Thrombectomy using suction filtration and veno-venous bypass: single center experience with a novel device.

OBJECTIVES: To describe the first single center experience with a novel aspiration thrombectomy device. BACKGROUND: The appearance of inferior vena cava or right-sided intracardiac thrombus may prompt consideration of percutaneous thrombectomy as a method to prevent new or worsening pulmonary embolism (PE). The AngioVac is a novel thrombectomy device composed of a cannula and extracorporeal circuit with filter for pump-assisted removal of intravascular debris which is coupled with a reinfusion catheter for return of blood to the patient. The device has been approved by the United States Food and Drug Administration since 2009. This report represents the first significant case series describing its use, feasibility and outcomes in evacuating large caval thrombi or intracardiac masses in PE. METHODS: This is a retrospective analysis of patient and case characteristics and in-hospital clinical outcomes of AngioVac thrombectomy in 14 consecutive patients treated between April 2010 and July 2013 at our institution. RESULTS: Fourteen consecutive patients (mean age 50, 64% female) underwent 15 AngioVac procedures over 40 months. Indications included intracardiac mass (73%), acute PE (33%), and caval thrombus (73%). Four patients (27%) were in shock at the start of the procedure. Peri-procedure mortality was 0% and in-hospital mortality was 13% at a mean follow-up of 23 days. There were no pulmonary hemorrhages, strokes or myocardial infarctions. Though 73% had a post procedural drop in hematocrit, only two bleeding events were related to access site and required a transfusion. CONCLUSIONS: AngioVac thrombectomy is feasible in critically ill patients with acute DVT or PE and large caval thrombi or intracardiac masses.

Popliteal venous aneurysms: characteristics, management strategies, and clinical outcomes--a modern single-center series.

BACKGROUND: Popliteal vein aneurysm (PVA) may be an incidental finding on imaging, but often presents in the context of acute venous thromboembolism (VTE). The role of anticoagulation with or without surgical excision versus expectant management is ill defined. METHODS: In this single-center, retrospective, cohort study, patient records from January 2002 to December 2013 were queried for terminology consistent with PVA. Demographic data and clinical outcomes were extracted via chart review. RESULTS: A total of 21 patients with PVA were identified (57% male). Mean follow-up was 38 ± 31 months. Mean PVA diameter was 2.5 ± 1.1 cm; 67% were saccular (with the remainder being fusiform), 19% contained thrombus, 67% were left sided, and bilateral PVA was present in 24% of cases. At the time of PVA diagnosis, 14% had pulmonary embolism. Treatment consisted of observation only (62%), anticoagulation (19%), surgery (5%), or both anticoagulation and surgery (14%). There were no recurrences of VTE once treated, although there was 1 acute deep venous thrombosis in a patient who was managed conservatively. Two patients had recurrent PVA after surgery, and there were 2 surgical complications (transient foot drop and hematoma). CONCLUSIONS: PVA is associated with VTE. Based on our series, it is unclear if incidentally discovered PVA (without VTE) warrants treatment with anticoagulation and/or surgical repair. Further multicenter studies are needed to establish the indications for safety and durability of surgery.

Increased local cytokine production at culprit superficial femoral artery plaques.

Characterization of local inflammation at culprit superficial femoral artery (SFA) stenosis has not been studied. We hypothesized that arterial cytokine concentrations would be greater at sites of stenosis. Twenty patients with ≥50 % angiographic stenosis of the SFA had blood drawn just proximal to the lesion and from a contralateral site free of disease. A microplate immunoassay was used to determine the concentrations of 42 distinct cytokines and growth factors. Exact conditional logistic analysis was used to compare measures at the two sites with interaction terms describing clinical factors used to identify difference mediators. Interaction terms identified clinical factors that could predict cytokine levels. The concentrations of soluble CD40 ligand (sCD40L; mean 212 and 177 pg/ml, p = 0.01) and tumor necrosis factor beta (TNF-B; mean 16.6 and 15.9 pg/ml, p = 0.04) were increased immediately proximal to areas of stenosis. Factors associated with greater concentrations at sites of stenosis were bilateral ankle-brachial index ≤0.90 (p = 0.04), no statin use (p = 0.02), claudication (p = 0.03), low leukocyte count (p = 0.03), absence of limb ischemia (p = 0.04) and lack of aspirin or clopidogrel therapy (p ≤ 0.06). Greater concentrations of sCD40L and TNF-B at sites of stenosis suggest that these cytokines play a role in the pathogenesis of symptomatic SFA disease. Our results also suggest that statin, aspirin and clopidogrel therapy may attenuate localized inflammation in the SFA, though due to a small sample size and the use of multiple comparisons across groups, these findings can be viewed as hypothesis generating only. In conclusion, selected cytokines are heightened at culprit SFA lesions and inflammation may be modulated by statin and antiplatelet therapy.

Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation.

Left ventricular (LV) hypertrophy commonly develops in response to chronic hypertension and is a significant risk factor for heart failure and death. The serine-threonine phosphatase calcineurin (Cn)A plays a critical role in the development of pathological hypertrophy. Previous experimental studies in murine models show that estrogen limits pressure overload-induced hypertrophy; our purpose was to explore further the mechanisms underlying this estrogen effect. Wild-type, ovariectomized female mice were treated with placebo or 17beta-estradiol (E2), followed by transverse aortic constriction (TAC), to induce pressure overload. At 2 weeks, mice underwent physiological evaluation, immediate tissue harvest, or dispersion of cardiomyocytes. E2 replacement limited TAC-induced LV and cardiomyocyte hypertrophy while attenuating deterioration in LV systolic function and contractility. These E2 effects were associated with reduced abundance of CnA. The primary downstream targets of CnA are the nuclear factor of activated T-cell (NFAT) family of transcription factors. In transgenic mice expressing a NFAT-activated promoter/luciferase reporter gene, E2 limited TAC-induced activation of NFAT. Moreover, the inhibitory effects of E2 on LV hypertrophy were absent in CnA knockout mice, supporting the notion that CnA is an important target of E2-mediated inhibition. In cultured rat cardiac myocytes, E2 inhibited agonist-induced hypertrophy while also decreasing CnA abundance and NFAT activation. Agonist stimulation also reduced CnA ubiquitination and degradation that was prevented by E2; all in vitro effects of estrogen were reversed by an estrogen receptor (ER) antagonist. These data support that E2 reduces pressure overload induced hypertrophy by an ER-dependent mechanism that increases CnA degradation, unveiling a novel mechanism by which E2 and ERs regulate pathological LV and cardiomyocyte growth.

Combined immunoelectron microscopic and computer-assisted image analyses to detect advanced glycation end-products in human myocardium.

Advanced glycation end-products (AGEs) result from oxidation-reduction reactions that ensue when a sugar becomes adducted to a protein. AGEs cause various complications of diabetes mellitus (DM). Experimental and clinical evidence suggest that AGEs also contribute to the complications of hypertension (HTN). Little is known about the abundance and localization of AGEs in human myocardium. In a few light microscopic studies, the AGE carboxymethyl lysine (CML) has been immunolabeled and localized virtually exclusively to the walls of small arteries. To more precisely delineate the abundance and localization of CML, we developed an immunoelectron microscopic (IEM) detection method using anti-CML monoclonal antibody 6D12 in conjunction with computer-assisted image analysis. Antibody was pre-absorbed with purified AGE-bovine serum albumin to assure specificity. Antigen-antibody (ag-ab) complexes were individually identified with protein A-conjugated colloidal gold and counted with an automated system. We applied this method in 21 patients (pts) undergoing epicardial biopsy during coronary bypass grafting (CBG) [20 M, 1 F; mean age 65 +/- 7.4 (+/- SEM) years]. Seven pts had neither DM nor HTN, seven had HTN, and seven had DM + HTN. In contrast to the prior light microscopic studies, we detected CML scattered throughout the cardiomyocyte in all pts, but in widely varying amounts. Ag-ab complexes were abundant in sections through myofilaments (mean count 23.6 +/- 9.2 per microm(2), range 9.4-48) and even more so in mitochondria (mean count 34.4 +/- 11.9 per microm(2), range 14.1-68.2, P < 0.001 vs. myofilaments). CML was also detected in vascular endothelial cells. There were no statistically significant differences based on presence or absence of HTN or DM. In conclusion, our IEM method is the first to provide detailed delineation of the localization and abundance of CML in myocardium. CML is very prevalent in CBG pts, suggesting that AGEs could play a role in abnormal cardiomyocyte function, including altered energy metabolism.

Abundance, localization, and functional correlates of the advanced glycation end-product carboxymethyl lysine in human myocardium.

Advanced glycation end-products (AGEs) play a role in the pathophysiology of diabetes mellitus (DM) and possibly hypertension (HTN). In experimental DM, AGEs accumulate in myocardium. Little is known about AGEs in human myocardium. We quantified abundance, localization, and functional correlates of the AGE carboxymethyl lysine (CML) in left ventricular (LV) myocardium from patients undergoing coronary bypass grafting (CBG). Immunoelectron microscopy was used to quantify CML in epicardial biopsies from 98 patients (71 M, 27 F) with HTN, HTN + DM or neither (controls), all with normal LV ejection fraction. Myofilament contraction-relaxation function was measured in demembranated myocardial strips. Echocardiography was used to quantify LV structure and function. We found that CML was abundant within cardiomyocytes, but minimally associated with extracellular collagen. CML counts/µm2 were 14.7% higher in mitochondria than the rest of the cytoplasm (P < 0.001). There were no significant sex or diagnostic group differences in CML counts [controls 45.6 ± 3.6/µm2 (±SEM), HTN 45.8 ± 3.6/µm2, HTN + DM 49.3 ± 6.2/µm2; P = 0.85] and no significant correlations between CML counts and age, HgbA1c or myofilament function indexes. However, left atrial volume was significantly correlated with CML counts (r = 0.41, P = 0.004). We conclude that in CBG patients CML is abundant within cardiomyocytes but minimally associated with collagen, suggesting that AGEs do not directly modify the stiffness of myocardial collagen. Coexistent HTN or HTN + DM do not significantly influence CML abundance. The correlation of CML counts with LAV suggests an influence on diastolic function independent of HTN, DM or sex whose mechanism remains to be determined.

Proximal versus distal embolic protection for carotid artery stenting: a national cardiovascular data registry analysis.

OBJECTIVES: The aim of this study was to compare the stroke/death rates between proximal embolic protection devices (P-EPDs) and distal filter embolic protection devices (F-EPDs) in elective carotid artery stenting (CAS). BACKGROUND: P-EPDs have theoretical advantages that may make them superior to F-EPDs for stroke prevention during CAS. METHODS: We examined 10,246 consecutive elective CAS procedures performed with embolic protection in the NCDR CARE registry between January 2009 and March 2013. We analyzed crude and propensity-matched rates of in-hospital combined death/stroke in patients treated with P-EPDs versus F-EPDs. Secondary analyses included 30-day adverse event rates and stroke rates by the involved cerebrovascular territory. RESULTS: P-EPDs were used in 590 of 10,246 cases (5.8%). Patients treated with P-EPDs had higher rates of symptomatic lesion status (46.8% vs. 39.7%, p<0.001), atrial fibrillation/flutter (16.1% vs. 13.0%, p=0.03), and history of a neurological event (51.2% vs. 46.6%, p=0.03). In unadjusted and propensity-matched analyses, differences in in-hospital stroke/death between P-EPD and F-EPD cohorts were nonsignificant (1.5% vs. 2.4%, p=0.16 and 1.6% vs. 2.0%, p=0.56, respectively). For patients with available data (n=7,693, 75.1%), 30-day adverse events rates were similar for P-EPDs and F-EPDs before (2.5% vs. 4.2%, p=0.07) and after (2.7% vs. 4.0%, p=0.22) propensity matching. CONCLUSIONS: Use of a P-EPD during CAS was associated with low rates of in-hospital stroke/death similar to those with an F-EPD in the first comparative effectiveness study of the devices. An adequately powered randomized trial comparing clinical outcomes between these devices is unlikely to be feasible.

The Massachusetts General Hospital Pulmonary Embolism Response Team (MGH PERT): creation of a multidisciplinary program to improve care of patients with massive and submassive pulmonary embolism.

New and innovative tools have emerged for the treatment of massive and submassive pulmonary embolism (PE). These novel treatments, when considered alongside existing therapy, such as anticoagulation, systemic intravenous thrombolysis, and open surgical pulmonary embolectomy, have the potential to improve patient outcomes. However, data comparing different treatment modalities are sparse, and guidelines provide only general advice for their use. Treatment decisions rest on clinician expertise and institutional resources. Because various medical and surgical specialties offer different perspectives and expertise, a multidisciplinary approach to patients with massive and submassive PE is required. To address this need, we created a novel multidisciplinary program - the Massachusetts General Hospital (MGH) Pulmonary Embolism Response Team (PERT) - which brings together multiple specialists to rapidly evaluate intermediate- and high-risk patients with PE, formulate a treatment plan, and mobilize the necessary resources to provide the highest level of care. Development of a clinical, educational, and research infrastructure, as well as the creation of a national PERT consortium, will make our experience available to other institutions and serve as a platform for future studies to improve the care of complex patients with massive and submassive PE.

Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling.

BACKGROUND: Hypertension (HTN) causes concentric left ventricular remodeling, defined as an increased relative wall thickness or overt left ventricular hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction. It is not known whether the myofilament contributes to diastolic dysfunction in patients with concentric remodeling. METHODS AND RESULTS: Intraoperative myocardial biopsies were obtained in 15 male patients undergoing coronary bypass grafting, all with normal left ventricular ejection fraction and wall motion. Eight patients had a history of HTN and concentric remodeling. Seven without HTN or remodeling served as controls. Myocardial strips were dissected and demembranated with detergent. Isometric tension was measured and sinusoidal length perturbation analysis performed at sarcomere length 2.2 µm and pCa 8 to 4.5. Sinusoidal analysis provides estimates of cross-bridge dynamics, including rate constants of attachment and detachment and cross-bridge attachment time. The normalized isometric tension-pCa relation was similar in HTN and controls. However, cross-bridge attachment time was significantly prolonged at submaximal [Ca(2+)] (pCa ≥6.5) in HTN patients. Analysis of protein phosphorylation revealed ≈25% reduction in phosphorylation of troponin I in HTN patients (P<0.05). CONCLUSIONS: Compared with controls, patients with HTN and concentric remodeling display prolonged cross-bridge attachment time at submaximal [Ca(2+)] without a change in the tension-pCa relation. Prolonged cross-bridge attachment time implicates altered cross-bridge dynamics as a cause of slowed relaxation in these patients. This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism.

Hypoxia decreases expression of soluble guanylate cyclase in cultured rat pulmonary artery smooth muscle cells.

Nitric oxide (NO) has an important role in modulating the pulmonary vascular tone. NO acts, in part, by stimulating soluble guanylate cyclase (sGC) to synthesize the intracellular second messenger cyclic GMP. In vascular smooth muscle cells, sGC is a heterodimer composed of alpha1 and beta1 subunits. The objective of this study was to test whether oxygen concentration regulates sGC expression in cultured rat pulmonary artery smooth muscle cells (rPaSMC). rPaSMC were exposed to 0, 3, and 20% oxygen for 1-48 h, and sGC subunit mRNA levels were measured. Compared with rPaSMC exposed to 20% oxygen, sGC alpha1 and beta1 subunit mRNA levels were markedly decreased in rPaSMC exposed to 0% and 3% oxygen. The decrease in sGC subunit mRNA levels in hypoxic rPaSMC was detected as early as 6 h of exposure. Compared with rPaSMC exposed to 20% oxygen, exposure of rPaSMC to 3% oxygen progressively decreased sGC subunit protein levels at 24 and 48 h. There was also a 30% and 50% decrease in sGC enzyme activity in cells exposed to hypoxia for 24 and 48 h (P < 0.05 and P < 0.001, respectively, as compared with cells maintained in normoxia). These results demonstrate that hypoxia decreases sGC expression in cultured pulmonary artery smooth muscle cells and suggest that, in hypoxic vascular smooth muscle, decreased cyclic GMP synthesis may limit the vasodilator response to NO.

Modulation of inducible nitric oxide synthase by hypoxia in pulmonary artery endothelial cells.

The effects of hypoxia on the regulation of inducible nitric oxide synthase (NOS) 2 expression were examined in cultured rat pulmonary microvascular endothelial cells (EC). EC did not express NOS 2 mRNA or protein when exposed to normoxia or hypoxia unless they were pretreated with interleukin (IL)-1beta and/or tumor necrosis factor (TNF)-alpha for 24 h. Induction of NOS 2 by IL-1beta+TNF-alpha was significantly attenuated by concomitant exposure of EC to hypoxia or treatment of EC with antioxidants such as tiron, diphenyliodonium, and catalase, suggesting that NOS 2 expression is dependent on the production of reactive oxygen species. Degradation of IkappaB and activation of NF-kappaB, which were both induced by treatment of EC with cytokines, were not altered when the cells were exposed to hypoxia, suggesting that the modulation of NOS 2 expression by hypoxia is unrelated to NF-kappaB activation. Following stimulation with IL-1beta+TNF-alpha for 24 h, incubation of EC in normoxia resulted in a progressive decline in NOS 2 expression and a calculated half-life of approximately 6 h for NOS 2 mRNA. Hypoxia significantly prolonged the half-life of NOS 2 mRNA (17 h, P < 0.05 versus normoxic EC). The half-life of NOS 2 mRNA was also prolonged by actinomycin D treatment (19.5 and 29.5 h for normoxic and hypoxic EC, respectively), suggesting that transcription of an RNA destabilizing factor or RNAse contributes to NOS 2 mRNA degradation. In EC transiently transfected with the rat NOS 2 promoter, hypoxia and the combination of IL-1beta+TNF-alpha independently increased promoter activity 2.2- and 3-fold, respectively. As opposed to the attenuating effect that hypoxia had on IL-1beta+TNF-alpha- dependent induction of NOS 2 gene expression, the concomitant treatment with IL-1beta+TNF-alpha and hypoxia synergistically increased NOS 2 promoter activity 17.6-fold. Taken together, these results suggest that hypoxia alone does not induce NOS 2 expression in cultured pulmonary microvascular EC, but may modulate cytokine induction of this enzyme at pretranscriptional, transcriptional, and posttranscriptional levels.