressure utilizing jugular venous pressure and the tissue Doppler tricuspid/mitral annular velocities

Purpose: Accurate prediction of left heart filling pressure is critical to the management of patients with Heart Failure (HF). However, reliability of conventional prediction such as the ratio of early transmitral velocity to tissue Doppler mitral annular early diastolic velocity (E/Ea) is not satisfactory. Purpose of this study was to validate our newly developed technique to predict Pulmonary Capillary Wedge Pressure (PCWP) utilizing Jugular Venous Pressure (JVP) and the ratio of tissue Doppler peak systolic velocity of the tricuspid annulus (St) to that of the mitral annulus (Sm). Methods: In 10 anesthetized closed-chest dogs, PCWP and JVP were measured through catheters. St, Sm and E/Ea were measured by trans-thoracic tissue Doppler echocardiography. PCWP, JVP, St, Sm and E/Ea were recorded over a variable preload range in normal heart, in left HF induced by coronary artery embolization, and in right HF induced by pulmonary artery embolization. Results: Regression analysis of pooled 146 data sets indicated that PCWP (2–40 mmHg) and E/Ea (3–14) correlated weakly (Figure A), while PCWP and JVP·St/Sm (-1–32mmHg) correlated tightly (Figure B). Receiver-operating characteristic (ROC) analysis identified cutoffs that maximized the sum of sensitivity and specificity for detecting PCWP > 18 mmHg (Figure C). E/Ea >6 had 89% sensitivity and 73% specificity. JVP·St/Sm >11 mmHg had 90% sensitivity and 90% specificity. Area under ROC curve for JVP·St/Sm (0.94) was significantly larger than that for E/Ea (0.79) (p<0.001). ![Figure][1] Figure 1 Conclusions: JVP corrected by the relation between right and left ventricular functions, JVP·St/Sm, accurately predicts PCWP. Our technique to predict PCWP may be useful in the management of HF patients. [1]: pending:yes

Feasibility and Safety of Using an Esophageal Protective System to Eliminate Esophageal Thermal Injury: Implications on Atrial‐Esophageal Fistula Following AF Ablation

Ablation for atrial fibrillation (AF) requires energy delivery in close proximity to the esophagus (Eso) which has accounted for the LA-Eso fistula, a rare but life-threatening complication. We evaluated an Eso cooling system to protect the Eso during RF ablation. An "in vitro" heart-Eso preparation was initially used to test a temperature-controlled fluid-circulating system (EPSac [esophageal protective system]-RossHart Technologies Inc.) and an expandable compliant Eso sac during cardiac RF delivery (4 mm tip, perpendicular to the heart, 15 g pressure) at 25, 35, and 45 W, 100 +/- 5 Omega for 30 seconds with the EPSac at 25, 15, 10, and 5 degrees C. All cardiac lesions were transmural. Eso thermal injury could only be avoided with the EPSac at 10 and 5 degrees C. The system was then tested in 6 closed chest dogs, each receiving 12 RFs (LA aiming at the Eso) for 30 seconds: without EPSac (control) at 35 W (1 dog); at 45 W with EPSac at 25 degrees C (1 dog), 10 degrees C (2 dogs), and 5 degrees C (2 dogs). The EPSac volume was intentionally increased to displace the Eso toward the LA (2 dogs 5 and 10 degrees C). Eso injured control and EPSac at 25 degrees C; Eso spared EPSac at 5 and 10 degrees C, without Eso displacement. Shallow external Eso injury noted when intentionally displacing the Eso toward the LA. The EPSac spares the Eso from collateral thermal injury. It requires circulating fluid at 5 or 10 degrees C and a compliant sac to avoid displacement of the Eso. Its safety and efficacy remain to be demonstrated in patients undergoing AF ablation.

Stretch‐Activated Receptors Mediate Cardiac Memory

Cardiac memory refers to long-lasting T-wave changes that follow an episode of altered ventricular activation sequence. Memory-induced alterations in repolarizing ion channel activity have been characterized. However, the mechanism by which changes in activation sequence produce these effects is unknown. We hypothesized that cardiac memory is mediated by the response of stretch-activated receptors (SARs) to a change in mechanical activation sequence. In anesthetized, closed-chest dogs, coronary sinus leads were used to pace the posterolateral left ventricle (LV) continuously for 1 hour at a rate of 120 bpm. The surface vectorcardiogram was used to quantify cardiac memory by measuring T-wave displacement after pacing. Streptomycin, which has been shown to block SARs, was given at a dose of 4 g intramuscularly 1 hour before experimental LV pacing sessions. T-wave displacement after control sessions of LV pacing in the absence of drug (n = 12) was compared to that produced by pacing after streptomycin administration (n = 10 sessions). There was a distinct and consistent cardiac memory seen after 1 hour of LV pacing under control conditions, with T-wave displacement of 1.28 +/- 0.43 mV (P < 0.001 vs baseline). Pretreatment with streptomycin had no direct effect on the electrocardiogram or hemodynamics, but decreased pacing-induced T-wave displacement to 0.50 +/- 0.28 mV (P < 0.001 vs control sessions). Streptomycin, a SAR blocker, dramatically attenuated the development of cardiac memory following epicardial pacing. These data suggest that SARs are a critical link between mechanical sequence of activation and regional modulation of action potential duration that is responsible for cardiac memory.

Right Ventricular Function in Cardiovascular Disease, Part II

Right ventricular (RV) function may be impaired in pulmonary hypertension (PH), congenital heart disease (CHD), and coronary artery disease and in patients with left-sided heart failure (HF) or valvular heart disease. In recent years, many studies have demonstrated the prognostic value of RV function in cardiovascular disease. In the past, however, the importance of RV function has been underestimated. This perception originated from studies on open-pericardium dog models and from the observation that patients may survive without a functional subpulmonary RV (Fontan procedure). In the 1940s, studies using open-pericardium dog models showed that cauterization of the RV lateral wall did not result in a decrease in cardiac output or an increase in systemic venous pressure.1–3 As was later demonstrated, the open-pericardium model did not take into account the complex nature of ventricular interaction. In 1982, Goldstein and colleagues2 showed that RV myocardial infarction (RVMI) in a closed-chest dog model led to significant hemodynamic compromise. These findings were further supported by clinical studies demonstrating an increased risk of death, arrhythmia, and shock in patients with RVMI.4 The study of the RV is a relatively young field. In 2006, the National Heart, Lung, and Blood Institute identified RV physiology as a priority in cardiovascular research.5 The goal of this review is to present a clinical perspective on RV physiology and pathobiology. In the first article of the series, the anatomy, physiology, embryology, and assessment of the RV were discussed. In this second part, we discuss the pathophysiology, clinical importance, and management of RV failure. RV failure is a complex clinical syndrome that can result from any structural or functional cardiovascular disorder that impairs the ability of the RV to fill or to eject blood. The cardinal clinical manifestations of RV failure are (1) fluid retention, which may lead …

Relationship Between Ventricular Contractility and Early Diastolic Intraventricular Pressure Gradients: A Diastolic Link to Systolic Function

Early diastolic intraventricular pressure gradient (IVPG), as derived by color M-mode echocardiography, has been proposed to correlate with left ventricular (LV) elastic recoil. However, any relationship to quantifiable indices of LV contractility is poorly defined. To relate IVPG with invasive and noninvasive indices of contractility, 6 closed-chest dogs each had a high-fidelity conductance catheter placed into the LV for continuous determination of end-diastolic pressures, volumes, +dP/dt(max), and the time constant of LV relaxation (tau) under baseline conditions and 4 different stages of beta-receptor modulation. At each stage, IVPGs were determined from color M-mode echocardiography images. Doppler-derived strain rate (epsilon') and myocardial systolic myocardial velocities (S(m)) were also measured. E(max) was obtained from the slope of the end-systolic pressure-volume relationship during caval occlusion. Results of contractility indices were compared to IVPG with regression analysis. IVPG ranged from 0.72 to 3.95 mm Hg whereas E(max) ranged from 0.66 to 14.9 mm Hg/mL and end-systolic volume ranged from 1.9 to 59.7 mL. IVPG correlated with epsilon' (r = 0.71), S(m) (r = 0.67), end-systolic volume (r = 0.53), and invasive indices (+dP/dt(max), r = 0.71, and E(max), r = 0.82). Early diastolic IVPGs are associated with LV contractility. These findings may explain the proposed mechanism in which potential energy stored during systole is released during diastole to provide for adequate ventricular filling, even under low filling pressures.

Characterization of the Acute Cardiac Electrophysiologic Effects of Ethanol in Dogs

Alcohol has been related to atrial fibrillation (holiday heart syndrome), but its electrophysiologic actions remain unclear. We evaluated the effects of alcohol in 23 anesthetized dogs at baseline and after 2 cumulative intravenous doses of ethanol: first dose 1.5 ml/kg (plasma level 200 mg/dl); second dose 1.0 ml/kg (279 mg/dl). In 13 closed-chest dogs (5 with intact autonomic nervous system, 5 under combined autonomic blockade and 3 sham controls), electrophysiologic evaluation and monophasic action potential (MAP) recordings were undertaken in the right atrium and ventricle. In 5 additional dogs, open-chest biatrial epicardial mapping with 8 bipoles on Bachmann's bundle was undertaken. In the remaining 5 dogs, 2D echocardiograms and ultrastructural analysis were performed. In closed-chest dogs with intact autonomic nervous system, ethanol had no effects on surface electrocardiogram and intracardiac variables. At a cycle length of 300 milliseconds, no effects were noted on atrial and ventricular refractoriness and on the right atrial MAP. These results were not altered by autonomic blockade. No changes occurred in sham controls. In open-chest dogs, ethanol did not affect inter-atrial conduction time, conduction velocity, and wavelength. Atrial arrhythmias were not induced in any dog, either at baseline or after ethanol. Histological and ultrastructural findings were normal but left ventricular (LV) ejection fraction decreased in treated dogs (77 vs. 73 vs. 66%; p = 0.04). Ethanol at medium and high doses depresses LV systolic function but has no effects on atrial electrophysiological parameters. These findings suggest that acute alcoholic intoxication does not directly promote atrial arrhythmias.

Towards automating the pulmonary artery catheter: a canine validation study

We aimed to develop and conduct animal testing of a unique technique for continuous and automatic monitoring of both cardiac output (CO) and left atrial pressure (LAP) by mathematical analysis of a pulmonary artery pressure (PAP) waveform. Our technique specifically analyzes the PAP waveform over long time scales in which the confounding wave and inertial effects are attenuated so as to simultaneously estimate average proportional CO and absolute LAP based on a lumped parameter model. The proportional CO estimates may then be conveniently calibrated with a single thermodilution measurement. To evaluate the technique, we performed an experiment in a closed-chest dog in which the PAP waveform and highly invasive, gold standard aortic flow probe CO and LAP catheter measurements were simultaneously recorded during various pharmacological interventions. We report that the technique achieved an overall CO error of 15.1% after a single calibration and an overall LAP error of 14.4%. For comparison, the LAP error via conventional end-diastolic PAP estimates was over twice as high. With further successful testing, the technique may ultimately be employed so as to effectively automate the pulmonary artery catheter. This work was supported by the NHLBI Grant HL-080568 and an award from the American Heart Association.

Preparation and evaluation of poly(L‐lactide‐co‐glycolide) (PLGA) microbubbles as a contrast agent for myocardial contrast echocardiography

A kind of absorbable PLGA microbubble-based contrast agent (PLGA microspheres with porous or hollow inner structure) was fabricated by an improved double emulsion-solvent evaporation method. The contrast efficiency was evaluated and proved both in vitro and in vivo. By adjusting the polymer concentration and volume of the inner aqueous phase during the fabrication of microbubbles, the inner structure of the microbubbles could be controlled. Both air-filled and perfluoropropane-filled microbubbles can opacify the left ventricle. However, when compared with air-filled microbubbles, perfluoropropane-filled microbubbles can produce significantly longer enhancement in left ventricle in the dog model due to the lower diffusivity and lower solubility of perfluoropropane in blood. A suspension of perfluoropropane-filled PLGA microbubbles (1.8 microm average microbubbles size, 2 x 10(8) microbubbles/mL concentration) has successfully and safely achieved myocardial opacification in closed-chest dogs. A perfusion defect was observed in both of the two dogs with acute myocardial infarction with Power Contrast Imaging (PCI) triggered technology. In the examination of contrast in both ventricular and myocardial opacification, the high mechanical index (MI) was found to have superior contrast sensitivity over the low MI for PLGA-based contrast agents.

In vivo study of microcirculation in canine myocardium using the IVIM method.

The intravoxel incoherent motion (IVIM) method was implemented in closed-chest dogs to obtain measurements on microcirculation in the left ventricular wall in vivo. Specifically, it enabled us to measure the mean microflow velocity (400 +/- 40 microm/s) and the vascular volume fraction (VVF) (11.1% +/- 2.2%), and observe the directional preference of capillary orientation. The apparent diffusion coefficients (ADCs) of water along and perpendicular to myofibers were also measured. With vasodilatation by adenosine infusion, a 25% increase in the VVF and a 7% increase in the mean microflow velocity were observed, while no change in the ADC was detected. A 28.5% decrease of the ADC was observed postmortem.

Lower receiving frequencies than transmitting frequencies could yield improved results for contrast imaging: an in vivo study in closed chest canines.

Ultrasonic imaging methods of receiving at higher frequencies, which are multiples of the transmitting frequencies (harmonic imaging), are well established as a means of improving myocardial visualization in association with intravenous contrast administration. This exploratory study examined the effect of using receive frequencies that were lower than the transmit frequencies while imaging closed chest dogs with an Ensemble wideband, phase inversion contrast program on a modified Siemens Elegra scanner. Intravenous bolus injections of 0.75 mL Definity and 1 mL QW7437 were administered to six anesthetized dogs. Intermittent imaging for contrast visualization was performed using either a broadband array, transmitting at 1.4 MHz and receiving at 2.6-3.2 MHz or a broadband 4-7.5 MHz transducer transmitting at 6.0 MHz and receiving at 4.2-4.5 MHz. Contrast enhancement was measured by videodensitometry, sampling mid-cavity and within the myocardium before and after injection. The changes in videodensity from control to after injection were calculated for each method. There was no significant difference in the change in intracavity videodensity between the two imaging strategies although there was near full intracavity saturation in all cases. However, the change in myocardial density was significantly greater for both contrast agents when using receiving frequencies lower than transmitting frequencies (P = 0.02 and 0.03). The difference in duration of the myocardial blush did not reach statistical significance but it tended to persist for longer with the lower receiving frequencies. Delivering sound energy at a slightly higher frequency and receiving at lower than the transmit frequency may be an advantageous method of enhancing myocardial perfusion signals during intravenous contrast echocardiography.

Effect of 60 minutes of rapid atrial pacing on atrial action potential duration in the in-situ canine heart.

Right atrial monophasic action potentials were recorded before and after 60 minutes of rapid atrial pacing (pacing cycle length (CL); 127 +/- 10 ms) in 12 closed-chest dogs. The right atrial (RA) monophasic action potential (MAP) duration at 90% repolarization (RAMAPD) was measured at CLs of 400 ms and 250 ms. CL-dependent changes in RAMAPD (CL 400 ms - 250 ms) before and after rapid atrial pacing were 24 +/- 1 ms and 16 +/- 5 ms, respectively (p < 0.02). RAMAP was recorded at each atrial pacing CL starting at 240 ms decreasing by 10-ms increments. RAMAPD alternans was observed in 10 of 12 dogs at a CL of 163 +/- 17 ms before and in 10 of 12 dogs at s CL of 198 +/- 29 ms (p < 0.01) after rapid atrial pacing. Sustained atrial fibrillation (AF) (>5 minutes) was induced in 1 of 12 dogs at a pacing CL of 130 ms before rapid atrial pacing and in 4 of 12 dogs at a pacing CL of 135 +/- 17 ms after rapid atrial pacing. Onset of AF was always preceded by the RAMAPD alternans. Sixty minutes of rapid atrial pacing leads to diminution of rate adaptation of atrial action potential duration (APD) and appearance of APD alternans of greater magnitude at longer CL, both of which may contribute to the initiation and perpetuation of AF during its early phase.

Increased Total Positive End-Expiratory Pressure Does Not Improve Hypoxemia during One-Lung Ventilation

In Reply:—On behalf of my co-authors I would like to thank Drs. Yokata and Sari for their correspondence and for sharing our interest in the pathophysiology of one-lung ventilation (OLV) as it applies to intraoperative management of patients during thoracic anesthesia. Their letter highlights three issues that arise out of our study of the interrelation of positive end-expiratory pressure (PEEP) and lung compliance with oxygenation during one-lung anesthesia:(1) Would it be more useful to use the inflection point derived from the expiratory limb of the pressure-volume (PV) curve of the ventilated lung, rather than the inspiratory lower inflection point (LIP), as a surrogate marker for the functional residual capacity (FRC) and the optimal endexpiratory lung volume? This is a possibility. As they mention, the expiratory inflection point has been demonstrated to be a useful guide for ventilatory management of patients with ARDS in the intensive care unit. Unfortunately, our experimental protocol did not allow for measurements on the expiratory portion of the PV curve. Although there are important differences in the respiratory mechanics between ARDS patients and those having intraoperative one-lung anesthesia, this would be a worthwhile question to study.(2) The level of auto-PEEP does not correlate with Pao2during one-lung ventilation (OLV). This is correct. A comparison of the PV curves of two patients with low levels of auto-PEEP in figure 2 and figure 3 of our manuscript demonstrates this point. 1The patient in figure 2 had an identifiable LIP, the application of PEEP raised the end-expiratory pressure closer to the LIP level and the patient had an improvement of Pao2with PEEP. The patient in figure 3 did not have a measurable LIP. Presumably this patient and others with similar PV patterns do not get down to the level of their FRC at end-expiration and are not helped by applied PEEP. So it is not merely the presence of auto-PEEP but also the underlying lung mechanics that determine whether a patient will benefit from PEEP during OLV.(3) Gravity and position may not be an important determinant of blood flow redistribution during OLV. The authors quote the study of Mure et al ., 2which was performed in closed-chest dogs to back up their point. While it is correct that we now appreciate that anatomic factors have a major contribution to the distribution of pulmonary blood flow, it is not clear how relevant this is to clinical OLV in the open-chest human. In fact, a recent report has confirmed the importance of operative position on oxygenation during OLV. A study by Watanabe et al ., 5demonstrated that there was a significant difference in oxygenation during OLV dependent on the patients position, with the mean Pao2in the lateral position exceeding that in the supine position by greater than 100 mmHg. Since the publication of our manuscript another study has been reported which validates our findings. Fujiwara et al . 3applied PEEP to the ventilated lung or continuous positive airway pressure (CPAP) to the nonventilated lung in a series of patients during OLV. They found that PEEP and CPAP were equivalent therapies and that both significantly increased Pao2during OLV. This is very different from the previous findings of Capan et al ., 4who showed that CPAP clearly increased mean Pao2during OLV while PEEP decreased mean Pao2. The difference between these two studies is in the patient populations. Capan studied patients with moderate or severe COPD having thoracotomies for lung cancer surgery. Fujiwara studied patients having OLV for esophageal surgery who are more likely to have normal pulmonary function. This supports our thesis that patients with normal or supra-normal lung elastic recoil (e.g . restrictive lung mechanics: pulmonary fibrosis, obesity) are the patients most likely to reach an end-expiratory lung volume below their FRC, and thus are the most likely to benefit from PEEP to the ventilated lung during OLV.

Evaluation of a new ultrasound contrast agent (AI-700) using two-dimensional and three-dimensional imaging during acute ischemia

Background: A new intravenous contrast agent, AI-700, was evaluated to determine whether a bolus injection could be used to detect myocardial perfusion abnormalities during acute ischemia by using 2-dimensional (2D) and 3-dimensional (3D) myocardial contrast echocardiography. Methods: 2D MCE was performed in 14 closed-chest dogs during coronary occlusion by using both continuous and triggered gray scale harmonic imaging and triggered power Doppler imaging. 3D MCE (open-chest) and nuclear perfusion imaging were performed in 10 of the 14 dogs. Postmortem triphenyl tetrazolium chloride (TTC) staining was performed to verify infarction. Results: Thirteen of the 14 dogs had infarct by TTC; all 10 that had nuclear imaging showed a perfusion defect. Of the 13 dogs that had infarction, perfusion defects were detected in all (13 of 13) by gray scale harmonic imaging (sensitivity = 100%), and in 11 of 13 by power Doppler imaging (sensitivity = 85%). All 10 dogs that had nuclear imaging showed perfusion defects by gray scale harmonic imaging (sensitivity = 100%) and 8 of 10 by power Doppler imaging (sensitivity = 80%). The perfusion defect size, derived from 3D imaging (25% ± 12%) correlated well with that from nuclear imaging (24% ± 12%) (y = 0.9x + 3.8, r = 0.96, mean difference = 1.3% ± 2.6%). The perfusion defect mass by 3D (22 ± 14 g) also correlated well with the infarct mass by TTC staining (24 ± 16 g) (y = 0.8x + 2.9, r = 0.89, P <.001, mean difference = −2.8 ± 7.6 g). Conclusion: After a single bolus of AI-700, both 2D and 3D MCE could accurately detect perfusion defects representing the area at risk of infarction during acute ischemia compared with nuclear imaging and predicted the size of infarction as verified by TTC staining. (J Am Soc Echocardiogr 2002;15:686-94.)

Dobutamine versus dipyridamole for inducing reversible perfusion defects in chronic multivessel coronary artery stenosis

We hypothesized that, although the effects of dipyridamole and dobutamine on myocardial blood volume (MBV) and mean microbubble velocity (VEL) are different, the magnitude of perfusion deficit during both forms of stress is the same because both drugs unmask abnormal myocardial blood flow (MBF) reserve. Both dipyridamole and dobutamine are used clinically as pharmacologic stress agents to induce reversible perfusion defects in patients with chronic coronary artery disease (CAD), but the basis for doing so for dobutamine is not clear. Eleven chronically instrumented closed-chest dogs with multivessel coronary stenosis were studied. Hemodynamics, radiolabeled microsphere-derived MBF, and myocardial contrast echocardiography (MCE)-derived myocardial perfusion were measured at rest, after dipyridamole infusion (0.56 mg x kg(-1)), and at peak dobutamine dose (either 30 or 40 microg x kg(-1) x min(-1)). Abnormal beds were defined as those demonstrating an MBF reserve <3 with dipyridamole. In the presence of either drug, MBV increased more in the normal bed than in the abnormal bed, but the increase was higher in both beds with dobutamine than with dipyridamole. The slope of the relationship between MBF reserve and MBV reserve was greater during dobutamine than dipyridamole (p < 0.05). The converse was true for VEL reserve (p < 0.05). Consequently, the relationship between the ratios of either variable, or the product of the two, between the abnormal bed and normal bed was similar for both drugs. Although the effects of dipyridamole and dobutamine on MBV and VEL are different, both are equally effective in detecting physiologically relevant coronary stenoses on MCE. Both can therefore be used interchangeably with myocardial perfusion imaging for the detection of CAD.

Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation.

The goal of this study was to determine the therapeutic efficacy of angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic receptor blockers in experimental chronic mitral regurgitation (MR), gaining knowledge using methods difficult to apply in humans. Both ACE inhibitors and beta-blockers are cornerstones in the treatment of human congestive heart failure. However, the roles of these treatments for chronic MR is unclear. Mitral regurgitation was created in 11 closed-chest dogs. Three months after the creation, the ACE inhibitor lisinopril 20 mg was given orally daily. After three months of lisinopril therapy, the beta-blocker atenolol was added to lisinopril for another three months. Atenolol was begun at a dose of 12.5 mg daily and increased gradually to 100 mg daily. Hemodynamics and left ventricular (LV) function were assessed throughout the study. Regurgitant fraction was consistently >50% over the course of this study. Pulmonary capillary wedge pressure and LV end-diastolic pressure were significantly increased after three months of MR and decreased during both lisinopril and the combined therapy in which it was not different from baseline. Left ventricular contractility measured by the end-systolic stiffness constant was depressed from 3.66 +/- 0.20 to 2.65 +/- 0.12 (p < 0.05) at three months of MR and rose insignificantly after lisinopril treatment (2.99 +/- 0.17). When atenolol was added, it rose significantly and returned to normal (3.50 +/- 0.22, p < 0.05). Although lisinopril significantly reduced preload, its effect on LV contractility was insignificant in experimental MR. Conversely, atenolol, when added to lisinopril, achieved maximum hemodynamic benefit and also restored LV contractility.

Oxygen radicals trigger activation of NF-kappaB and AP-1 and upregulation of ICAM-1 in reperfused canine heart.

We investigated whether oxygen radicals generated during ischemia-reperfusion trigger postischemic inflammation in the heart. Closed-chest dogs underwent 90-min coronary artery occlusion, followed by 1- or 3-h reperfusion: 10 dogs received the cell-permeant oxygen radical scavenger N-(2-mercaptopropionyl)-glycine (MPG; 8 mg x kg(-1) x h(-1) intracoronary) beginning 5 min before reperfusion, and 9 dogs received vehicle. Blood flow (microspheres), intercellular adhesion molecule (ICAM)-1 protein expression (immunohistochemistry), ICAM-1 gene activation (Northern blotting), nuclear DNA binding activity of nuclear factor (NF)-kappaB and AP-1 (electrophoretic mobility shift assays), and neutrophil (PMN) accumulation (myeloperoxidase activity) were assessed in myocardial tissue samples. ICAM-1 protein expression was high in vascular endothelium after ischemia-reperfusion but was markedly reduced by MPG. MPG treatment also markedly decreased expression of ICAM-1 mRNA and tissue PMN accumulation. Nuclear DNA binding activities of NF-kappaB and AP-1, increased by ischemia-reperfusion, were both markedly decreased by MPG at 1 h of reperfusion. However, by 3 h, AP-1 activity was only modestly reduced by MPG and NF-kappaB activity was not significantly different from ischemic-reperfused controls. These results suggest that oxygen radicals generated in vivo during reperfusion trigger early activation of NF-kappaB and AP-1, resulting in upregulation of the ICAM-1 gene in vascular endothelium and subsequent tissue accumulation of activated PMNs.