Influence of diagnosis of venous thromboembolism on immature platelets, absolute platelet count and platelet aggregation over time.

The extent of the involvement of platelets in venous thromboembolisms (VTE) is still not fully understood. Immature platelets are large, RNA-rich, prothrombotic platelets. They are involved in arterial thromboembolisms and are associated with adverse cardiovascular events. Their role in VTE has not been investigated before. The aim of this study was to assess different platelet parameters including immature platelet fraction (IPF), immature platelet count (IPC), absolute platelet count and platelet aggregation (PA) over time in patients with VTE at time of diagnosis, as well as at 3-10 days and at 90-110 days after diagnosis. 50 healthy volunteers similar in age and sex to patients served as controls at diagnosis. IPF was measured by the Sysmex XE-5000 analyzer, PA was assessed using the Multiplate analyzer. Diagnosis of VTE had no relevant effect on IPF and IPC whereas absolute platelet count and PA were significantly decreased compared to controls. In the course of VTE, IPF decreased significantly, whereas IPC, absolute platelet count and PA increased. In conclusion, VTE was associated with relevant changes of the absolute platelet count and PA at diagnosis, as well as changes in IPF and IPC over time reflecting a relevant and measurable platelet consumption in VTEs.

Hybrid PET/MR imaging for the prediction of left ventricular recovery after percutaneous revascularisation of coronary chronic total occlusions.

PURPOSE: To evaluate myocardial viability assessment with hybrid 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/magnetic resonance imaging ([18F]FDG-PET/MR) in predicting left ventricular (LV) wall motion recovery after percutaneous revascularisation of coronary chronic total occlusion (CTO). METHODS AND RESULTS: Forty-nine patients with CTO and corresponding wall motion abnormality (WMA) underwent [18F]FDG-PET/MR imaging for viability assessment prior to percutaneous revascularisation. After 3-6 months, 23 patients underwent follow-up MR to evaluate wall motion recovery. In total, 124 segments were assigned to the CTO territories, while 80 segments displayed impaired wall motion. Of these, 68% (54) were concordantly viable in PET and MR; conversely, only 2 segments (2%) were assessed non-viable by both modalities. However, 30% showed a discordant viability pattern, either PET non-viable/MR viable (3 segments, 4%) or PET viable/MR non-viable (21 segments, 26%), and the latter revealed a significant wall motion improvement at follow-up (p = 0.033). Combined imaging by [18F]FDG-PET/MR showed a fair accuracy in predicting myocardial recovery after CTO revascularisation (PET/MR area under ROC curve (AUC) = 0.72, p = 0.002), which was superior to LGE-MR (AUC = 0.66) and [18F]FDG-PET (AUC = 0.58) alone. CONCLUSION: Hybrid PET/MR imaging prior to CTO revascularisation predicts more accurately the recovery of dysfunctional myocardium than PET or MR alone. Its complementary information may identify regions of viable myocardium with increased potential for functional recovery.

Extracorporeal life support system during cardiovascular procedures: Insights from the German Lifebridge registry.

The frequency of mechanical circulatory support (MCS) device application has increased in recent years. Besides implantation in the emergency setting, such as circulatory arrest, MCS is also increasingly used electively to ensure hemodynamic stability in high-risk patients, for example, during percutaneous coronary interventions (PCI), valve interventions or off-pump coronary bypass surgery. Lifebridge (Zoll Medical GmbH, Germany) is a compact percutaneous MCS device widely used in daily clinical routine. The present study aimed to investigate the indications, feasibility, and outcomes after use of Lifebridge in cardiac interventions, evaluating a large-scale multicenter database. A total of 60 tertiary cardiovascular centers were questioned regarding application and short-term outcomes after the use of the Lifebridge system (n = 160 patients). Out of these 60 centers, eight consented to participate in the study (n = 39 patients), where detailed data were collected using standardized questionnaires. Demographic and clinical characteristics of the patient population, procedural as well as follow-up data were recorded and analyzed. In 60 interrogated centers, Lifebridge was used in 74% of emergency cases and 26% in the setting of planned interventions. The subcohort interrogated in detail displayed the same distribution of application scenarios, while the main cardiovascular procedure was high-risk PCI (82%). All patients were successfully weaned from the device and 92% (n = 36) of the patients studied in detail survived after 30 days. As assessed 30 days after insertion of the device, bleeding requiring red blood cell (RBC) transfusion constituted the main complication, occurring in 49% of cases. In our analysis of clinical data, the use of Lifebridge in cardiac intervention was shown to be feasible. Further prospective studies are warranted to identify patients who benefit from hemodynamic MCS support despite the increased rate of RBC transfusion due to challenges in access sites during cardiovascular procedures.

Myocardial perfusion quantification using simultaneously acquired 13 NH3 -ammonia PET and dynamic contrast-enhanced MRI in patients at rest and stress.

PURPOSE: Systematic differences with respect to myocardial perfusion quantification exist between DCE-MRI and PET. Using the potential of integrated PET/MRI, this study was conceived to compare perfusion quantification on the basis of simultaneously acquired 13 NH3 -ammonia PET and DCE-MRI data in patients at rest and stress. METHODS: Twenty-nine patients were examined on a 3T PET/MRI scanner. DCE-MRI was implemented in dual-sequence design and additional T1 mapping for signal normalization. Four different deconvolution methods including a modified version of the Fermi technique were compared against 13 NH3 -ammonia results. RESULTS: Cohort-average flow comparison yielded higher resting flows for DCE-MRI than for PET and, therefore, significantly lower DCE-MRI perfusion ratios under the common assumption of equal arterial and tissue hematocrit. Absolute flow values were strongly correlated in both slice-average (R2 = 0.82) and regional (R2 = 0.7) evaluations. Different DCE-MRI deconvolution methods yielded similar flow result with exception of an unconstrained Fermi method exhibiting outliers at high flows when compared with PET. CONCLUSION: Thresholds for Ischemia classification may not be directly tradable between PET and MRI flow values. Differences in perfusion ratios between PET and DCE-MRI may be lifted by using stress/rest-specific hematocrit conversion. Proper physiological constraints are advised in model-constrained deconvolution.

High on-treatment platelet reactivity and outcomes after percutaneous endovascular procedures in patients with peripheral artery disease.

BACKGROUND: High on-treatment platelet reactivity (HPR) predicts adverse cardiovascular events in patients with coronary artery disease. The impact of HPR in patients with peripheral artery disease (PAD) after peripheral endovascular procedures is unclear. PATIENTS AND METHODS: A total of 385 patients with PAD and successful percutaneous endovascular procedure were included. Patients received aspirin as a long-term treatment in addition to the P2Y12 receptor antagonist clopidogrel, as recommended after such a procedure for at least 1 month. Platelet function was assessed on a Multiplate analyzer. The primary endpoint was target lesion revascularization (TLR) at one year. Restenosis (≥ 75 %) in duplex sonography, mortality at one year and identification of independent predictors of TLR were secondary endpoints. RESULTS: TLR rates were similar in HPR and no-HPR patients (14.3 % vs. 12.7 %, hazard rate (HR) 0.94, 95 % CI 0.48 - 1.84, P = 0.86). Restenosis (≥ 75 %) in duplex sonography did not differ between the two study groups (15.6 % vs. 16.9 %, HR 1.16, 95% CI 0.62 - 2.12, P = 0.64). Independent predictors of TLR were intervention of restenotic lesions, total vessel occlusions and critical limb ischemia, but not HPR (adjusted HR 1.07, 95% CI 0.55 - 2.10, P = 0.84). No difference in mortality at one year was observed (1.3 % vs. 1.6 %, HR 1.28, 95 % CI 0.15 - 11.0, P = 0.82). CONCLUSIONS: In patients with PAD, HPR did not have a significant impact on outcomes within the first year after percutaneous endovascular intervention.

Endovascular therapy for steno-occlusive subclavian and innominate artery disease.

BACKGROUND: This study investigated the safety and outcome of endovascular therapy for steno-occlusive subclavian or innominate artery disease at a single center over a long period of more than 2 decades. METHODS AND RESULTS: We retrospectively analyzed all endovascular procedures of stenosis or occlusion of the subclavian or innominate artery between January 1990 and October 2013. During the observation period, a total of 130 procedures were attempted in 127 mostly symptomatic patients with stenosis (n=108; 83%) or occlusion (n=22; 17%) of the subclavian (n=119; 92%) and innominate (n=11; 8%) artery. The overall technical success rate was 97.7% (n=127/130). Accounting for the type of lesion, the success rate for stenosis was 100% (n=108/108) and for total occlusion, 86% (n=19/22). The periprocedural complication rate was low and included stroke, transient ischemic attack, and access site complications of 0.8%, 1.5%, and 3.8%, respectively. During a mean follow-up of 28 months the rate of restenosis (>70%) was 12%. Due to the overall low event rate no significant lesion or procedural risk factor for the development of restenosis could be identified. CONCLUSIONS: Stenosis and occlusion of the subclavian and innominate artery can be treated safely and successfully by endovascular therapy with excellent long-term patency.

Bare metal vs. drug-eluting stents for extracranial vertebral artery disease: a meta-analysis of nonrandomized comparative studies.

PURPOSE: To compare through meta-analysis the use of drug-eluting stents (DES) vs. bare metal stents (BMS) in the treatment of extracranial vertebral artery (EVA) disease. METHODS: A literature search of the PubMed database was conducted to identify English-language articles in which both BMS and DES stenting were performed for EVA stenosis by the same investigator(s). Further, eligible studies had to provide data on in-stent restenosis during follow-up. The search identified 9 nonrandomized studies that met the inclusion criteria. The random effects model was employed to pool data. Meta-regression analyses were performed to evaluate the relationships between risk of restenosis and the age of patients, the length of follow-up, or the percentage of male patients. RESULTS: Reported technical success was high (range 99.2%-100%) and comparable for BMS [100% (276/276)] and DES [99.4% (166/167)]. The use of DES was associated with significantly lower (p<0.0001) overall restenosis rates [8.2% (14/170) over follow-up periods averaging 16 to 43 months] compared to BMS [23.7% (68/287) over mean follow-up periods of 19 to 46 months]. Moreover, DES showed significantly lower symptomatic restenosis rates as compared to BMS [4.7% (8/169) for DES vs. 11.6% (32/275) for BMS; p=0.005]. There was no change in the risk of restenosis for any factor explored in the meta-regression analysis. CONCLUSION: This meta-analysis demonstrates that the use of DES for extracranial vertebral artery stenting significantly reduces both the rate of restenosis and recurrence of symptoms as compared to BMS. In future, randomized trials are needed to support these findings.

An autocalibrating algorithm for non-invasive cardiac output determination based on the analysis of an arterial pressure waveform recorded with radial artery applanation tonometry: a proof of concept pilot analysis.

We aimed to describe and evaluate an autocalibrating algorithm for determination of cardiac output (CO) based on the analysis of an arterial pressure (AP) waveform recorded using radial artery applanation tonometry (AT) in a continuous non-invasive manner. To exemplarily describe and evaluate the CO algorithm, we deliberately selected 22 intensive care unit patients with impeccable AP waveforms from a database including AP data obtained with AT (T-Line system; Tensys Medical Inc.). When recording AP data for this prospectively maintained database, we had simultaneously noted CO measurements obtained from just calibrated pulse contour analysis (PiCCO system; Pulsion Medical Systems) every minute. We applied the autocalibrating CO algorithm to the AT-derived AP waveforms and noted the computed CO values every minute during a total of 15 min of data recording per patient (3 × 5-min intervals). These 330 AT-derived CO (AT-CO) values were then statistically compared to the corresponding pulse contour CO (PC-CO) values. Mean ± standard deviation for PC-CO and AT-CO was 7.0 ± 2.0 and 6.9 ± 2.1 L/min, respectively. The coefficient of variation for PC-CO and AT-CO was 0.280 and 0.299, respectively. Bland-Altman analysis demonstrated a bias of +0.1 L/min (standard deviation 0.8 L/min; 95% limits of agreement -1.5 to 1.7 L/min, percentage error 23%). CO can be computed based on the analysis of the AP waveform recorded with AT. In the selected patients included in this pilot analysis, a percentage error of 23% indicates clinically acceptable agreement between AT-CO and PC-CO.

Simultaneous 18-FDG PET and MR imaging in lower extremity arterial disease.

Background: Simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) is a novel hybrid imaging method integrating the advances of morphological tissue characterization of MRI with the pathophysiological insights of PET applications. Aim: This study evaluated the use of simultaneous 18-FDG PET/MR imaging for characterizing atherosclerotic lesions in lower extremity arterial disease (LEAD). Methods: Eight patients with symptomatic stenoses of the superficial femoral artery (SFA) under simultaneous acquisition of 18-FDG PET and contrast-enhanced MRI using an integrated whole-body PET/MRI scanner. Invasive plaque characterization of the SFA was performed by intravascular imaging using optical coherence tomography. Histological analysis of plaque specimens was performed after directional atherectomy. Results: MRI showed contrast enhancement at the site of arterial stenosis, as assessed on T2-w and T1-w images, compared to a control area of the contralateral SFA (0.38 ± 0.15 cm vs. 0.23 ± 0.11 cm; 1.77 ± 0.19 vs. 1.57 ± 0.15; p-value <0.05). On PET imaging, uptake of 18F-FDG (target-to-background ratio TBR > 1) at the level of symptomatic stenosis was observed in all but one patient. Contrast medium-induced MR signal enhancement was detected in all plaques, whereas FDG uptake in PET imaging was increased in lesions with active fibroatheroma and reduced in fibrocalcified lesions. Conclusion: In this multimodal imaging study, we report the feasibility and challenges of simultaneous PET/MR imaging of LEAD, which might offer new perspectives for risk estimation.

Novel role of the CXC chemokine receptor 3 in inflammatory response to arterial injury: involvement of mTORC1.

Atherosclerosis, restenosis, and posttransplant graft atherosclerosis are characterized by endothelial damage, infiltration of inflammatory cells, and proliferation of smooth muscle cells. The CXCR3-activating chemokines interferon-gamma inducible protein 10 (IP10) and MIG (monokine induced by interferon-gamma) have been implicated in vascular repair and remodeling. The underlying molecular mechanisms, however, remain elusive. Here, we show that wire-mediated arterial injury induced local and systemic expression of IP10 and MIG, resulting in enhanced recruitment of CXCR3(+) leukocytes and hematopoietic progenitor cells. This was accompanied by profound activation of mammalian target of rapamycin complex (mTORC)1, increased reactive oxygen species production, apoptosis, and intimal hyperplasia. Genetic and pharmacological inactivation of CXCR3 signaling not only suppressed recruitment of inflammatory cells but also abolished mTORC1 activation, reduced reactive oxygen species generation, and blocked apoptosis of vascular cells, resulting in significant reduction of intimal hyperplasia in vivo. In vitro, stimulation of T cells with IP10 directly activated mTORC1 and induced generation of reactive oxygen species and apoptosis in an mTORC1-dependent manner. These results strongly indicate that CXCR3-dependent activation of mTORC1 directly links stimulation of the Th1 immune system with the proliferative response of intimal cells in vascular remodeling.

Role of bone marrow-derived cells in the genetic control of restenosis.

OBJECTIVE: Angiographic indexes of restenosis after coronary stent placement in patients show a bimodal pattern suggesting the existence of two populations with different risk of restenosis. This is reflected in the arterial remodeling response of inbred mouse strains arguing for a genetic control of the mechanisms leading to lumen narrowing. As bone marrow-derived cells (BMCs) contribute to vascular healing after arterial injury, we investigated the role of BMCs in the genetic control of restenosis. METHODS AND RESULTS: 129X1/SvJ mice developed significantly more neointima and late lumen loss compared to C57BL/6 mice. Gene expression analysis of intimal tissue revealed major differences in the expression of inflammatory and hematopoietic stem and progenitor cell-associated genes in response to arterial injury. In 129X1/SvJ mice stronger mobilization of lin(-)sca-1(+)CXCR4(+) cells was observed after vascular injury. Bone marrow transplantation identified the extent of neointima formation as clearly dependent on the genetic background of BMCs (ie, mice with 129X1/SvJ BMCs developed more intimal hyperplasia). The inflammatory response and the recruitment of BMCs to the site of arterial injury were significantly increased in mice with 129X1/SvJ BMCs. CONCLUSIONS: The genetically controlled mechanisms leading to lumen narrowing in vascular remodeling are dependent on mobilization and recruitment capacities of particular BMCs.

Real-world clinical experience with the percutaneous extracorporeal life support system: Results from the German Lifebridge® Registry.

BACKGROUND: The concept of percutaneous extracorporeal life support (ECLS) is based on immediate cardiovascular stabilization allowing for sufficient end-organ perfusion, thus improving the outcome in patients with circulatory arrest. Lifebridge® (Zoll Medical GmbH, Germany) is a portable ECLS device designed for rapid application due to its automated set-up. METHODS: A total of 60 tertiary cardiovascular centers were interrogated with regard to application and short-term results after use of Lifebridge ECLS system. Detailed data were collected by standardized case report forms in all centers consented to participate in the study. Demographic and clinical baseline characteristics of the patient population, procedural and follow-up data were recorded and analyzed. RESULTS: In total, 444 patients were analyzed regarding mortality. The detailed study cohort consisted of 112 patients. A total of 80% of the study subjects represented patients post cardiopulmonary resuscitation, 43% were in cardiogenic shock and 50% suffered from acute myocardial infarction. The survival rates were 36% immediately after device implementation and 16% after 30 days. Multivariable analysis revealed that only serum lactate concentration at admission could be proven as independent predictor of patients' outcome. Patients with lactate concentrations above 10 mmol/L exhibited > 95% mortality (p < 0.05 versus below 10 mmol/L). CONCLUSION: The present study provides real-world clinical data of patients treated with a transportable automated ECLS system. In conclusion, Lifebridge is a safely applicable cardiorespiratory stabilization tool associated with acceptable complication rates. Nevertheless, mortality rates were high in these critically ill patients, especially in those showing high lactate concentrations at admission.

EMAP-II downregulation contributes to the beneficial effects of rapamycin after vascular injury.

AIMS: Neointima formation after vascular injury is strongly associated with inflammation. Rapamycin inhibits human neointima formation and reduces expression of the proinflammatory cytokine endothelial-monocyte activating peptide II (EMAP-II) in vitro. Here we investigated the interplay between EMAP-II and rapamycin after vascular injury in vivo. METHODS AND RESULTS: In a mouse model of vascular injury, mice were either not treated, given everolimus, a rapamycin derivate, or subjected to simultaneous challenge with everolimus and EMAP-II. EMAP-II expression was measured in coronary artery smooth muscle cells (CASMC) and monocytic cells in vitro and in patients after percutaneous coronary intervention (PCI). After vascular injury, rapamycin reduced neointima formation and adventitial thickening. Immunohistochemistry revealed reduced EMAP-II protein expression and suppressed recruitment of inflammatory cells. Simultaneous challenge with EMAP-II counteracted these effects of rapamycin. Expression of EMAP-II and its inhibition by rapamycin was confirmed in CASMC and monocytic cells. In patients, EMAP-II upregulation was confined to PCI of distal coronary artery segments and profoundly suppressed by oral rapamycin treatment. CONCLUSION: These data suggest important yet unrecognized roles of EMAP-II and adventitial inflammation in neointima formation: Through inhibition of EMAP-II, rapamycin reduces the recruitment of inflammatory cells to the adventitia and supports an early and bland healing.

Endovascular Treatment for Steno-Occlusive Iliac Artery Disease: Safety and Long-Term Outcome.

We evaluated safety and long-term outcome of endovascular therapy for steno-occlusive iliac artery disease. All endovascular procedures of iliac artery lesions performed at our institution between 2001 and 2014 (n = 676) were retrospectively analyzed. The overall technical success rate was 99% and yielded 100% for stenoses (n = 596) and 95% for chronic total occlusions (n = 80). Lesion complexity defined by the Trans-Atlantic Inter-Society Consensus (TASC) II classification had no impact on success rates (TASC A + B vs C + D; 99.5% vs 98.6%, P = .359). During a median follow-up of 11 months, the overall rate of restenosis was 9.4%. After 1 and 3 years, the primary patency rates were 94% and 86% and the secondary patency rate was 100%, respectively. The TASC II classification had no impact on long-term patency rates (TASC A + B vs C + D; 86% vs 81%). In a multivariable analysis, stent diameter remained the only significant predictor for restenosis (hazard ratio: 0.58; 95% confidence interval: 0.41%-0.81%; P = .002). In this single-center retrospective study, endovascular therapy for steno-occlusive iliac artery disease was associated with high technical and clinical success rates as well as an excellent long-term patency rate irrespective of lesion complexity.

Drug-eluting stents versus bare metal stents for the prevention of restenosis in patients with renovascular disease.

AIMS: The aim of this study was to assess the impact of drug-eluting stents (DES) compared to bare metal stents (BMS) for the endovascular treatment of atherosclerotic renal artery stenosis (ARAS). METHODS AND RESULTS: We retrospectively evaluated all of our endovascular BMS and DES implantations performed in de novo ARAS between 2000 and 2014 at our institution. The occurrence of in-stent restenosis (ISR) detected by ultrasound or angiography, kidney function, blood pressure (BP), and the number of antihypertensive drugs were analysed as endpoints. Overall, 338 renal arteries were treated in 298 patients. BMS were implanted in 163 (48%), and DES in 175 lesions (52%). Of the 175 lesions treated with DES, 55 (31%) were treated with a BMS-in-DES hybrid technique. For reasons of comparability, only lesions treated with balloon sizes of 4-6.5 mm were included in the final analysis. After 12 months, the rate of ISR >50% was 18.6% in the BMS group and 7.2% in the DES group (p=0.031). None of the BMS-in-DES-treated (hybrid) lesions developed ISR (hybrid technique vs. BMS only p=0.008, hybrid technique vs. DES only p=0.034). Systolic BP and number of antihypertensive drugs remained unchanged in the BMS group but declined in the DES group (p=0.02). Renal function significantly deteriorated in the BMS group (p=0.03) but did not change significantly in the DES group (p=0.188). CONCLUSIONS: DES were superior to BMS in preventing ISR. Overall, the BMS-in-DES-technique (hybrid) achieved the lowest risk for ISR.

Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory.

Current knowledge about the molecular mechanisms of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) in the hippocampus and its function for memory formation in the behaving animal is limited. NMDAR-independent LTP in the CA1 region is thought to require activity of postsynaptic L-type voltage-dependent Ca2+ channels (Cav1.x), but the underlying channel isoform remains unknown. We evaluated the function of the Cav1.2 L-type Ca2+ channel for spatial learning, synaptic plasticity, and triggering of learning-associated biochemical processes using a mouse line with an inactivation of the CACNA1C (Cav1.2) gene in the hippocampus and neocortex (Cav1.2(HCKO)). This model shows (1) a selective loss of protein synthesis-dependent NMDAR-independent Schaffer collateral/CA1 late-phase LTP (L-LTP), (2) a severe impairment of hippocampus-dependent spatial memory, and (3) decreased activation of the mitogen-activated protein kinase (MAPK) pathway and reduced cAMP response element (CRE)-dependent transcription in CA1 pyramidal neurons. Our results provide strong evidence for a role of L-type Ca2+ channel-dependent, NMDAR-independent hippocampal L-LTP in the formation of spatial memory in the behaving animal and for a function of the MAPK/CREB (CRE-binding protein) signaling cascade in linking Cav1.2 channel-mediated Ca2+ influx to either process.