Subsequent development of fibroatheromas with inflamed fibrous caps can be predicted by intracoronary near infrared spectroscopy.

OBJECTIVE: To prospectively evaluate whether the development of fibroatheromas exhibiting features of potential instability can be detected and predicted by serial invasive imaging. METHODS AND RESULTS: Multivessel intravascular ultrasound and near infrared spectroscopy (NIRS) were performed in diabetic/hypercholesterolemic pigs 3, 6, and 9 months after induction. Animals were euthanized at 9 months and histological/immunohistochemical evaluation of the arteries was performed (n=304 arterial segments). Intravascular ultrasound demonstrated, over time, a progressive increase in plaque + media and necrotic core areas and positive vascular remodeling. By histology, NIRS+ lesions were significantly more likely to be a high-risk fibroatheroma (P=0.0001) containing larger plaque (P<0.0001) and necrotic core areas (P<0.0019) and thinner fibrous caps (P=0.04). NIRS + fibroatheromas possessed a greater concentration of inflammatory cells demonstrating protease activity (P=0.006), and proliferating (P=0.016), and apoptotic cells (P=0.04) within the fibrous cap. Eighty-eight percent of NIRS+ lesions at 3 and 6 months subsequently developed into a fibroatheroma at 9 months (P<0.01). By multivariate analysis NIRS positivity at 6 months predicted the subsequent presence of a fibroatheroma at 9 months (P=0.005; odds ratio, 2.71). CONCLUSIONS: The future development of inflamed fibroatheromas with thinner fibrous caps, greater plaque, and necrotic core areas, and posessing characteristics of increased plaque instability were detected by intravascular ultrasound/NIRS imaging.

Akt pathway is hypoactivated by synergistic actions of diabetes mellitus and hypercholesterolemia resulting in advanced coronary artery disease.

Atherosclerosis is an inflammatory process leading to enhanced cellular proliferation, apoptosis, and vasa vasorum (VV) neovascularization. While both diabetes mellitus (DM) and hypercholesterolemia (HC) predispose to atherosclerosis, the precise interaction of these risk factors is unclear. Akt is a central node in signaling pathways important for inflammation, and we hypothesized that DM/HC would lead to aberrant Akt signaling and advanced, complex atherosclerosis. DM was induced in pigs by streptozotocin and HC by a high-fat diet. Animals were randomized to control (non-DM, non-HC), DM only, HC only, and DM/HC groups. Coronary artery homogenates were analyzed by immunoblotting for proteins involved in the Akt pathway, including phosphorylated (p)-Akt (Ser473), p-GSK-3beta (Ser9), activated NF-kappaB p65, and VEGF. Immunohistochemical staining for Ki67 (cell proliferation), terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) (apoptosis), and von Willebrand factor (vWF) (neovascularization) was performed. Neovascularization was visualized with micro-computerized tomography (CT). Only DM/HC animals developed advanced atherosclerosis and showed decreased p-Akt (Ser473) and p-GSK-3beta (Ser9) levels (P < 0.01 and P < 0.05, respectively). DM/HC arteries demonstrated increased cellular proliferation (P < 0.001), apoptosis (P < 0.01), and activation of NF-kappaB p65 (P < 0.05). Induction of DM/HC also resulted in significant VV neovascularization by enhanced VEGF expression (P < 0.05), increased vWF staining (P < 0.01), and increased density by micro-CT. In conclusion, DM and HC synergistically resulted in complex atherosclerosis associated with attenuated p-Akt (Ser473) levels. Aberrant Akt signaling correlated with increased inflammation, cellular proliferation, apoptosis, and VV neovascularization. Our results revealed a synergistic effect of DM and HC in triggering abnormal Akt signaling, resulting in advanced atherosclerosis.

Intracoronary delivery of mesenchymal stem cells at high flow rates after myocardial infarction improves distal coronary blood flow and decreases mortality in pigs.

OBJECTIVES: Evaluate the effects of pressure and duration of intracoronary (IC) infusion of mesenchymal stem cells (MSCs) on delivery efficiency and safety after myocardial infarction (MI). BACKGROUND: Standard IC delivery of MSCs can lead to intravascular plugging and reduced coronary blood flow. The optimal delivery pressure and duration is unknown. METHODS: Immediately after MI pigs were randomized to 1 of 3 delivery protocols of 5 x 10(7) iron-fluorescent microspheres labeled MSCs, control received 2 ml infusions at 1 ml/min (five times), very high flow rate (VHFR) a single 10 ml infusion at 60 ml/min and the high flow rate (HFR) group a single 10 ml infusion at 20 ml/min. TIMI grade flow was assessed throughout the procedure and at sacrifice (day 14). MSCs distribution was analyzed in isolated hearts by 4.7T MRI. Delivery efficiency was quantified via fluorescent microsphere recovery using a magnetic separation technique and by light microscopy. RESULTS: TIMI grade flow did not change following MI (all groups TIMI 3). However, following MSCs delivery only 18% (2/11) of control animals had TIMI 3 blood flow vs. 56% (5/9) in VHFR and 67% (4/6) in HFR (P = 0.03). As a consequence, 63% of control animals died within 24 hr, 33% in VHFR and none in HFR (P = 0.02). MSCs delivery in the infarct tissue did not differ between the groups (P = 0.06). CONCLUSIONS: A single MSCs infusion at 20 ml/min resulted in improved coronary blood flow and decreased mortality, without sacrificing delivery efficiency.

Site-specific atherogenic gene expression correlates with subsequent variable lesion development in coronary and peripheral vasculature.

OBJECTIVE: The relationship between specific gene regulation and subsequent development and progression of atherosclerosis is incompletely understood. We hypothesized that genes in the vasculature related to cholesterol metabolism, inflammation, and insulin signaling pathways are differentially regulated in a site-specific and time-dependent manner. METHODS AND RESULTS: Expression of 59 genes obtained from coronary, carotid, and thoracic aortic arteries were characterized from diabetic (DM)/hypercholesterolemic (HC) swine (n=52) 1, 3, and 6 months after induction. Lesion development in the 3 arterial beds was quantified and characterized at 1, 3, 6, and 9 months. Progressive lesion development was observed in the coronary>thoracic aorta>>carotid arteries. Genes involved in cholesterol metabolism and insulin pathways were upregulated in coronaries>thoracic aortae>carotids. Inflammatory genes were more markedly upregulated in coronary arteries than the other 2 arteries. Genes implicated in plaque instability (eg, matrix metalloproteinase-9, CCL2 and Lp-PLA(2) mRNAs) were only upregulated at 6 months in coronary arteries. CONCLUSIONS: Variable gene expression, both in regard to the arterial bed and duration of disease, was associated with variable plaque development and progression. These findings may provide further insight into the atherosclerotic process and development of potential therapeutic targets.

The vulnerable artery: early and rapid deposition of lipid in coronary arteries is associated with subsequent development of thin-cap fibroatheromas.

AIMS: We aimed to determine whether intravascular ultrasound (IVUS) and near infrared spectroscopy (NIRS) could identify arteries which would subsequently develop a thin-cap fibroatheroma (TCFA). METHODS AND RESULTS: Three-vessel angiography, IVUS and NIRS evaluations were performed at three, six and nine months after induction of diabetes mellitus and hypercholesterolaemia in 13 Yorkshire pigs (n=37 arteries). In vivo total arterial plaque plus media (P+M) area, echo-attenuated plaque (AP) area by IVUS, and lipid core burden index (LCBI) by NIRS were compared to histology at nine months. P+M mean area increased over time (3 vs. 6 months p<0.01; 6 vs. 9 months p<0.01), as did the AP area and mean LCBI between three and six months (p<0.01). There were 69 TCFAs within 18 arteries. The mean LCBI at six months was greater in arteries containing a TCFA (77.8±17.4 vs. 34.3±11.4; p=0.04) as was the ∆LCBI from three to six months (55.3±16.9 vs. 3.3±16.0; p=0.03). Arteries which contained TCFA at nine months had greater AP area by IVUS at six months (p=0.007). CONCLUSIONS: The early and persistent accumulation of total arterial lipid detected by NIRS was associated with the future development of TCFAs.

Vascular responses to drug-eluting and bare metal stents in diabetic/hypercholesterolemic and nonatherosclerotic porcine coronary arteries.

BACKGROUND: Animal models used to gain insight into the vascular response to drug-eluting stents are generally juvenile and nonatherosclerotic, whereas stents are placed in patients with complex atherosclerosis and comorbidities. Hence, models reflecting these complexities are needed to help elucidate the vascular effects of drug-eluting stents. We compared the vascular responses with bare metal stent (BMS) and paclitaxel-eluting stent (PES) implantation in a diabetic/hypercholesterolemic (DM/HC) porcine model of advanced coronary atherosclerosis with the standard juvenile porcine model. METHODS AND RESULTS: Two studies using similar stent procedural protocols were performed in either DM/HC (n=20) or domestic swine (non-DM/HC, n=20). Animals pretreated with dual-antiplatelet therapy, underwent BMS or PES implantation (1/artery, 2 stents per animal) and were euthanized 30 or 90 days later. DM/HC resulted in a 24% increase in platelet aggregation (P=0.05 versus baseline), whereas dual-antiplatelet therapy reduced platelet aggregation in both groups (P<0.0001). DM/HC pigs developed substantially greater neointimal area versus non-DM/HC pigs, regardless of stent type, (P=0.004 for BMS at 30 days and P=0.002 at 90 days, P=0.005 for PES at 30 days, P=0.002 at 90 days). Compared with non-DM/HC pigs, reendothelialization was delayed in DM/HC pigs, more so after PES implantation. Increased para-strut leukocytes were observed for PES compared with BMS in the DM/HC pigs at both 30 days (P=0.023) and 90 days (P=0.04). As well, increased T-lymphocyte infiltration was seen in the DM/HC pigs. CONCLUSIONS: Stent implantation in a DM/HC swine model provides a metabolic environment closer to human disease, including hyperglycemia, hypercholesterolemia, and increased platelet aggregation. This model augmented differences in the vascular response between PES and BMS that are not as clearly evident in the non-DM/HC swine, including increased neointimal area, delayed reendothelialization, and greater, persistent vascular inflammation.

Complicaciones eléctricas posimplante de válvula aórtica percutáneo: evolución clínica y eléctrica / Clinical Outcomes of Electrical Disorders after Transcatheter Aortic Valve Implantation

Introducción El implante valvular aórtico percutáneo es una opción terapéutica cada vez más utilizada en pacientes en los que se descarta la cirugía. A pesar de que las alteraciones agudas de la conducción son una de las complicaciones más frecuentes, su significado clínico y electrocardiográfico no es del todo claro. Objetivos Determinar las implicaciones pronósticas del desarrollo de alteraciones agudas de la conducción luego del implante valvular aórtico percutáneo. Resultados Entre marzo de 2009 y febrero de 2012 se incluyeron para el análisis 47 pacientes; de ellos, 30 (63%) presentaron alteraciones agudas de la conducción: 19 pacientes solo bloqueo completo de rama izquierda (BCRI), 9 pacientes solo bloqueo auriculoventricular completo (BAVC) y 2 pacientes presentaron ambos trastornos, los que totalizaron 21 BCRI y 11 BAVC. A 12 (25%) se les implantó un marcapasos definitivo previo al alta: en 11 por BAVC y en 1 por BCRI agudo más fibrilación auricular. En solo un paciente el BAVC revirtió en hemodinamia. Los pacientes que persistieron con BAVC posintervención presentaron una media de estimulación ventricular en la intervalometría al mes del 90%, mientras que en el paciente con BAVC que revirtió en hemodinamia fue de solo el 3% y en el paciente con BCRI más fibrilación auricular fue < 10%. La incidencia de insuficiencia cardíaca en el posoperatorio fue mayor en los pacientes con alteraciones agudas de la conducción (p = 0,007), al igual que la estadía hospitalaria (p = 0,045). En el seguimiento no hubo diferencias en la tasa de reinternación ni en la mortalidad. Conclusiones En el presente estudio el desarrollo de alteraciones agudas de la conducción mostró un aumento en la incidencia de insuficiencia cardíaca y en los días de internación, sin incremento en la tasa de otros eventos mayores. La colocación de un marcapasos definitivo luego del BAVC podría realizarse en forma inmediata, ya que el trastorno generalmente es irreversible.(AU)

Introduction The indication of transcatheter aortic valve implantation in patients considered not suitable candidates for surgery is increasing. Despite acute disorders of the conduction system are common complications, their clinical and electrocardiographic significance is not completely clear. Objectives To determine whether acute disorders of the conduction system after transcatheter aortic valve implantation has prognostic implications. Results Between March 2009 and February 2012, 47 patients were included in the analysis. Thirty patients (63%) had acute disorders of the conduction system: 19 patients presented isolated complete left bundle branch block (LBBB), 9 patients isolated complete atrioventricular block (CAVB), and 2 patients both conduction disorders, with a total of 21 LBBBs and 11 CAVBs. A definite pacemaker was implanted in 12 patients (25%) before discharge: in 11 due to CAVB and in 1 due to acute LBBB plus atrial fibrillation. Complete AVB reverted in the catheterization laboratory in only one patient. At one month, average ventricular pacing was 90% in patients with persistent CAVB after the intervention, only 3% in the only patient in whom CAVB reverted at the catheterization laboratory and < 10% in the patient with LBB plus atrial fibrillation. The incidence of postoperative heart failure and hospital stay was greater in patients with acute disorders of the conduction system (p = 0.007 and p = 0.045, respectively). There were no differences in new hospitalizations and mortality during follow-up. Conclusions In this study, the development of acute disorders of the conduction system was associated with increased incidence of heart failure and hospital stay but not with the incidence of major events. A definite pacemaker could be implanted immediately after CAVB develops as the conduction disorder is generally irreversible.(AU)

Complicaciones eléctricas posimplante de válvula aórtica percutáneo: evolución clínica y eléctrica / Clinical Outcomes of Electrical Disorders after Transcatheter Aortic Valve Implantation

Introducción El implante valvular aórtico percutáneo es una opción terapéutica cada vez más utilizada en pacientes en los que se descarta la cirugía. A pesar de que las alteraciones agudas de la conducción son una de las complicaciones más frecuentes, su significado clínico y electrocardiográfico no es del todo claro. Objetivos Determinar las implicaciones pronósticas del desarrollo de alteraciones agudas de la conducción luego del implante valvular aórtico percutáneo. Resultados Entre marzo de 2009 y febrero de 2012 se incluyeron para el análisis 47 pacientes; de ellos, 30 (63%) presentaron alteraciones agudas de la conducción: 19 pacientes solo bloqueo completo de rama izquierda (BCRI), 9 pacientes solo bloqueo auriculoventricular completo (BAVC) y 2 pacientes presentaron ambos trastornos, los que totalizaron 21 BCRI y 11 BAVC. A 12 (25%) se les implantó un marcapasos definitivo previo al alta: en 11 por BAVC y en 1 por BCRI agudo más fibrilación auricular. En solo un paciente el BAVC revirtió en hemodinamia. Los pacientes que persistieron con BAVC posintervención presentaron una media de estimulación ventricular en la intervalometría al mes del 90%, mientras que en el paciente con BAVC que revirtió en hemodinamia fue de solo el 3% y en el paciente con BCRI más fibrilación auricular fue < 10%. La incidencia de insuficiencia cardíaca en el posoperatorio fue mayor en los pacientes con alteraciones agudas de la conducción (p = 0,007), al igual que la estadía hospitalaria (p = 0,045). En el seguimiento no hubo diferencias en la tasa de reinternación ni en la mortalidad. Conclusiones En el presente estudio el desarrollo de alteraciones agudas de la conducción mostró un aumento en la incidencia de insuficiencia cardíaca y en los días de internación, sin incremento en la tasa de otros eventos mayores. La colocación de un marcapasos definitivo luego del BAVC podría realizarse en forma inmediata, ya que el trastorno generalmente es irreversible.

Introduction The indication of transcatheter aortic valve implantation in patients considered not suitable candidates for surgery is increasing. Despite acute disorders of the conduction system are common complications, their clinical and electrocardiographic significance is not completely clear. Objectives To determine whether acute disorders of the conduction system after transcatheter aortic valve implantation has prognostic implications. Results Between March 2009 and February 2012, 47 patients were included in the analysis. Thirty patients (63%) had acute disorders of the conduction system: 19 patients presented isolated complete left bundle branch block (LBBB), 9 patients isolated complete atrioventricular block (CAVB), and 2 patients both conduction disorders, with a total of 21 LBBBs and 11 CAVBs. A definite pacemaker was implanted in 12 patients (25%) before discharge: in 11 due to CAVB and in 1 due to acute LBBB plus atrial fibrillation. Complete AVB reverted in the catheterization laboratory in only one patient. At one month, average ventricular pacing was 90% in patients with persistent CAVB after the intervention, only 3% in the only patient in whom CAVB reverted at the catheterization laboratory and < 10% in the patient with LBB plus atrial fibrillation. The incidence of postoperative heart failure and hospital stay was greater in patients with acute disorders of the conduction system (p = 0.007 and p = 0.045, respectively). There were no differences in new hospitalizations and mortality during follow-up. Conclusions In this study, the development of acute disorders of the conduction system was associated with increased incidence of heart failure and hospital stay but not with the incidence of major events. A definite pacemaker could be implanted immediately after CAVB develops as the conduction disorder is generally irreversible.