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.

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.

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.

A percutaneous aortic device for cerebral embolic protection during cardiovascular intervention.

BACKGROUND: Embolic stroke is a major cause of morbidity in aortic and cardiac interventional procedures. Although cerebral embolic protection devices have been developed for carotid interventions and for open heart surgery, a percutaneous device for cerebral embolic protection during aortic and cardiac interventions would be desirable. METHODS: The Embrella Embolic Deflector (Embrella Cardiovascular Inc, Wayne, Pa) is a percutaneously placed embolic protection device, inserted by a 6F access in the pig's right forelimb, and deployed in the aorta, covering the brachiocephalic vessel origins. The device functions by deflecting embolic debris downstream in the aortic circulation. A swine model (n = 3) was developed for testing the deployment, retrieval, and efficacy of the device using a carotid filtration circuit for collection of emboli. Human atheromatous material was prepared as embolization particles with diameters between 150 and 600 µm. Deflection efficiency of the device was calculated by comparing numbers of embolic particles in the carotid circulation during protected and unprotected injections. RESULTS: The device was reliably deployed, positioned, and retrieved (n = 24). There was no significant drop in blood pressure across the membrane of the device to suggest reduction of cerebral blood flow. The device did not become occluded by embolic debris despite an embolic load many times that encountered in the clinical situation. Particles entering the carotid circulation after aortic injection of emboli were reduced from 19% of total (unprotected) to 1.3% (protected, P < .0001), with 98.7% of all injected particles being deflected downstream. There was no evidence of arterial injury related to the device found at necropsy. CONCLUSION: The Embrella Embolic Deflector performs safely and reliably in the swine model of human atheroembolism. It effectively deflects almost all emboli downstream, away from the carotid circulation. The deflector shows promise as an aortic embolic protection device and merits further investigation.

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.

PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure.

The type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) is the major calcium (Ca2+) release channel required for skeletal muscle excitation-contraction (EC) coupling. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA. PKA is activated during sympathetic nervous system (SNS) stimulation. We show that PKA phosphorylation of RyR1 at Ser2843 activates the channel by releasing FKBP12. When FKB12 is bound to RyR1, it inhibits the channel by stabilizing its closed state. RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are "leaky." RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle. These findings identify a novel mechanism that regulates RyR1 function via PKA phosphorylation in response to SNS stimulation. PKA hyperphosphorylation of RyR1 may contribute to impaired skeletal muscle function in HF, suggesting that a generalized EC coupling myopathy may play a role in HF.

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.

Effect of passive cardiac containment on ventricular synchrony and cardiac function in awake dogs.

OBJECTIVE: Passive restraint of the left ventricle (LV) has been shown to have beneficial effects on acute hemodynamics and reverse remodeling in both animal and human models. The goals of this study were to test whether a left ventricular support device (LVSD) improves LV synchrony and/or affects cardiac performance. METHODS: Ten dogs were chronically instrumented to measure hemodynamics and LV volume (sonomicrometry). Congestive heart failure (CHF) was induced by repeated intracoronary microembolization via a chronically implanted coronary catheter. The LVSD was implanted after establishment of CHF in five animals, and five animals were observed as controls. All animals were then observed for 8 weeks. A mathematical model to measure LV synchrony was used to evaluate LV motion over time. RESULTS: Mean arterial pressure and LV pressures was significantly increased after LVSD therapy, and LV pressure-volume relationships were shifted leftwards, although no change was seen in ejection fraction, end-systolic elastance, or LV dP/dt versus control. There was no significant change in diastolic function in LVSD animals compared with control animals. End-diastolic volumes were reduced by 15% after 8 weeks with LVSD treatment, versus an increase of 8% in control animals (p<0.05). Synchrony was significantly improved with LVSD therapy compared with control (9% vs 76% of baseline) in 1 of 11 ventricular dimension axes (Anterior-Apex). CONCLUSIONS: LVSD therapy provided only minimal improvement in ventricular synchrony and partially improved hemodynamics. Further study into mechanisms of benefit are warranted.

Direct left ventricle-to-coronary artery stent restores perfusion to chronic ischemic swine myocardium.

BACKGROUND: Direct left ventricle (LV)-to-coronary artery shunts (VSTENT) have been proposed as an alternative means of myocardial revascularization. The goal of this study was to examine quantitative changes in myocardial perfusion and possible mechanisms of revascularization with an LV-to-coronary shunt. METHODS: Ameroid occluders were implanted on the proximal left anterior descending coronary artery (LAD) of 6 pigs to create chronic ischemia. Four weeks later, a VSTENT was placed to directly connect the distal LAD with the LV chamber. Animals survived for an additional 3 weeks and received periodic bromodeoxyuridine (BrdU) injections to identify dividing cells to identify and quantify angiogenesis. Regional myocardial perfusion (RMP) was measured with color microspheres under adenosine vasodilatory stress before and 3 weeks after VSTENT implantation. Vascularity was assessed histologically by an overall vascularity index and a growth index reflecting the density of BrdU-positive vascular cells. RESULTS: Three weeks after VSTENT placement, RMP improved from 38.4% +/- 19.6% of non-ischemic flow to 86.8% +/- 13.7% in treated animals (P < .05). This benefit was accompanied by histological evidence of increased vascularity and vascular proliferation. Four of 5 animals had patent and functional devices at the end of the study. CONCLUSION: Chronic VSTENT placement improves RMP and may promote arterial remodeling in chronically ischemic porcine myocardium.

Direct left ventricle to great cardiac vein retroperfusion: a novel alternative to myocardial revascularization.

BACKGROUND: As the number of patients with diffuse coronary artery disease continues to grow, there is renewed interest in alternative methods of perfusing the ischemic myocardium. We tested the feasibility of myocardial retroperfusion via a direct left ventricle-to-great cardiac vein (LV-GCV) conduit to support regional contractility in this setting. METHODS: LV-GCV flow was established using an extracorporeal circuit in 5 dogs. Left ventricle (LV) pressure, aortic pressure, regional myocardial segment length, and circuit blood flow were measured prior to left anterior descending coronary artery (LAD) ligation, following LAD ligation, and after LV-GCV circuit placement. To eliminate backward flow during diastole, an in-line flow regulator was placed. Regional myocardial function was quantified by pressure-segment length loop area divided by end-diastolic segment length (PSLA/EDSL). RESULTS: LAD ligation reduced PSLA/EDSL from 10.0 +/- 1.2 mm Hg mm to 1.6 +/- 0.3 mm Hg mm (P < .05). With LV-GCV retroperfusion, mean peak systolic flow was +152 +/- 14 mL/min, mean peak diastolic flow was -39 +/- 11 mL/min, and net mean flow was +36 +/- 13 mL/min. Regional function recovered to approximately 39% of baseline (3.9 +/- 0.4 mm Hg mm, P < .05). Upon elimination of backflow, mean flow increased to +41 +/- 12 mL/min and regional function recovered even further to approximately 47% of baseline (4.6 +/- 0.7 mm Hg mm, P < .05). CONCLUSIONS: A LV-GCV circuit can significantly restore regional function to the acutely ischemic myocardium. An inline valve that eliminates backward diastolic flow improves regional function even further. This approach may provide an effective therapy for diffuse coronary disease not amenable to traditional revascularization strategies.

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.

Mechanisms of heart failure with well preserved ejection fraction in dogs following limited coronary microembolization.

OBJECTIVE: It has been suggested that in some settings, heart failure (HF) may occur with normal ejection fraction (EF) as a consequence of undetected systolic dysfunction. However, others have argued that this can only occur in the presence of diastolic dysfunction. We therefore sought to determine the contribution of diastolic dysfunction in an animal model of HF with normal EF. METHODS AND RESULTS: Limited myocardial injury was induced in 21 dogs chronically instrumented to measure hemodynamics and LV properties by daily coronary microembolization ( approximately 115 microm beads) until LV end diastolic pressure (LVEDP) was > or =16 mm Hg. Nine dogs developed HF within 16+/-6 days (LVEDP 12+/-2 vs. 21+/-2 mm Hg, p<0.001) with no significant change in dP/dt(max) (2999+/-97 vs. 2846+/-189 mm Hg/s), mean arterial pressure (103+/-4 vs. 100+/-4 mm Hg), EF (57+/-5% vs. 53+/-4%) or E(es) (end-systolic elastance, 3.1+/-0.9 vs. 2.9+/-0.8 mm Hg/ml) but with an approximately 10 ml increase in V(o) (14+/-12 vs. 25+/-16 ml; p<0.01). The EDPVR and time constant of relaxation (tau, 25+/-3 vs. 28+/-3 ms) did not change significantly. These animals were hemodynamically stable out to 3 1/2 months. Neurohormonal activation occurred (elevations of NE, AngII, BNP) and there was intravascular volume expansion by approximately 16% (p<0.05). CONCLUSIONS: A small amount of myocardial injury can lead to neurohormonal activation with intravascular volume expansion and elevation of LVEDP in the absence of reductions in dP/dt(max) or EF and without diastolic dysfunction. Thus, HF with preserved EF does not a priori equate with diastolic heart failure.

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.

Left ventricular systolic performance in failing heart improved acutely by left ventricular reshaping.

OBJECTIVE: If the geometric distortion during dilated heart failure could be corrected, the tension on the myocytes would be decreased, thereby leading to an improvement in left ventricular systolic function. We tested the effects of the CardioClasp (CardioClasp Inc, Pine Brook, NJ), a left ventricular reshaping device, on the failing heart, and our empirical data were compared with computationally derived data. METHODS: Heart failure was induced by 4-week rapid cardiac pacing. At the terminal experiment, an isolated failing heart preparation (isovolumic contraction, n = 5) or an intact failing heart in vivo (n = 7) was used. The effects of the reshaping device on left ventricular performance were assessed by the slopes (Ees) of the left ventricular end-systolic pressure-volume relations, hemodynamics, and echocardiograph before and after placing the CardioClasp on the heart. The change in Ees as the result of left ventricular reshaping was also estimated from computed theoretical analysis and compared with empirical data. RESULTS: There was a significant change in left ventricular dimension after placing the CardioClasp on the heart. In isolated heart preparation, Ees significantly increased from 1.40 +/- 0.44 mm Hg/mL to 2.42 +/- 0.63 mm Hg/mL after placing the device on the heart but returned to the baseline level (1.46 +/- 0.27 mm Hg) after removing it. Left ventricular developed pressure and left ventricular fractional area shortening were significantly increased as the result of left ventricular reshaping. Ees derived from computed theoretical analysis was highly correlated with confirming empirical data. CONCLUSIONS: The CardioClasp can reshape the left ventricle and improve left ventricular systolic performance in failing hearts.

Exercise training normalizes altered calcium-handling proteins during development of heart failure.

The cardiac sarcoplasmic reticulum calcium-ATPase (SERCA2a), Na+/Ca2+ exchanger (NCX1), and ryanodine receptor (RyR2) are proteins involved in the regulation of myocyte calcium. We tested whether exercise training (ET) alters those proteins during development of chronic heart failure (CHF). Ten dogs were chronically instrumented to permit hemodynamic measurements. Five dogs underwent 4 wk of cardiac pacing (210 beats/min for 3 wk and 240 beats/min for the 4th wk), whereas five dogs underwent the same pacing regimen plus daily ET (5.1 +/- 0.3 km/h, 2 h/day). Paced animals developed CHF characterized by hemodynamic abnormalities and reduced ejection fraction. ET preserved resting hemodynamics and ejection fraction. Left ventricular samples were obtained from all dogs and another five normal dogs for mRNA (Northern analysis, band intensities normalized to glyceraldehyde-3-phosphate dehydrogenase) and protein level (Western analysis, band intensities normalized to tubulin) measurements. In failing hearts, SERCA2a was decreased by 33% (P < 0.05) and 65% (P < 0.05) in mRNA and protein level, respectively, compared with normal hearts; there was only an 8.6% reduction in mRNA and a 32% reduction in protein in exercised animals (P < 0.05 from CHF). mRNA expression of NCX1 increased by 44% in paced-only dogs compared with normal (P < 0.05) but only by 22% in trained dogs (P < 0.05 vs. CHF); protein level of NCX1 was elevated in paced-only dogs (71%, P < 0.05) but partially normalized by ET (33%, P < 0.05 from CHF). RyR2 was not altered in any of the dogs. In conclusion, long-term ET may ameliorate cardiac deterioration during development of CHF, in part via normalization of myocardial calcium-handling proteins.

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.

Peri-strut low-intensity areas in optical coherence tomography correlate with peri-strut inflammation and neointimal proliferation: an in-vivo correlation study in the familial hypercholesterolemic coronary swine model of in-stent restenosis.

BACKGROUND: Peri-strut low-intensity area (PLI) is a common imaging finding during the evaluation of in-stent neointima using optical coherence tomography (OCT). We aimed to determine the biological significance of PLI by comparing in-vivo OCT images with the corresponding histological sections obtained from the familial hypercholesterolemic swine model of coronary stenosis. METHODS: A total of 26 coronary vessels of nine familial hypercholesterolemic swine were injured with 30% balloon overstretch and then immediately followed by everolimus eluting or bare metal stent placement at 20% overstretch. At 30 days, all stented vessels were subjected to in-vivo OCT analysis and were harvested for histological evaluation. For OCT analysis, stent cross-sections (three per stent) were categorized into presence (PLI+) or absence (PLI-) of PLI. In histology, inflammation and fibrin deposition were scored semiquantitatively from 0 (none) to 3 (severe). RESULTS: PLI was found in 64.9% of stent sections. Peri-strut inflammation was more frequently observed in OCT sections PLI (+) compared with PLI (-) (56.0 vs. 7.4%, P=0.01). In contrast, peri-strut fibrin deposits was similar in both groups (PLI+=58.0% vs. PLI-=59.3%, P=0.94). Histological neointimal thickness was significantly higher in PLI (+) sections (mean±SE: 0.68±0.06 vs. 0.34±0.02 mm; P<0.01), yielding a higher percent area stenosis compared with PLI (-) (mean±SE: 59.0±4.4 vs. 34.1±2.2%, P<0.01). The PLI diagnostic sensitivity and specificity for inflammation were 80 and 76.1%, respectively (>56% PLI, area under the curve=0.86, P<0.01), whereas for fibrin deposition, the sensitivity and specificity were 42.2 and 76.1%, respectively (area under the curve=0.56, P=NS). Area under the receiver operating characteristic curve was significantly higher for identifying inflammation than fibrin (0.86 vs. 0.56, P<0.01). The severity of PLI correlated with the neointimal thickness when assessed by OCT (R=0.79, P<0.001). CONCLUSION: The presence of PLI in OCT correlates with neointimal thickness and appears to have a diagnostic value in the recognition of peri-strut inflammation, therefore possibly serving as a surrogate for in-vivo assessment of stent efficacy.

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.

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.