Sudden Death after Chest Pain: Feasibility of Virtual Autopsy with Postmortem CT Angiography and Biopsy

Purpose:To determine the potential of minimally invasive postmortem computed tomographic (CT) angiography combined with image-guided tissue biopsy of the myocardium and lungs in decedents who were thought to have died of acute chest disease and to compare this method with conventional autopsy as the reference standard.Materials and Methods:The responsible justice department and ethics committee approved this study. Twenty corpses (four female corpses and 16 male corpses; age range, 15-80 years), all of whom were reported to have had antemortem acute chest pain, were imaged with postmortem whole-body CT angiography and underwent standardized image-guided biopsy. The standard included three biopsies of the myocardium and a single biopsy of bilateral central lung tissue. Additional biopsies of pulmonary clots for differentiation of pulmonary embolism and postmortem organized thrombus were performed after initial analysis of the cross-sectional images. Subsequent traditional autopsy with sampling of histologic specimens was performed in all cases. Thereafter, conventional histologic and autopsy reports were compared with postmortem CT angiography and CT-guided biopsy findings. A Cohen k coefficient analysis was performed to explore the effect of the clustered nature of the data.Results:In 19 of the 20 cadavers, findings at postmortem CT angiography in combination with CT-guided biopsy validated the cause of death found at traditional autopsy. In one cadaver, early myocardial infarction of the papillary muscles had been missed. The Cohen κ coefficient was 0.94. There were four instances of pulmonary embolism, three aortic dissections (Stanford type A), three myocardial infarctions, three instances of fresh coronary thrombosis, three cases of obstructive coronary artery disease, one ruptured ulcer of the ascending aorta, one ruptured aneurysm of the right subclavian artery, one case of myocarditis, and one pulmonary malignancy with pulmonary artery erosion. In seven of 20 cadavers, CT-guided biopsy provided additional histopathologic information that substantiated the final diagnosis of the cause of death.Conclusion:Postmortem CT angiography combined with image-guided biopsy, because of their minimally invasive nature, have a potential role in the detection of the cause of death after acute chest pain.© RSNA, 2012.

Acute visual loss after preoperative embolization of an ethmoidal metastasis

An unintentional embolization of retinal arteries is rare and has been documented as a complication after embolization of arteries supplying head and neck tumors. However, occlusion of the central retinal artery with severe loss of vision has never been reported to be a complication from embolization of tumor-supplying ethmoidal branches of the ophthalmic artery. A 40 year-old male patient with a history of right nephrectomy for renal cell carcinoma underwent preoperative radiological embolization of an ethmoidal metastasis after having experienced a life-threatening sinus bleeding. Repeated probing of the ophthalmic artery with an endovascular microcatheter for particle embolization of the tumor-supplying arteries was performed under anticoagulation with heparin. Postoperatively, a standard ophthalmological examination including extended vascular evaluation by angiography was performed. After extended probing of the ophthalmic artery a marked reduction in its blood flow occurred. Despite post-interventional imaging showing persisting perfusion of the central retinal and ciliary arteries, the patient developed complete loss of vision on this side four days later. At this time fundoscopy and fluorescein angiography revealed a recanalized central artery occlusion, while indocyanin angiography showed infarctions of the choroid. Radiological intervention via the ophthalmic artery can result in complete loss of vision, even after limited and transient obstruction of the vessel.

Retrospective multicenter study of Solitaire FR for revascularization in the treatment of acute ischemic stroke

The purpose of this study was to evaluate safety and efficacy of the Solitaire FR device in the treatment of patients with acute ischemic stroke secondary to large artery occlusion.

[Complement--a phylogenetically old system as a new player in the development of atherosclerosis]

Atherosclerotic diseases such as coronary artery disease and ischaemic stroke are caused by chronic inflammation in arterial vessel walls. The complement system is part of the innate immune system. It is involved in many processes contributing to onset and development of atherosclerotic plaques up to the final stage of acute thrombotic events. This is due to its prominent role in inflammatory processes. In addition, there is increasing evidence that interactions between complement and coagulation provide a link between inflammation and thrombosis. On the other hand, the complement system also has an atheroprotective function through the clearance of apoptotic material. The knowledge of these complex mechanisms will become increasingly important, also for clinicians, since it may lead to novel therapeutic and diagnostic options. Therapies targeting the complement system have the potential to reduce tissue damage caused by acute ischaemic events. Whether early anti-inflammatory and anti-complement therapy may be able to prevent atherosclerosis, remains a hot topic for research.

Cause or effect of arteriogenesis: compositional alterations of microparticles from CAD patients undergoing external counterpulsation therapy

Recently, a clinical study on patients with stable coronary artery disease (CAD) showed that external counterpulsation therapy (ECP) at high (300 mmHg) but not at low inflation pressure (80 mmHg) promoted coronary collateral growth, most likely due to shear stress-induced arteriogenesis. The exact molecular mechanisms behind shear stress-induced arteriogenesis are still obscure. We therefore characterized plasma levels of circulating microparticles (MPs) from these CAD patients because of their ambivalent nature as a known cardiovascular risk factor and as a promoter of neovascularization in the case of platelet-derived MPs. MPs positive for Annexin V and CD31CD41 were increased, albeit statistically significant (P<0.05, vs. baseline) only in patients receiving high inflation pressure ECP as determined by flow cytometry. MPs positive for CD62E, CD146, and CD14 were unaffected. In high, but not in low, inflation pressure treatment, change of CD31CD41 was inversely correlated to the change in collateral flow index (CFI), a measure for collateral growth. MPs from the high inflation pressure group had a more sustained pro-angiogenic effect than the ones from the low inflation pressure group, with the exception of one patient showing also an increased CFI after treatment. A total of 1005 proteins were identified by a label-free proteomics approach from MPs of three patients of each group applying stringent acceptance criteria. Based on semi-quantitative protein abundance measurements, MPs after ECP therapy contained more cellular proteins and increased CD31, corroborating the increase in MPs. Furthermore, we show that MP-associated factors of the innate immune system were decreased, many membrane-associated signaling proteins, and the known arteriogenesis stimulating protein transforming growth factor beta-1 were increased after ECP therapy. In conclusion, our data show that ECP therapy increases platelet-derived MPs in patients with CAD and that the change in protein cargo of MPs is likely in favor of a pro angiogenic/arteriogenic property.

Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation

The purpose of this document is to make the output of the International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT) Standardization and Validation available to medical and scientific communities, through a peer-reviewed publication, in the interest of improving the diagnosis and treatment of patients with atherosclerosis, including coronary artery disease.

Intracerebroventricularly delivered VEGF promotes contralesional corticorubral plasticity after focal cerebral ischemia via mechanisms involving anti-inflammatory actions

Vascular endothelial growth factor (VEGF) has potent angiogenic and neuroprotective effects in the ischemic brain. Its effect on axonal plasticity and neurological recovery in the post-acute stroke phase was unknown. Using behavioral tests combined with anterograde tract tracing studies and with immunohistochemical and molecular biological experiments, we examined effects of a delayed i.c.v. delivery of recombinant human VEGF(165), starting 3 days after stroke, on functional neurological recovery, corticorubral plasticity and inflammatory brain responses in mice submitted to 30 min of middle cerebral artery occlusion. We herein show that the slowly progressive functional improvements of motor grip strength and coordination, which are induced by VEGF, are accompanied by enhanced sprouting of contralesional corticorubral fibres that branched off the pyramidal tract in order to cross the midline and innervate the ipsilesional parvocellular red nucleus. Infiltrates of CD45+ leukocytes were noticed in the ischemic striatum of vehicle-treated mice that closely corresponded to areas exhibiting Iba-1+ activated microglia. VEGF attenuated the CD45+ leukocyte infiltrates at 14 but not 30 days post ischemia and diminished the microglial activation. Notably, the VEGF-induced anti-inflammatory effect of VEGF was associated with a downregulation of a broad set of inflammatory cytokines and chemokines in both brain hemispheres. These data suggest a link between VEGF's immunosuppressive and plasticity-promoting actions that may be important for successful brain remodeling. Accordingly, growth factors with anti-inflammatory action may be promising therapeutics in the post-acute stroke phase.

Vascular endothelial growth factor induces contralesional corticobulbar plasticity and functional neurological recovery in the ischemic brain

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor, which also has neuroprotective activity. In view of these dual actions on vessels and neurons, we were interested whether VEGF promotes long distance axonal plasticity in the ischemic brain. Herein, we show that VEGF promotes neurological stroke recovery in mice when delivered in a delayed way starting 3 days after middle cerebral artery occlusion. Using anterograde tract-tracing experiments that we combined with histochemical and molecular biological studies, we demonstrate that although VEGF promoted angiogenesis predominantly in the ischemic hemisphere, pronounced axonal sprouting was induced by VEGF in the contralesional, but not the ipsilesional corticobulbar system. Corticobulbar plasticity was accompanied by the deactivation of the matrix metalloproteinase MMP9 in the lesioned hemisphere and the transient downregulation of the axonal growth inhibitors NG2 proteoglycan and brevican and the guidance molecules ephrin B1/2 in the contralesional hemisphere. The regulation of matrix proteinases, growth inhibitors, and guidance molecules offers insights how brain plasticity is controlled in the ischemic brain.

The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury

The migration of polymorphonuclear granulocytes (PMN) into the brain parenchyma and release of their abundant proteases are considered the main causes of neuronal cell death and reperfusion injury following ischemia. Yet, therapies targeting PMN egress have been largely ineffective. To address this discrepancy we investigated the temporo-spatial localization of PMNs early after transient ischemia in a murine transient middle cerebral artery occlusion (tMCAO) model and human stroke specimens. Using specific markers that distinguish PMN (Ly6G) from monocytes/macrophages (Ly6C) and that define the cellular and basement membrane boundaries of the neurovascular unit (NVU), histology and confocal microscopy revealed that virtually no PMNs entered the infarcted CNS parenchyma. Regardless of tMCAO duration, PMNs were mainly restricted to luminal surfaces or perivascular spaces of cerebral vessels. Vascular PMN accumulation showed no spatial correlation with increased vessel permeability, enhanced expression of endothelial cell adhesion molecules, platelet aggregation or release of neutrophil extracellular traps. Live cell imaging studies confirmed that oxygen and glucose deprivation followed by reoxygenation fail to induce PMN migration across a brain endothelial monolayer under flow conditions in vitro. The absence of PMN infiltration in infarcted brain tissues was corroborated in 25 human stroke specimens collected at early time points after infarction. Our observations identify the NVU rather than the brain parenchyma as the site of PMN action after CNS ischemia and suggest reappraisal of targets for therapies to reduce reperfusion injury after stroke.

Loss of astrocyte polarization upon transient focal brain ischemia as a possible mechanism to counteract early edema formation

Brain edema is the main cause of death from brain infarction. The polarized expression of the water channel protein aquaporin-4 (AQP4) on astroglial endfeet surrounding brain microvessels suggests a role in brain water balance. Loss of astrocyte foot process anchoring to the basement membrane (BM) accompanied by the loss of polarized localization of AQP4 to astrocytic endfeet has been shown to be associated with vasogenic/extracellular edema in neuroinflammation. Here, we asked if loss of astrocyte polarity is also observed in cytotoxic/intracellular edema following focal brain ischemia after transient middle cerebral artery occlusion (tMCAO). Upon mild focal brain ischemia, we observed diminished immunostaining for the BM components laminin α4, laminin α2, and the proteoglycan agrin, in the core of the lesion, but not in BMs in the surrounding penumbra. Staining for the astrocyte endfoot anchorage protein β-dystroglycan (DG) was dramatically reduced in both the lesion core and the penumbra, and AQP4 and Kir4.1 showed a loss of polarized localization to astrocytic endfeet. Interestingly, we observed that mice deficient for agrin expression in the brain lack polarized localization of β-DG and AQP4 at astrocytic endfeet and do not develop early cytotoxic/intracellular edema following tMCAO. Taken together, these data indicate that the binding of DG to agrin embedded in the subjacent BM promotes polarized localization of AQP4 to astrocyte endfeet. Reduced DG protein levels and redistribution of AQP4 as observed upon tMCAO might therefore counteract early edema formation and reflect a beneficial mechanism operating in the brain to minimize damage upon ischemia.

[Guidance of interventions in subintimal recanalization and fenestration of dissection membranes using a novel dual-lumen intravascular ultrasound catheter]

PURPOSE: To evaluate the feasibility and effectiveness of IVUS-guided puncture for gaining controlled target lumen reentry in subintimal recanalization of chronic iliac/femoral artery occlusions and in fenestration of aortic dissections. MATERIALS AND METHODS: Between 5/2004 and 12/2005 12 consecutive patients (7 male, 5 female; mean age 64.6 +/- 12.0 years) with chronic critical limb ischemia and ischemic complications of aortic dissection were treated using the Pioneer catheter. This 6.2-F dual-lumen catheter combines a 20-MHz IVUS transducer with a pre-shaped extendable, hollow 24-gauge nitinol needle. This coaxial needle allows real-time IVUS-guided puncture of the target lumen and after successful reentry a 0.014" guidewire may be advanced through the needle into the target lumen. 7 patients were treated for aortic dissection and 5 patients (with failed previous attempts at subintimal recanalization) for chronic arterial occlusion. Patients with aortic dissection (5 type A dissections, 2 type B dissections) had developed renal ischemia (n = 2), renal and mesenteric ischemia (n = 2), or low extremity ischemia (n = 3). Patients with chronic arterial occlusions (2 common iliac artery occlusions, 3 superficial femoral artery occlusions) experienced ischemic rest pain (n = 4), and a non-healing foot ulcer (n = 1). RESULTS: The technical success rate using the Pioneer catheter was 100%. The recanalization/fenestration time was 37 +/- 12 min. Procedure-related complications did not occur. In 10 cases a significant improvement of clinical symptoms was evident. One patient with aortic dissection and ischemic paraplegia required subsequent surgical intervention. One patient had persistent ischemic rest pain despite successful recanalization of a superficial femoral artery occlusion. CONCLUSION: The Pioneer catheter is a reliable device which may be helpful for achieving target lumen reentry in subintimal recanalization of chronic occlusions and in fenestration of aortic dissections.

Polymer stent coating for prevention of neointimal hyperplasia

AIMS: Restenosis has been the principal limitation of bare metal stents. Based upon the presumption that platelet and inflammatory cell recruitment initiate neointimal proliferation, we explored a novel polymer coating that reduces cell-stent interactions. The purpose of the present study was to investigate the effect of poly(L-lysine)-graft-poly(ethyleneglycol) (PLL-g-PEG) adsorbed to stent surfaces to reduce neointimal hyperplasia in the porcine restenosis model. METHODS AND RESULTS: Seven animals were instrumented each with 2 stainless steel stents (15 mm length, 2.5-3.5 mm diameter), randomly implanted in 1 major epicardial coronary artery. One stent was dip-coated with PLL-g-PEG, whereas the other stent served as the uncoated control stent. All animals were sacrificed after 6 weeks for histological examination. Neointimal hyperplasia was significantly less (-51%) in the PLL-g-PEG-coated stents (1.15 +/- 0.59 mm2) than in the uncoated control stents (2.33 +/- 1.01 mm2; p < 0.001). Conversely, lumen size was larger in the PLL-g-PEG-coated stents (2.91 +/- 1.17 mm2) than in the uncoated stents (2.04 +/- 0.64 mm2; p < 0.001). High magnification histomorphologic examination revealed no signs of inflammation or thrombus formation in either stent group. CONCLUSIONS: Polymeric steric stabilization of stents with PLL-g-PEG significantly reduces neointimal hyperplasia in the porcine restenosis model. Reduction of cell-stent interactions mediated by PLL-g-PEG appear to improve biocompatibility of stainless steel stents without evidence of adverse inflammatory or prothrombotic effects.

Influence of water immersion, water gymnastics and swimming on cardiac output in patients with heart failure

Background Whole-body water immersion leads to a significant shift of blood from the periphery into the intra-thoracic circulation, followed by an increase in central venous pressure and heart volume. In patients with severely reduced left ventricular function, this hydrostatically in-duced volume shift might overstrain the cardiovascular adaptive mechanisms and lead to cardiac decompensation. The aim of this study is to assess the hemodynamic response to water immer-sion, gymnastics and swimming in patients with heart failure (CHF). Methods We examined 10 patients with compensated CHF (62.9 +/- 6.3 years, EF 31.5 +/- 4.1%, peak VO2 19.4 +/- 2.8 ml/kg/min.), 10 patients with coronary artery disease (CAD) but preserved left ventricular function (57.2 +/- 5.6 years, EF 63.9 +/- 5.5%, peak VO2 28.0 +/- 6.3 ml/kg/min.) and 10 healthy subjects (32.8 +/- 7.2 years, peak VO2 45.6 +/- 6.0 ml/kg/min.). Hemodynamic response to thermo-neutral (32 degrees C) water immersion and exercise was measured using a non-invasive foreign gas rebreathing method during stepwise water immersion, water gymnastics and swimming. Results Water immersion up to the chest increased cardiac index by 19% in healthy subjects, by 21% in CAD patients and 16% in CHF patients. While some CHF patients showed a decrease of stroke volume during immersion, all subjects were able to increase cardiac index (by 87% in healthy subjects, 77% in CAD patients and 53% in CHF patients). Oxygen uptake during swim-ming was 9.7 +/- 3.3 ml/kg/min. in CHF patients, 12.4 +/- 3.5 ml/kg/min. in CAD patients and 13.9 +/- 4.0 ml/kg/min. in healthy subjects. Conclusions Patients with severely reduced left ventricular function but stable clinical conditions and a minimal peak VO2 of at least 15 ml/kg/min. during a symptom-limited exercise stress test tolerate water immersion and swimming in thermo-neutral water well. Although cardiac in-dex and oxygen uptake are lower compared with CAD patients with preserved left ventricular function and healthy controls, these patients are able to increase cardiac index adequately during water immersion and swimming.

Impact of left ventricular hypertrophy late after aortic valve replacement for aortic stenosis on cardiovascular morbidity and mortality

AIMS: The goal of this study was to assess the prevalence of left ventricular (LV) hypertrophy in patients with aortic stenosis late (>6 months) after aortic valve replacement and its impact on cardiac-related morbidity and mortality. METHODS AND RESULTS: In a single tertiary centre, echocardiographic data of LV muscle mass were collected. Detailed information of medical history and angiographic data were gathered. Ninety-nine of 213 patients (46%) had LV hypertrophy late (mean 5.8 +/- 5.4 years) after aortic valve replacement. LV hypertrophy was associated with impaired exercise capacity, higher New York Heart Association dyspnoea class, a tendency for more frequent chest pain expressed as higher Canadian Cardiovascular Society class, and more rehospitalizations. 24% of patients with normal LV mass vs. 39% of patients with LV hypertrophy reported cardiac-related morbidity (p = 0.04). In a multivariate logistic regression model, LV hypertrophy was an independent predictor of cardiac-related morbidity (odds ratio 2.31, 95% CI 1.08 to 5.41), after correction for gender, baseline ejection fraction, and coronary artery disease and its risk factors. Thirty seven deaths occurred during a total of 1959 patient years of follow-up (mean follow-up 9.6 years). Age at aortic valve replacement (hazard ratio 1.85, 95% CI 1.39 to 2.47, for every 5 years increase in age), coexisting coronary artery disease at the time of surgery (hazard ratio 3.36, 95% CI 1.31 to 8.62), and smoking (hazard ratio 4.82, 95% CI 1.72 to 13.45) were independent predictors of overall mortality late after surgery, but not LV hypertrophy. CONCLUSIONS: In patients with aortic valve replacement for isolated aortic stenosis, LV hypertrophy late after surgery is associated with increased morbidity.

Assessing intravascular volume by difference in pulse pressure in pigs submitted to graded hemorrhage

We assessed changes in intravascular volume monitored by difference in pulse pressure (dPP%) after stepwise hemorrhage in an experimental pig model. Six pigs (23-25 kg) were anesthetized (isoflurane 1.5 vol%) and mechanically ventilated to keep end-tidal CO2 (etCO2) at 35 mmHg. A PA-catheter and an arterial catheter were placed via femoral access. During and after surgery, animals received lactated Ringer's solution as long as they were considered volume responders (dPP>13%). Then animals were allowed to stabilize from the induction of anesthesia and insertion of catheters for 30 min. After stabilization, baseline measurements were taken. Five percent of blood volume was withdrawn, followed by another 5%, and then in 10%-increments until death from exsanguination occurred. After withdrawal of 5% of blood volume, all pigs were considered volume responders (dPP>13%); dPP rose significantly from 6.1+/-3.3% to 19.4+/-4.2%. The regression analysis of stepwise hemorrhage revealed a linear relation between blood loss (hemorrhage in %) and dPP (y=0.99*x+14; R2=0.7764; P<.0001). In addition, dPP was the only parameter that changed significantly between baseline and a blood loss of 5% (P<0.01), whereas cardiac output, stroke volume, heart rate, MAP, central venous pressure, pulmonary artery occlusion pressure, and systemic vascular resistance, respectively, remained unchanged. We conclude that in an experimental hypovolemic pig model, dPP correlates well with blood loss.