Chronic myocardial and coronary arterial effects of intracoronary supersaturated oxygen therapy in swine with normal and ischemic-reperfused myocardium.

The study assessed chronic myocardial, coronary and systemic effects of intracoronary supersaturated oxygen (SSO2) therapy. Left anterior descending coronary arteries of 40 swine were stented and randomized to 90-min selective intracoronary infusion of SSO2 (pO2 760-1000 mmHg) or normoxemic saline. In 20 out of 40 animals, SSO2 delivery followed a 60-min balloon occlusion to induce myocardial infarction (MI). In both normal and MI models, intracoronary treatment with hyperoxemic SSO2 therapy showed no evidence of coronary thrombosis. There were no biologically relevant differences between treatments at either time point in regard to coronary intervention site healing and neointimal growth. No signs of any myocardial or systemic toxicity were observed after 7 or 30 days. A trend was observed toward reduced incidence of microscopic MI scars and reduced infarct size in histopathology, as well as toward better recovery of echocardiographically evaluated global and regional contractility at 30 days. No treatment related infarcts or thromboemboli were observed in the downstream organs.

Experimental Evaluation of a Novel Percutaneous Transseptal Catheter-Based Mitral Valve Replacement Technology.

BACKGROUND: Transcatheter mitral valve replacement is a novel therapeutic approach aiming to treat patients with severe mitral regurgitation. This study aimed to evaluate the biological and technical performance of a novel transseptal transcatheter mitral valve replacement system (Cephea Valve Technologies, Santa Cruz, CA) in a preclinical model. METHODS: Biological performance and healing response were evaluated following open-heart surgical implantation procedures in 10 sheep utilizing an antegrade transatrial access. Valve performance was assessed with fluoroscopy, echocardiography, and histology at 30 (n=2), 60 (n=3), and 90 days (n=5). Feasibility of transseptal valve delivery and performance was tested acutely in 10 pigs. RESULTS: In the chronic studies, all animals survived without problems until completion of the study. The hemodynamics of the study valves were excellent with low rates of paravalvular leak. There was no left ventricular outflow tract obstruction. Pathological evaluation showed excellent position and condition of the mitral implants without evidence for thrombosis, endocarditis, or excessive calcification. Subsequently, mitral valves were implanted in 10 pigs using a dedicated transseptal delivery system. The implants remained in stable position with excellent hemodynamic profile. Correct valve position and function was confirmed by echocardiography and autopsy. CONCLUSIONS: The transseptal delivery of the Cephea transcatheter mitral valve replacement system in an experimental model was feasible and safe. The chronic studies demonstrated a favorable healing response. Further human studies are needed to evaluate the performance of this novel valve system in patients with severe mitral regurgitation.

Preclinical in vivo long-term evaluation of the novel Mitra-Spacer technology: experimental validation in the ovine model.

AIMS: The Mitra-Spacer (Cardiosolutions, Bridgewater, MA, USA) is designed to treat mitral regurgitation by introducing a dynamic spacer that constantly adapts to the changing haemodynamic conditions during the cardiac cycle. We aimed to evaluate the performance and safety of this device in the chronic ovine model. METHODS AND RESULTS: Eight sheep were enrolled in this study. Through a left thoracotomy, the Mitra-Spacer was inserted via the transapical approach and advanced into the left atrium (LA) under imaging guidance. Device performance and safety were evaluated up to 90 days using fluoroscopy, echocardiography and histopathology. The volume within the balloon spacer shifted during the cardiac cycle in all cases. Seven animals survived up to 90 days for terminal imaging and tissue harvest. Echocardiography showed no change in left ventricle (LV) ejection fraction from baseline to 90 days. There were no observations of changes in LV diastolic function, pulmonary vein inflow, or tricuspid valve function. Histological analysis demonstrated no significant injury to the mitral apparatus. CONCLUSIONS: In the healthy ovine model, Mitra-Spacer implantation was feasible and safe. At 90 days, no evidence of structural damage to the mitral apparatus or deterioration of cardiac performance was demonstrated.

Biological effect on restenosis and vascular healing of encapsulated paclitaxel nanocrystals delivered via coated balloon technology in the familial hypercholesterolaemic swine model of in-stent restenosis.

AIMS: The aim of this study was to evaluate the biological efficacy of a novel lower-dose (2.5 µg/mm2) encapsulated paclitaxel nanocrystal-coated balloon (Nano-PCB) in the familial hypercholesterolaemic swine (FHS) model of iliofemoral in-stent restenosis. METHODS AND RESULTS: Nano-PCB pharmacokinetics were assessed in 20 femoral arteries (domestic swine). Biological efficacy was evaluated in ten FHS: 14 days following bare metal stent implantation each stent segment was randomised to a clinically available PCB (IN.PACT, n=14), the Nano-PCB (n=14) or an uncoated balloon (n=12). Angiographic, optical coherence tomography and histological evaluation was performed at 28 days after treatment. Arterial paclitaxel concentration was 120.7 ng/mg at one hour and 7.65 ng/mg of tissue at 28 days with the Nano-PCB. Compared to the control uncoated group, both PCBs significantly reduced percent area stenosis (Nano-PCB: 36.0±14.2%, IN.PACT: 29.3±9.2% vs control: 67.9±15.1%, p<0.001). Neointimal distribution in the entire stent length was more homogenous in the Nano-PCB. Histological evaluation showed comparable degrees of neointimal proliferation in both PCBs; however, the Nano-PCB showed slightly higher levels of neointimal maturity and endothelialisation. CONCLUSIONS: Lower-dose encapsulated paclitaxel nanocrystals delivered via a coated balloon displayed comparable biological efficacy with superior healing features compared to a clinically validated PCB technology.

Early feasibility evaluation of thoracoscopically assisted transcatheter ventricular reconstruction in an experimental model of ischaemic heart failure with left anteroapical aneurysm.

AIMS: To test the feasibility of a thoracoscopically assisted, off-pump, transcatheter ventricular reconstruction (TCVR) approach in an ovine model of left ventricular (LV) anteroapical aneurysm. METHODS AND RESULTS: Myocardial infarction (MI) was induced by coil occlusion of the middle left anterior descending artery and diagonals. Two months after MI creation, TCVR was performed via a minimal thoracotomy in eight sheep. Under endoscopic and fluoroscopic guidance, trans-interventricular septal puncture was performed from the LV epicardial scar. A guidewire was externalised via a snare placed in the right ventricle from the external jugular vein. An internal anchor was inserted over the wire and positioned on the right ventricular septum and an external anchor was deployed on the LV anterior epicardium. Serial pairs of anchors were placed and plicated together to exclude the scar completely. Immediately after TCVR, echocardiography showed LV end-systolic volume decreased from pre-procedure 58.8±16.6 ml to 25.1±7.6 ml (p<0.01) and the ejection fraction increased from 32.0±7.3% to 52.0±7.5% (p<0.01). LV twist significantly improved (3.83±2.21 vs. pre-procedure -0.41±0.94, p=0.01) and the global peak-systolic longitudinal strain increased from -5.64% to -10.77% (p<0.05). CONCLUSIONS: TCVR using minimally invasive access techniques on the off-pump beating heart is feasible and resulted in significant improvement in LV performance.

First in vivo evaluation of a flexible self-apposing left atrial appendage closure device in the canine model.

OBJECTIVES: Aimed to evaluate the feasibility of deployment and healing response of a novel transcatheter left atrial appendage (LAA) occlusion device in the canine model BACKGROUND: LAA occlusion is proposed to reduce the risk of stroke in atrial fibrillation patients METHODS: Transseptal puncture and device deployment was guided under fluoroscopy and transesophageal echocardiography (TEE) in five dogs. First, a distal cylindrical bulb occluder was released and secured to the appendage wall with hooks. Subsequently, a proximal sail was unfolded, covering the LAA ostium. Rotational angiography, TEE, and histology outcomes were assessed 30 days following implantation RESULTS: Pre-operative TEE revealed the mean diameter of the LAA ostium to be 17.2 ± 1.6 mm with a depth of 18.5 ± 1.7 mm. The landing zone for the distal bulb was measured to be 12.8 ± 1.3 mm. The mean bulb diameter at implant was 16.8 ± 1.8 mm. Post-operative TEE showed adequate positioning and successful LAA occlusion with all implanted devices. Pericardial effusion requiring pericardiocentesis was seen in one animal following device implantation. At 30 days, TEE revealed full occlusion of all LAA ostia with the exception of a minimal peri-device leak (<3 mm) observed in one animal. No pericardial effusion or device-related thrombus formation was found at termination. Histological analysis confirmed circumferential occlusion of all appendages and complete neointimal coverage on the luminal aspect of the occluder CONCLUSION: The percutaneous delivery of a novel self-positioning LAA occlusion device is feasible and safe in a canine model. At 30 days, all devices displayed complete healing and occlusion of the LAA without any device related adverse events.

Long term impact of balloon post-dilatation on neointimal formation: an experimental comparative study between second-generation self-expanding versus balloon-expandable stent technologies.

Background: Self-expanding stents (SES) are reemerging as therapeutic alternatives to treat coronary artery disease. It has been proposed that SES can improve clinical outcomes by inducing less injury at implantation and achieving better vessel wall apposition.To date, little data exists comparing the vascular response to both methods of deployment in a controlled experimental setting. Objective: To quantify differences in vascular injury and healing between second-generation SES and balloon-expandable stents (BES) and the effects of balloon post-dilatation in a porcine coronary model. Methods: Seventy-five bare SES (AXXESS or vProtect) and 42 BES (Vision) were implanted in porcine coronaries. A subset of these received balloon post-dilatation(SES 1 D 5 22, BES 1 D 5 20). Follow-up was scheduled at 30 (BES 5 10, BES 1 D 56, SES 5 19, SES 1 D 5 8), 90 (BES 5 6, BES 1 D 5 8, SES 5 19, SES 1 D 5 8), and 180 days (BES 5 6, BES 1 D 5 6, SES 5 15, SES 1 D 5 6). Results: In vivo imaging and histological analysis showed that neointimal formation peaks early (30 days) in BES. Conversely, for SES, the peak occurred later (90 days). However, the neointimal formation achieved in either group equalized at 180 days. For SES, post-dilatation shortened the peak of neointimal formation to 30 days. Conversely, for BES, post-dilatation delayed the peak of neointimal formation to 90 days. At 30 days, histology showed that SES had significantly less injury. However, at 90 days, injury scores tended to be higher for SES. By 180 days, injury scores were comparable between both groups. Conclusions: The mechanism of stent expansion influences the degree of vascular injury and healing. The synergistic use of balloon post dilatation changes the dynamics of healing and may impact the potential beneficial effects inherent to SES technologies.

Off-pump epicardial ventricular reconstruction restores left ventricular twist and reverses remodeling in an ovine anteroapical aneurysm model.

OBJECTIVE: The loss of normal apical rotation is associated with left ventricular (LV) remodeling and systolic dysfunction in patients with congestive heart failure after myocardial infarction. The objective of the present study was to evaluate the effect of epicardial ventricular reconstruction, an off-pump, less-invasive surgical reshaping technique, on myocardial strain, LV twist, and the potential alteration of myocardial fiber orientation in an ovine model of LV anteroapical aneurysm. METHODS: LV anteroapical myocardial infarction was induced by coil embolization of the left anterior descending artery. Eight weeks after occlusion, epicardial ventricular reconstruction was performed using left thoracotomy under fluoroscopic guidance in 8 sheep to completely exclude the scar. The peak systolic longitudinal/circumferential strains and LV twist were evaluated using speckle tracking echocardiography before (baseline), after device implantation, and at 6 weeks of follow-up. RESULTS: Epicardial ventricular reconstruction was completed in all sheep without any complications. Immediately after device implantation, LV twist significantly increased (4.18 ± 1.40 vs baseline 1.97 ± 1.92; P = .02). The ejection fraction had increased 17% and LV end-systolic volume had decreased 40%. The global longitudinal strain increased from -5.3% to -9.1% (P < .05). Circumferential strain increased in both middle and apical LV segments, with the greatest improvement in the inferior lateral wall (from -11.4% to -20.6%, P < .001). These effects were maintained ≥6 weeks after device implantation without redilation. CONCLUSIONS: Less invasive than alternative therapies, epicardial ventricular reconstruction on the off-pump beating heart can restore LV twist and systolic strain and reverse LV remodeling in an ovine anteroapical aneurysm model.

Epicardial catheter-based ventricular reconstruction: a novel therapy for ischaemic heart failure with anteroapical aneurysm.

OBJECTIVES: Surgical ventricular reconstruction has been used to treat ischaemic cardiomyopathy with large akinetic or dyskinetic areas. However, application of this approach requires a sternotomy, cardiopulmonary bypass and a left ventriculotomy. This study assessed the feasibility and efficacy of minimally invasive, off-pump, epicardial catheter-based ventricular reconstruction (ECVR) in an anteroapical aneurysm ovine model. METHODS: Left ventricular (LV) anteroapical myocardial infarction was induced percutaneously by coil embolization of the left anterior descending coronary artery. Eight weeks after infarction, via mini left thoracotomy and without cardiopulmonary bypass, ECVR was performed in six sheep. The scar was excluded by placing anchor pairs on the LV epicardial anterior wall and the right ventricular side of the interventricular septum under fluoroscopic guidance. LV performance was evaluated before, immediately after device implantation and after 6 weeks by echocardiography. Terminal histopathology was performed. RESULTS: ECVR was completed expeditiously in all animals without complications. Parameters obtained 6 weeks after device implantation were compared with baseline (pre-device). End-systolic volume was decreased by 38% (25.6 ± 6.1 ml vs baseline 41.2 ± 7.2 ml, P = 0.02) with preservation of stroke volume. Ejection fraction was significantly increased by 13% (48.5 ± 7% vs baseline 35.8 ± 7%, P = 0.02). The circumferential strain in the anterior septum (-7.67 ± 5.12% vs baseline -0.96 ± 2.22%, P = 0.03) and anterior wall (-9.01 ± 3.51% vs baseline -4.15 ± 1.36%, P = 0.01) were significantly improved. The longitudinal strain in apex was reversed (-3.08 ± 1.53% vs baseline 3.09 ± 3.39%, P = 0.01). Histopathology showed full endocardial healing over the anchors with appreciable reduction of the chronic infarct in the LV. CONCLUSIONS: ECVR without cardiopulmonary bypass is a less invasive alternative to current standard therapies, reverses LV remodelling and improves cardiac performance in an ovine model of anteroapical aneurysm.

Benefits of standardizing the treatment of arrhythmias in the sheep (Ovis aries) model of chronic heart failure after myocardial infarction.

Large animal models of heart failure are essential in preclinical device testing. In sheep, catheter-based coil embolization of the left anterior descending and diagonal artery provides a minimally invasive and reproducible model of myocardial infarction (MI). Although widely used, this model has historically been plagued with a 30% mortality rate, both in the literature and in our own experience. Our study endeavored to decrease the mortality rate by targeting the most common cause of death, intractable arrhythmias, during creation of the ovine MI model. To this end, we evaluated 2 methods of managing perioperative antiarrhythmic therapy and cardiopulmonary resuscitation during model creation. The first group of sheep was managed at the discretion of the individual operator, whereas the second group was treated according to a standardized protocol that included mandatory pretreatment with amiodarone. Sheep experiencing life-threatening arrhythmias, most commonly ventricular fibrillation, were either resuscitated according to operator-driven instructions or the standardized protocol. By comparing these 2 treatment groups, we have shown that using a standardized protocol is advantageous in reducing mortality associated with the ovine MI model. Since implementing the standardized protocol, our laboratory has lowered the expected mortality rate to 10% during catheter-based induction of ovine MI and has greatly reduced the number of animals required for study needs. In addition, the standardized protocol has proven beneficial in training new staff members. By implementing this standardized method of model management, the outcomes of model creation have been optimized.

Safety and feasibility of percutaneous delivery of a novel circulatory assist device (CircuLite® SYNERGY®) in the swine model.

AIMS: To demonstrate the feasibility and safety of percutaneous delivery of the novel inflow cannula of the CircuLite® SYNERGY® pocket Micro-pump via transseptal access in the swine model. METHODS AND RESULTS: After transseptal puncture, the inflow cannula system was advanced into the left atrium (LA) via the right external jugular vein and anchored onto the atrial septum under fluoroscopic and intracardiac echo guidance in 14 acute animals. Subsequently, chronic studies were performed to examine the long-term healing response to the cannula implantation with an artery-LA shunt (n=10) and overall safety of the Micro-pump components (n=6). Acute studies proved the concept of transcatheter delivery of the inflow cannula via superior venous access. The cannula tips were securely anchored in all chronic animals and appropriately endothelialised as early as two weeks. No thrombi or septal damage was observed. For the chronic pump group, device speed of 22,000 rpm (~2.0 L/min) was maintained without any adverse cardiac events. Plasma free haemoglobin assays confirmed the absence of clinically significant haemolysis. CONCLUSIONS: The transcatheter delivery of the inflow cannula via superior venous access to the LA is feasible and safe. This percutaneous delivery presents a significantly less invasive alternative to deliver partial circulatory support devices.

Catheter-based endomyocardial delivery of mesenchymal precursor cells using 3D echo guidance improves cardiac function in a chronic myocardial injury ovine model.

The administration of bone marrow-derived stem cells may provide a new treatment option for patients with heart failure. Transcatheter cell injection may require multi-imaging modalities to optimize delivery. This study sought to evaluate whether endomyocardial injection of mesenchymal precursor cells (MPCs) could be guided by real-time 3D echocardiography (RT3DE) in treating chronic, postinfarction (MI) left ventricular (LV) dysfunction in sheep. Four weeks after induction of an anterior wall myocardial infarction in 39 sheep, allogeneic MPCs in doses of either 25 × 10(6) (n = 10), 75 × 10(6) (n = 9), or 225 × 10(6) (n = 10) cells or nonconditioned control media (n = 10) were administered intramyocardially into infarct and border zone areas using a catheter designed for combined fluoroscopic and RT3DE-guided injections. LV function was assessed before and after injection. Infarct dimension and vascular density were evaluated histologically. RT3DE-guided injection procedures were safe. Compared to controls, the highest dose MPC treatment led to increments in ejection fraction (3 ventricula 3% in 225M MPCs vs. -5 ± 4% in the control group, p < 0.01) and wall thickening in both infarct (4 ± 4% in 225M MPCs vs. -3 ± 6% in the control group, p = 0.02) and border zones (4 ± 6% in 225M MPCs vs. -8 ± 9% in the control group, p = 0.01). Histology analysis demonstrated significantly higher arteriole density in the infarct and border zones in the highest dose MPC-treated animals compared to the lower dose or control groups. Endomyocardial implantation of MPCs under RT3DE guidance was safe and without observed logistical obstacles. Significant increases in LV performance (ejection fraction and wall thickening) and neovascularization resulted from this technique, and so this technique has important implications for treating patients with postischemic LV dysfunction.

Concomitant intravenous nitroglycerin with intracoronary delivery of AAV1.SERCA2a enhances gene transfer in porcine hearts.

SERCA2a gene therapy improves contractile and energetic function of failing hearts and has been shown to be associated with benefits in clinical outcomes, symptoms, functional status, biomarkers, and cardiac structure in a phase 2 clinical trial. In an effort to enhance the efficiency and homogeneity of gene uptake in cardiac tissue, we examined the effects of nitroglycerin (NTG) in a porcine model following AAV1.SERCA2a gene delivery. Three groups of Göttingen minipigs were assessed: (i) group A: control intracoronary (IC) AAV1.SERCA2a (n = 6); (ii) group B: a single bolus IC injection of NTG (50 µg) immediately before administration of intravenous (IV) AAV1.SERCA2a (n = 6); and (iii) group C: continuous IV NTG (1 µg/kg/minute) during the 10 minutes of AAV1.SERCA2a infusion (n = 6). We found that simultaneous IV infusion of NTG and AAV1.SERCA2a resulted in increased viral transduction efficiency, both in terms of messenger RNA (mRNA) as well as SERCA2a protein levels in the whole left ventricle (LV) compared to control animals. On the other hand, IC NTG pretreatment did not result in enhanced gene transfer efficiency, mRNA or protein levels when compared to control animals. Importantly, the transgene expression was restricted to the heart tissue. In conclusion, we have demonstrated that IV infusion of NTG significantly improves cardiac gene transfer efficiency in porcine hearts.

Coronary bare metal stent implantation in homozygous LDL receptor deficient swine induces a neointimal formation pattern similar to humans.

INTRODUCTION: To date, most of all new developments in stent technologies are tested in normal animals. Although invaluable in the evaluation of device safety, the juvenile domestic swine (DS) do not follow the biological healing response occurring in humans following coronary stent implantation. By using a novel swine breed afflicted with familial hypercholesterolemia (FHS), we aimed to analyse the vascular response occurring following bare metal stent (BMS) implantation by comparing in vivo endovascular imaging and histological data. METHODS: A total of 26 swine were included in this study (12 FHS and 14 DS). Sixty eight BMS (FHS=28 versus DS=40) were implanted using a 10% overstretch ratio. Imaging evaluation (IVUS and OCT) was conducted in all animals at 30 (n=14) or 90 (n=12) days following stent implantation. After imaging, the stented coronary segments were harvested for histological evaluation. RESULTS: At 30 days, the degree of neointimal formation analysed by OCT (%AS=DS 21.9 ± 10% versus FHS 25.4 ± 12%; p=0.18) and histology (DS 24.6 ± 10% versus FHS 23.58 ± 10%; p=0.8) was similar between both animal groups. At 90 days, the degree of neointimal formation in the DS group decreased in all analysed variables (-40% in IVUS neointimal volume, -57% in OCT %AS, and -30% in %AS by histology) compared to the progression of neointimal formation observed in the FHS group (+29% in IVUS neointimal volume, +27% in OCT %AS and +43% in %AS by histology). CONCLUSION: The pattern of neointimal formation following BMS implantation in the FHS follows a progressive course that does not occur in the DS. Therefore, by providing a progressive neointimal biological response to BMS implantation, the FHS could serve as an ideal efficacy model for the validation of drug eluting stent technologies.

In vivo intravascular ultrasound analysis of the absorption rate of the Angio-Seal vascular closure device in the porcine femoral artery.

AIMS: Device-based arterial closure is currently used to achieve haemostasis following percutaneous intervention. Little is known about the in vivo patterns of device absorption. We aimed to characterise the absorption dynamics following implantation of the Angio-Seal VIP closure device (AVCD) (St. Jude Medical, St. Paul, MN, USA) by using serial intravascular ultrasound (IVUS) and histology. METHODS AND RESULTS: Eleven AVCD were implanted following 6 Fr femoral arterial sheath in six pigs. Using carotid access, angiograms and IVUS were performed at baseline, 3, 5, 7, 14, 30 and 42 days following deployment. At termination, arteries were processed for histology at 14 (n=3), 30(n=4) and 42 days (n=4). By IVUS, following implantation the intravascular component (IC) area remained unchanged up to 14 days and decreased by 50% at 30 days and 95% by 42 days. By histology, there was a progressive decline in the IC area at 14 days and decrease by 30% at 30 days and 77% by 42 days. Histology demonstrated almost complete absorption of the IC and no signs of severe chronic granulomatous inflammation. CONCLUSIONS: IVUS serial imaging demonstrated almost complete absorption of the IC by 42 days in normal porcine femoral arteries. There was no evidence of severe chronic granulomatous vascular inflammation demonstrated by histology.

Myoblast transfer in ischemic heart failure: effects on rhythm stability.

Skeletal myoblast (SM) implantation promotes recovery of myocardial function after ischemic injury. Clinical observations suggest an association of SM implantation and ventricular arrhythmias. Support for this link has been sought in animal studies, but none employing models of congestive heart failure. In a canine model of postinfarction congestive heart failure (CHF) we compared the frequency of rhythm disturbances using ambulatory electrocardiography monitoring following skeletal myoblast or saline (SAL) implantation. In 19 mongrel dogs ischemic injury and CHF were induced by intracoronary microsphere infusions. Direct intramyocardial injection of autologous skeletal myoblasts (ASM) (2.7-8.3 x 10(8) cells) or SAL controls was administered to 11 and 8 dogs, respectively. Serial echocardiography and 24-h ambulatory electrocardiography were recorded at baseline (after CHF induction) and at 4 weeks and at 8-10 weeks after injection. Comparisons between groups of left ventricular ejection fraction (LVEF) and the frequency of ventricular arrhythmias, supraventricular arrhythmias, and measures of heart rate variability (HRV) were made at each of the three time points. LVEF increased from 41 +/- 6% to 47 +/- 2% (p < 0.03) in the ASM group, and did not change (42 +/- 6% to 40 +/- 2%, p = ns) in SAL. After injection, no differences were seen in the number of dogs demonstrating ventricular tachycardia (n = 3 vs. n = 2, p = ns) or frequent PVCs (n = 3 vs. n = 3, p = ns) in the ASM versus SAL groups, respectively. Significant changes were observed in a time-domain measure of HRV, standard deviation of normal-to-normal RR interval (in ms: 4 weeks 174 +/- 95 vs. 242 +/- 19; 8 weeks 174 +/- 78 vs. 276 +/- 78, ASM vs. SAL), but not in other time domain parameters. In this canine model of ischemic CHF, ASM implantation did not result in a significant increase in ventricular arrhythmias compared to controls animals. The potential for ASM implantation to affect time-domain parameters of HRV merits further study.

Prolonged effects of B-type natriuretic peptide infusion on cardiac remodeling after sustained myocardial injury.

B-type natriuretic peptide (BNP) is an established first-line therapy for acute decompensated heart failure (HF), but its efficacy in preventing left ventricular (LV) remodeling after myocardial injury is unknown. The goal of this study was to evaluate the effects of BNP therapy on remodeling after ischemic injury in an awake canine model. Dogs were chronically instrumented for hemodynamics. Ischemia was created by daily coronary embolization (Embo; 3.1 x 10(4) beads/day) for 3 wk; 60 min after the first embolization, BNP (100 ng x kg(-1) x min(-1); n = 6) or saline (control; n = 6) was continuously infused via a left atrial catheter for 3 wk. Hemodynamics and echocardiography were performed in an awake state at baseline, 3 wk after Embo + BNP infusion, and 4 wk after stopping Embo + BNP infusion. End-systolic elastance (E(es)) and LV change in pressure over time (dP/dt) were preserved throughout Embo + BNP therapy versus control therapy (E(es): 3.76 +/- 1.01 vs. 1.41 +/- 0.16 mmHg/ml; LV dP/dt: 2,417 +/- 96 vs. 2,068 +/- 95 mmHg/s; both P < 0.05 vs. control). LV end-diastolic dimension was significantly smaller in BNP-treated dogs compared with control dogs (4.29 +/- 0.10 vs. 4.77 +/- 0.17 cm), and ejection fraction was maintained in treated dogs vs. control dogs (53 +/- 1% vs. 46 +/- 2%) (both P < 0.05 vs. control). Cyclooxygenase (COX)-2 expression in terminal LV tissue was significantly reduced after BNP therapy. Treatment with continuous infusion of BNP preserved LV geometry, improved systolic function, and prevented the progression of systolic HF after persistent ischemic injury.

Extracardiac ablation of the left ventricular septum in beating canine hearts using high-intensity focused ultrasound.

BACKGROUND: High-intensity focused ultrasound (HIFU) produces immediate focal lesions without direct tissue contact. Previously, we reported the HIFU potential for cardiac ablation. The purpose of this study was to evaluate the possibility of myocardial ablation in the left ventricle of beating dog hearts with monitoring by 2-dimensional echocardiography. METHODS: The operating frequency and the acoustic intensity were 5.25 MHz and 23 kW/cm(2), and the focal length and diameter were 3.3 mm axial and 0.37 mm wide at a distance of 35 mm from the transducer. Three dogs underwent a left-sided thoracotomy. The right ventricular surface was coupled with the transducer. The timing of the HIFU exposure was set during the early systolic phase using an electrocardiographic triggering system. The focal point was set in the left ventricular septum using 2-dimensional echocardiography mounted in the HIFU transducer. Ultrasound energy was delivered for 0.2 seconds. For each dog, we created 18 lesions. Exposures were performed 20, 30, or 40 times. Lesion size was assessed by manually measuring its length and width. RESULTS: All lesions except one were clearly visible. The histologic lesion area was 18.7 +/- 8.3, 26.3 +/- 8.7, and 35.5 +/- 15.7 mm(2) (20, 30, and 40 times, respectively). The intraclass correlation coefficients were found to be 0.72, 0.63, 0.75, and 0.73 for lesion length, width, area, and depth, respectively. CONCLUSION: HIFU can be used to create targeted, well-demarcated thermal lesions in the ventricular septum myocardium during cardiac contraction.

Bradycardic therapy improves left ventricular function and remodeling in dogs with coronary embolization-induced chronic heart failure.

Both beta-adrenergic blockade and bradycardia may contribute to the therapeutic effect of beta-blockers in chronic heart failure (CHF). This study tested the relative importance of bradycardia by comparing cilobradine (Cilo), a sinus node inhibitor, with a beta-blocker, metoprolol (Meto), in an established canine model of CHF. Dogs were chronically instrumented for hemodynamic and left ventricular (LV) volume measurements. CHF was created by daily coronary embolization via a chronically implanted coronary (left anterior descending coronary artery) catheter. After establishment of CHF, control (n=6), Meto (30 mg/day, n=5), Cilo (low) (1 mg/kg/day, n=5), or Cilo (high) (3 mg/kg/day, n=5) was given orally for 12 weeks. Systemic hemodynamics, echocardiography, and pressure volume analysis were measured at baseline, at CHF, and 3 months after treatment in an awake state. Protein levels of cardiac sarcoplasmic reticulum calcium-ATPase (SERCA2a), ryanodine receptor (RyR2), and Na+-Ca2+ exchanger (NCX1) were measured by Western blot. RyR2 protein kinase A (PKA) phosphorylation was determined by back-phosphorylation. After 12 weeks, Meto and Cilo (high and low) produced similar bradycardic effects, accompanied by a significantly improved LV dP/dt versus control [Meto, 2602+/-70; Cilo (low), 2517+/-45; Cilo (high), 2579+/-78; control, 1922+/-115 mm Hg/s; p<0.05]. Both Meto and Cilo (high) normalized protein levels of SERCA2a and NCX1 and reversed PKA hyperphosphorylation of RyR2, in contrast to controls. High-dose cilobradine effectively produced bradycardia and improved cardiac function after CHF, comparable with metoprolol. Restored protein levels of SERCA2a and improved function of RyR2 may be important mechanisms associated with cilobradine therapy.