Effects of estrogen on the vascular injury response in estrogen receptor alpha, beta (double) knockout mice.

The two known estrogen receptors, ERalpha and ERbeta, mediate the effects of estrogen in all target tissues, including blood vessels. We have shown previously that estrogen inhibits vascular injury response to the same extent in female wild-type (WT), ERalpha knockout (ERalphaKO(CH)), and ERbeta knockout (ERbetaKO(CH)) mice. We generated mice harboring disruptions of both ERalpha and ERbeta genes (ERalpha,betaKO(CH)) by breeding and studied the effect of 17beta-estradiol (E2) on vascular injury responses in ovariectomized female ERalpha,betaKO(CH) mice and WT littermates. E2 inhibited increases in vascular medial area following injury in the WT mice but not in the ERalpha,betaKO(CH) mice, demonstrating for the first time that the two known estrogen receptors are necessary and sufficient to mediate estrogen inhibition of a component of the vascular injury response. Surprisingly, as in WT littermates, E2 still significantly increased uterine weight and inhibited vascular smooth muscle cell (VSMC) proliferation following injury in the ERalpha,betaKO(CH) mice. These data support that the role of estrogen receptors differs for specific components of the vascular injury response in the ERalpha,betaKO(CH) mice. The results leave unresolved whether E2 inhibition of VSMC proliferation in ERalpha,betaKO(CH) mice is caused by a receptor-independent mechanism, an unidentified receptor responsive to estrogen, or residual activity of the ERalpha splice variant reported previously in the parental ERalphaKO(CH) mice. These possibilities may be resolved by studies of mice in which ERalpha has been fully disrupted (ERalphaKO(St)), which are in progress.

A complex role for the progesterone receptor in the response to vascular injury.

Clinical studies of hormone replacement therapy to prevent cardiovascular diseases have heightened interest in the cardiovascular effects of progestins. However, the role of the progesterone receptor (PR) in vascular biology has not been studied in vivo. We studied ovariectomized female PR knockout (PRKO) mice and their wild-type (WT) littermates using the mouse carotid artery injury model. Placebo-treated PRKO mice showed significantly greater vascular medial hypertrophy and vascular smooth muscle cell (VSMC) proliferation in response to vascular injury than did WT mice. Progesterone had no significant effect in the PRKO mice, but worsened the response to injury in WT mice. VSMCs cultured from PRKO mouse aortae were markedly hyperproliferative, and their growth was not affected by progesterone. In contrast to the in vivo findings, progesterone inhibited proliferation of WT-derived VSMCs. Furthermore, reintroduction of PR into PRKO-derived VSMCs using adenoviral methods restored progesterone-mediated inhibition of proliferation to these cells. This effect was reversed by the PR antagonist, RU 486. Thus, the effects of PR and progesterone differ markedly between cultured VSMCs and intact blood vessels. These data demonstrate a direct role for the PR in regulating the response to vascular injury and VSMC proliferation.

Safety and efficacy of a steerable temperature monitoring microwave catheter system for ventricular myocardial ablation.

INTRODUCTION: Radiofrequency current delivered during cardiac ablation is limited by a rise in impedance secondary to coagulum formation on the ablation electrode. Microwave antennas continue to deliver energy despite the presence of coagulum; thus, temperature control of the ablation electrode may be even more important for microwave than for radiofrequency ablations to avoid thromboembolic risks. The purpose of this study was to test the safety and efficacy of an ablation system utilizing a feedback control system to maintain a fixed target temperature for creating lesions with multiple applications of microwave energy. METHODS AND RESULTS: Microwave ablation was assessed using an 8.5-French catheter at 2 to 4 sites in 11 dogs. Microwave energy delivery was performed for 60 seconds three times at the same site. Power was regulated using a feedback control mechanism to maintain a target temperature of 75 degrees C. Ambulatory ECG monitoring was performed before and after ablation to assess arrhythmia occurrence. After follow-up, the dogs were euthanized, and lesion dimensions measured after fixation. The mean power applied to achieve the target temperature of 75 degrees C was 9.3+/-44 W. The mean depth of the lesions was 8.8+/-4.2 mm. The mean volume of the lesions was 304+/-240 mm3. Forty-four percent of the lesions were transmural. No endocardial thrombus was found. Ventricular tachycardia was observed acutely but resolved after 1 week. CONCLUSION: Temperature feedback control systems for microwave ablation using a temperature-controlled system is feasible for myocardial ablation and creates uniform and large lesions; however, such large lesions can be acutely proarrhythmic.

Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice.

The protective effects of estrogen in the cardiovascular system result from both systemic effects and direct actions of the hormone on the vasculature. Two estrogen receptors have been identified, ERalpha and ERbeta. We demonstrated previously that estrogen inhibits the response to vascular injury in both wild-type and ERalpha-deficient mice, and that ERbeta is expressed in the blood vessels of each, suggesting a role for ERbeta in the vascular protective effects of estrogen. In the present study, we examined the effect of estrogen administration on mouse carotid arterial injury in ERbeta-deficient mice. Surprisingly, in ovariectomized female wild-type and ERbeta knockout mice, 17beta-estradiol markedly and equally inhibited the increase in vascular medial area and the proliferation of vascular smooth muscle cells after vascular injury. These data demonstrate that ERbeta is not required for estrogen-mediated inhibition of the response to vascular injury, and suggest that either of the two known estrogen receptors is sufficient to protect against vascular injury, or that another unidentified estrogen receptor mediates the vascular protective effects of estrogen.

Localization of the sites of conduction abnormalities in a mouse model of myotonic dystrophy.

INTRODUCTION: A mouse strain lacking functional myotonic dystrophy protein kinase (DMPK) has recently been developed. DMPK-/- mice exhibit muscular and conduction abnormalities consistent with the disease; however, the site of abnormal cardiac conduction is unknown. METHODS AND RESULTS: Nine homozygous DMPK-/- mice and seven age matched wild-type (WT) controls underwent in vivo electrophysiologic studies using an endocardial 2-French catheter. Baseline intervals as well as Wenckebach and 2:1 cycle lengths were measured to assess AV and ventriculoatrial (VA) conduction. Effective refractory periods (ERP) and functional refractory periods were determined during atrial and ventricular premature stimulation. His-bundle recordings were obtained on all the studied animals (16/16). DMPK-/- mice had significantly prolonged PR (48.1 +/- 5.5 vs 40.9 +/- 3.9 msec, P = 0.010) and AH (36.7 +/- 4.0 vs 31.6 +/- 4.8 msec, P = 0.037) intervals compared to WT controls. HV intervals were very significantly prolonged as well (14.7 +/- 2.0 vs 10.3 +/- 0.8 msec; P < 0.0001). Three of 9 DMPK-/- and 1 of 7 WT mice exhibited VA block. Atrial ERP was reached before AV node ERP in 2 (22%) of 9 of the knockout mice and 5 (71%) of 7 of the controls (P = 0.06). Only one mouse (DMPK-/-) exhibited infra-Hisian block on premature atrial stimulation. CONCLUSION: In this mouse model of myotonic dystrophy, AV conduction abnormalities were localized to the supra-Hisian and infra-Hisian conduction tissues, with a higher predilection to the latter, a finding similar to the human form of the disease.

Assessment of atrioventricular nodal physiology in the mouse.

Transgenic mice are increasingly being utilized for understanding cardiac electrophysiologic abnormalities. However, little is known about the normal atrioventricular nodal and infraHisian physiology in the mouse because of the prior inability to record a His-bundle deflection. We present the first comprehensive examination of the murine atrioventricular nodal and His-Purkinje systems employing His-bundle recordings. Normal, healthy, male C57BL/6J mice (n = 48) underwent an in vivo electrophysiology study using a 2 F octapolar electrode catheter. Effective refractory periods were determined during premature atrial and ventricular stimulation. The PR interval measured 44 +/- 6 ms with a mean sinus cycle length of 185 +/- 42 ms. Baseline AH intervals were 36 +/- 5 ms and HV intervals were 10 +/- 2 ms. At a pacing cycle length of 140 ms the atrioventricular nodal effective refractory period (AVNERP) and atrial effective refractory period (AERP) were 86 +/- 19 ms and 57 +/- 17 ms, respectively. The mean AV Wenckebach and 2:1 paced cycle length were 103 +/- 14 ms and 84 +/- 13 ms, respectively. Premature atrial stimulation curves were asymptotic without discontinuity. A subset of nine mice was studied after administration of isoproterenol. The sinus cycle length, AVNERP and AERP decreased significantly from baseline measurements. This method establishes a practical and feasible technique to record in vivo His-bundle electrograms in the mouse to assess atrioventricular nodal and infraHisian physiology. Use of this model will allow for the examination of abnormalities of atrioventricular nodal and infraHisian conduction in transgenic murine models.

DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model.

Myotonic dystrophy (DM) is the most common form of muscular dystrophy and is caused by expansion of a CTG trinucleotide repeat on human chromosome 19. Patients with DM develop atrioventricular conduction disturbances, the principal cardiac manifestation of this disease. The etiology of the pathophysiological changes observed in DM has yet to be resolved. Haploinsufficiency of myotonic dystrophy protein kinase (DMPK), DM locus-associated homeodomain protein (DMAHP) and/or titration of RNA-binding proteins by expanded CUG sequences have been hypothesized to underlie the multi-system defects observed in DM. Using an in vivo murine electrophysiology study, we show that cardiac conduction is exquisitely sensitive to DMPK gene dosage. DMPK-/- mice develop cardiac conduction defects which include first-, second-, and third-degree atrioventricular (A-V) block. Our results demonstrate that the A-V node and the His-Purkinje regions of the conduction system are specifically compromised by DMPK loss. Importantly, DMPK+/- mice develop first-degree heart block, a conduction defect strikingly similar to that observed in DM patients. These results demonstrate that DMPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsufficiency of DMPK with cardiac disease in myotonic dystrophy.

Familial hypertrophic cardiomyopathy mice display gender differences in electrophysiological abnormalities.

Genetically-manipulated mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+) display a phenotype characteristic of familial hypertrophic cardiomyopathy (FHC). Male and female (30 +/- 8 week old) heterozygous alpha-MHC403/+ mice and litter-mate controls were evaluated using a surface electrocardiogram (ECG) and an in vivo cardiac electrophysiology study (EPS). Wild type animals had normal intracardiac electrophysiology, with no significant differences between male and female control mice during EPS. The female wild-type mice did have slower heart rates and longer ECG intervals than their male wild-type counterparts. The female alpha-MHC403/+ mice had similar ECG's, cardiac conduction times, and refractory periods compared with female wild-type mice. In contrast, male FHC mice had distinctive ECG and electrophysiologic abnormalities including right axis deviation, prolonged ventricular repolarization and prolonged sinus node recovery times. During programmed ventricular stimulation, 62% of male alpha-MHC403/+ mice and 28% of female alpha-MHC403/+ mice had inducible ventricular tachycardia. These studies identify gender-specific electrophysiologic abnormalities in alpha-MHC403/+ FHC mice, concordant with the histological and hemodynamic derangements previously reported.

Ventricular remodeling in a mouse model of myocardial infarction.

We investigated the suitability of studying ventricular remodeling in a mouse model of myocardial infarction (MI). We performed left coronary ligation (n = 22) or a sham procedure (n = 21) on normal C57BL/6J mice. Six weeks later, animals underwent echocardiography and hemodynamic evaluation. Left ventricular (LV) volume at a common distending pressure was calculated from passive pressure-volume curves. The MI group exhibited lower systolic blood pressure (P < 0.05), higher LV end-diastolic pressure (P < 0.05), and lower peak first derivative of LV pressure (dP/dt, P < 0.05) than the sham group. Mice with moderate (< 40%, n = 11) and large (> or = 40%, n = 11) MIs displayed increased LV mass-to-body weight ratio (P < 0.02 and P < 0.01, respectively, vs. sham group), whereas only the large-MI group exhibited increased right ventricular mass-to-body weight ratio (P < 0.01). LV volumes were increased in the moderate-MI group (P = 0.059 vs. sham group) and to a much greater extent in the large-MI group (P < 0.0001 vs. sham group). The moderate- and large-MI groups also exhibited increases in LV end-diastolic diameter (P < 0.03 and P < 0.0001, respectively, vs. sham group) and LV end-systolic diameter (P < 0.01 and P < 0.0001, respectively, vs. sham group) with decreased fractional shortening (P < 0.01 for both). These data demonstrate ventricular remodeling in a mouse model of MI and confirm the feasibility of quantifying indexes of remodeling in vivo and postmortem. This model will be of particular usefulness when applied to transgenic strains.

Divergent effects of angiotensin-converting enzyme inhibition and angiotensin II-receptor antagonism on myocardial cellular proliferation and collagen deposition after myocardial infarction in rats.

There is mechanistic rationale to suggest differential effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 (AT1)-receptor antagonism on ventricular remodeling after myocardial infarction (MI). We compared the effects of ACE inhibition, AT1-receptor antagonism, and their combination on post-MI ventricular remodeling in rats. We induced MI in 62 rats, which then received one of four treatments: (a) placebo; (b) the ACE inhibitor, enalapril; (c) the AT1-receptor antagonist, losartan; and (d) enalapril and losartan in combination. Two weeks after MI, we examined: (a) heart weight (HW)/body weight (BW) ratio; (b) nonmyocyte cellular proliferation in the noninfarct zone by using proliferating cell nuclear antigen staining; and (c) collagen content within the noninfarct zone. Placebo-treated, infarcted rats developed significant increases in HW/BW ratio (p < 0.001), left ventricular (LV) volume (p < 0.01), nonmyocyte cellular proliferation (p < 0.04), and collagen content (p < 0.01) compared with noninfarcted controls. Enalapril, losartan, and combination therapy limited the increase in HW/BW ratio (all p values <0.01 vs. placebo). Enalapril inhibited nonmyocyte proliferation (p < 0.01 vs. placebo), whereas losartan had a smaller effect (p = NS vs. placebo; p < 0.03 vs. enalapril); combined treatment also reduced nonmyocyte cellular proliferation but did not reach statistical significance (p = 0.08 vs. placebo). Enalapril and combination treatment significantly diminished collagen content (both p values <0.01 vs. placebo), whereas losartan did not. Thus, ACE inhibition and AT1-receptor antagonism equally limited myocardial hypertrophy after MI in rats, but ACE inhibition more effectively prevented nonmyocyte cellular proliferation and collagen deposition in the noninfarcted myocardium. Combination therapy was no more effective than was ACE inhibition alone. These data suggest that the myocyte hypertrophic response after MI is strongly influenced by activation of the AT1 receptor, whereas nonmyocyte cellular proliferation and collagen deposition result, in part, from mechanisms separate from AT1-receptor activation.

Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice.

The atheroprotective effects of estrogen in women are well recognized, but the underlying mechanisms responsible are not well understood. Blood vessel cells express the classic estrogen receptor, ER alpha (ref. 2-6), and are directly affected by estrogen, which inhibits the development of atherosclerotic and injury-induced vascular lesions. We have generated mice in which the ER alpha gene is disrupted and have used a mouse model of carotid arterial injury to compare the effects of estrogen on wild-type and estrogen receptor-deficient mice. Increases in vascular medial area and smooth muscle cell proliferation were quantified following vascular injury in ovariectomized mice treated with vehicle or with physiologic levels of 17 beta-estradiol. Surprisingly, in both wild-type and estrogen receptor-deficient mice, 17 beta-estradiol markedly inhibited to the same degree all measures of vascular injury. These data demonstrate that estrogen inhibits vascular by a novel mechanism that is independent of the classic estrogen receptor, ER alpha.

Electrophysiological abnormalities and arrhythmias in alpha MHC mutant familial hypertrophic cardiomyopathy mice.

A new mouse cardiac electrophysiology method was used to study mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+), which results in histological and hemodynamic abnormalities characteristic of familial hypertrophic cardiomyopathy (FHC) and sudden death of uncertain etiology during exercise. Wild-type animals had completely normal cardiac electrophysiology. In contrast, FHC mice demonstrated (a) electrocardiographic abnormalities including prolonged repolarization intervals and rightward axis; (b) electrophysiological abnormalities including heterogeneous ventricular conduction properties and prolonged sinus node recovery time; and (c) inducible ventricular ectopy. These data identify distinct electrophysiologic abnormalities in FHC mice with a specific alpha-myosin mutation, and also validate a novel method to explore in vivo the relationship between specific genotypes and their electrophysiologic phenotypes.

In vivo cardiac electrophysiology studies in the mouse.

BACKGROUND: This report describes a novel in vivo mouse epicardial cardiac electrophysiology study based on clinical protocols used to evaluate cardiac conduction in human patients. The technique allows extensive electrophysiological evaluation, including the response to pacing, programmed stimulation, and pharmacological agents. METHODS AND RESULTS: Surface six-lead ECG data from 18 C57BL/6J mice are presented. Normal cardiac conduction properties for 14 of 18 mice that underwent the procedure are summarized, including determination of sinus node recovery times, AV conduction properties, and atrial, AV, and ventricular effective refractory periods. A subset of six mice was studied after the administration of either procainamide (n = 3) or quinidine (n = 3). All animals in the procainamide group developed either second-degree or complete AV block spontaneously. The sinus cycle length and refractory periods prolonged on procainamide or quinidine, but no tachyarrhythmias could be induced with atrial or ventricular programmed stimulation. CONCLUSIONS: This mouse electrophysiology method allows rapid assessment of the conduction properties of the murine heart. The ability to analyze cardiac conduction in normal and transgenic mice provides a powerful tool for examining molecular electrophysiological mechanisms in normal physiology and disease states.

Estrogen inhibits the response-to-injury in a mouse carotid artery model.

The atheroprotective effects of estrogen are well documented, but the mechanisms responsible for these effects are not well understood. To study the role of physiologic (nanomolar) estrogen levels on the arterial response-to-injury, we applied a mouse carotid artery injury model to ovariectomized C57BL/6J mice. Mice were treated with vehicle (-E2, n = 10) or 17 beta-estradiol (+E2, n = 10) for 7 d, subjected to unilateral carotid injury, and 14 d later contralateral (normal = NL) and injured carotids from -E2 and +E2 animals were pressure fixed, harvested, and analyzed by quantitative morphometry. E2 levels in +E2 mice were consistently in the nanomolar range (2.1-2.5 nM) at days 0, 7, and 14. At 14 d, measures of both intimal and medial area were markedly increased in the -E2 group: (-E2 vs NL, P < 0.05 for both), but were unchanged from normal levels in the +E2 group (+E2 vs NL, P = NS and +E2 vs -E2, P < 0.05 for both). Cellular proliferation, as assessed by bromodeoxyuridine (BrdU) labeling, was significantly increased over NL in the -E2 mice, but this increase was markedly attenuated in the estrogen replacement group (total BrdU positive cells/section: NL = 6.4 +/- 4.5; -E2 = 113 +/- 26, +E2 = 40 +/- 3.7; -E2 vs NL, P < 0.05; +E2 vs NL, P = NS; -E2 vs +E2, P < 0.05). These data (a) demonstrate significant suppression of the mouse carotid response-to-injury by physiologic levels of estrogen replacement; (b) support the utility of this model in the study of the biologic effects of estrogen on the vascular-injury response; and (c) suggest a direct effect of estrogen on vascular smooth muscle cell proliferation in injured vessels.

A new platinum balloon-expandable stent (Angiostent) mounted on a high pressure balloon: acute and late results in an atherogenic swine model.

BACKGROUND: Randomized studies have proven the efficacy and safety of stent placement to treat de novo coronary stenosis. However, the poor radio-opacity and the use of an additional high-pressure balloon to fully expand the stent are the major limitations of the currently clinically-approved stents. OBJECTIVE: We evaluated the safety, efficacy, angiographic and histologic effect of a new platinum balloon expandable stent mounted on a high-pressure balloon in Yucatan miniature swine fed high cholesterol diet. METHODS: Fifteen Angiostents (NuMED, Inc., Hopkinton, NY and Angiodynamics, Glens Falls, NY) (coronary stent was 3, 3.5, or 4 mm in diameter and 12 mm long; renal and carotid stents were 5 mm in diameter and 13 mm long) mounted on a high-pressure balloon were placed percutaneously in blood vessels of 10 pigs [5 in circumflex (CX), 2 in left anterior descending (LAD), 5 in renal and 3 in carotid arteries]. The stent was 10-20% larger than the native vessel diameter. All animals received 5000 I.U. of heparin during the procedure and were maintained on 325 mg aspirin daily. Follow-up angiography and histology in the animals was performed at 2, 4, 12, 20, 26 and 52 weeks. RESULTS: The stents were easily visualized with fluoroscopy and placed in all animals without episodes of balloon rupture or embolization. There was no episode of acute thrombosis. Follow-up angiography in the animals revealed patency of all renal and carotid stents, however, 2/7 coronary stents in the animals revealed angiographic lumen narrowing (> 20%) at 20 and 52 weeks. Histologic examination revealed neointimal formation at the stent site with an average neointimal thickness ranging from 325-650 microns. CONCLUSION: This stent was safe in this animal model, easily deployed, had excellent radio-opacity and with good short-term patency without anticoagulation. Clinical trials and experience is underway.

Antifibrinolytic activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis.

The extensive homology between apolipoprotein(a) and plasminogen has led to the hypothesis that the increased risk for atherosclerosis, cardiac disease and stroke associated with elevated levels of apolipoprotein(a) may reflect modulation of fibrinolysis. We have investigated the role of apolipoprotein(a) on clot lysis in transgenic mice expressing the human apolipoprotein(a) gene. These mice develop fatty streak lesions resembling early lesions of human atherosclerosis. Pulmonary emboli were generated in mice by injection, through the right jugular vein, of a human platelet-rich plasma clot radiolabelled with technetium-99m-labelled antifibrin antibodies. Tissue plasminogen activator was introduced continuously via the right jugular vein. Clot lysis, determined by ex vivo imaging, was depressed in mice carrying the apolipoprotein(a) transgene relative to their sex-matched normal littermates. These results directly demonstrate an in vivo effect of apolipoprotein(a) on fibrinolysis, an effect that may contribute to the pathology associated with elevated levels of this protein.

A new low profile balloon atrial septostomy catheter: initial animal and clinical experience.

OBJECTIVE: To evaluate the safety and efficacy of a new low profile balloon septostomy catheter in neonatal animals as well as in one newborn infant. BACKGROUND: Balloon atrial septostomy remains one of the most commonly performed palliative procedures in pediatric cardiology. The currently available septostomy catheter requires a large introducer sheath (6 or 7F), does not have an end hole for confirmation of position or pressure measurement and is limited in patients with a small left atrium due to its large balloon inflated diameter. METHODS: Four neonatal piglets (average weight 3.9 kg) underwent percutaneous balloon atrial septostomy using the new balloon catheter inflated to 1 cc via a 5F sheath in the femoral vein. Two other piglets (average weight 4.9 kg) underwent septostomy with the conventional catheter inflated to 3.5 cc via a 6 or 7F sheath in the femoral vein. All animals underwent transthoracic echocardiography pre and post septostomy. All animals were sacrificed after the procedure and the size of the atrial defect created was measured. One neonate with Taussig-Bing anomaly underwent septostomy with the new balloon catheter. RESULTS: The left atrium was entered in all piglets. It was easier to enter the left atrium with an end hole catheter which was exchanged over a wire with the septostomy catheter. Septostomy was performed with the new or conventional catheters without complications. Echocardiography demonstrated a very small patent foramen ovale prior to the procedure and a large atrial defect after septostomy. The average size of the defect created by the new catheter was 11.3 x 10 mm in diameter and 11 x 10 mm using the conventional catheter. A 10 x 10 mm atrial communication was created in the neonate. CONCLUSIONS: This study demonstrates the safety and efficacy of this new catheter. This catheter will be of potential importance in patients with a small left atrium and in small neonates with congenital heart disease requiring septostomy.

Utility of in vivo, intracardiac two-dimensional echocardiography in the assessment of myocardial risk area and myocardial dyssynergy during coronary occlusion and reperfusion.

We have previously reported the potential use of intracardiac echocardiography (ICE) in a variety of clinical settings, including detection of pericardial effusion, intracardiac masses, congenital cardiac defects, and during simulated balloon valvuloplasty. The utility of intracardiac ultrasound imaging of the left ventricle (LV) in patients with coronary disease needs to be further explored. We performed this study with the purpose of evaluating risk area and regional wall-motion abnormalities produced by ischemia using ICE. Ten episodes of ischemia were produced by transiently occluding the left anterior descending coronary artery in five dogs. ICE was performed with a modified 5-MHz transesophageal echocardiographic probe placed in the right atrium. Continuous short-axis images of the LV were obtained before, during, and after coronary occlusion. Risk area was defined using myocardial contrast echocardiography. In all cases, ICE provided high resolution images of the LV. Risk area and regional wall-motion abnormalities were readily detected. There was good correlation between the risk area (x) and extent of dyssynergy (y), defined by the equation y = 0.76x + 6.38 (r = 0.80, P less than 0.01). We conclude that ICE provides potentially useful information concerning regional LV dysfunction, and, when combined with myocardial contrast echocardiography, area at risk. This technique may be useful during interventional procedures once a catheter-based ultrasound transducer with adequate depth of field to provide images of the entire LV can be developed.

Experimental volume replacement through lower extremity veins.

Hypovolemic shock was produced in anesthetized pigs by removal of 40% of blood volume over 10 minutes. Following blood loss, the inferior vena cava (IVC) was occluded below the renal veins to simulate the hemodynamics of emergency surgical treatment. Control animals were not treated. Experimental animals received intravenous lactated Ringer's solution equal to three times the blood loss given through catheters either in the IVC or the superior vena cava (SVC) to determine if lower extremity access would be efficacious in this model. To define the path taken by the resuscitation fluids, an additional group of animals received technetium-99m-labelled crystalloid through lower extremity catheters with continuous recording of isotope counts in the IVC and right atrium. The treated animals in all experimental groups had significant improvements in mean arterial pressure, cardiac output, and pH compared with controls. There was no significant difference in hemodynamic response in animals receiving volume replacement through the IVC compared with the SVC. When fluid was infused below a clamped IVC, the arrival of isotope in the right atrium was delayed only 1.5 seconds. We conclude that in a model simulating emergency control of potentially lethal hemorrhage, the beneficial effects of fluid resuscitation are unrelated to the site of venous access. Lower extremity veins provide a valuable site for volume replacement even with IVC occlusion. These findings should have direct application to resuscitation and surgical care of seriously injured patients.

Successful placement and re-expansion of a new balloon expandable stent to maintain patency of the ductus arteriosus in a newborn animal model.

OBJECTIVE: We performed this study in order to evaluate the usefulness of a new balloon expandable stent for maintaining ductal patency in a neonatal piglet model and to evaluate the ability to re-expand the stent weeks following initial implantation. BACKGROUND: Maintaining patency of the ductus arteriosus without administration of Prostaglandin E has been reported previously using balloon dilation and stent implantation techniques. However, the experience is limited and the currently available stents are not modified for neonates. METHODS: 14 newborn piglets all at age 12 days and median weight 3.6 Kg (range 2.7-4.3 Kg), underwent initial balloon dilation of the ductus arteriosus. Angiography after dilation demonstrated no significant left to right shunt. All piglets underwent successful stent (3.5 mm x 17 mm) placement in the ductus arteriosus. RESULTS: Percutaneous ductal stent implantation via the arterial route was successful in all piglets with angiographic demonstration of a significant left to right shunt. Follow-up studies at weekly intervals with color flow Doppler were used to confirm patency of the stents. In 3 piglets the stent was not patent at initial follow-up and autopsy revealed sub-optimal stent placement. In two animals the stent was later re-expanded to 4 mm at 22 days, in one to 4 mm at 30 days and in one to 6 mm at 15 days, maintaining flow for an additional period of 15 to 34 days.(ABSTRACT TRUNCATED AT 250 WORDS)