Lahr, Brian D.

Background Pericardiectomy for post-radiation constrictive pericarditis has been reported to generally have unfavorable outcomes. This study sought to evaluate surgical outcomes in a large cohort of patients undergoing pericardiectomy for radiation-associated pericardial constriction. Methods A retrospective analysis of all patients (≥18years) who underwent pericardiectomy for a diagnosis of constrictive pericarditis with a prior history of mediastinal irradiation from June 2002 to June 2019 was conducted. There were 100 patients (mean age 57.2±10.1 years, 49% females) who met the inclusion criteria. Records were reviewed to look at surgical approach, extent of resection, early mortality and late survival. Results The overall operative mortality was 10.1% (n=10). The rate of operative mortality decreased over the study period; however, the test of trend was not statistically significant (P=0.062). Hodgkin’s disease was the most common malignancy (64%) for which mediastinal radiation had been received. Only 27% patients had an isolated pericardiectomy, and concomitant pericardiectomy and valve surgery was performed in 46% patients. Radical resection was performed in 50% patients, whereas 47% patients underwent a subtotal resection. Prolonged ventilation (26%), atrial fibrillation (21%) and pleural effusion (16%) were the most common post-operative complications. The overall 1,5- and 10-years survival was 73.6%, 53.4% and 32.1% respectively. Increasing age (HR 1.044, 95%CI 1.017-1.073) appeared to have a significant negative effect on overall survival in the univariate model. Conclusion Pericardiectomy performed for radiation associated constrictive pericarditis has poor long-term outcomes. The early mortality, though high (~10%), has been showing a decreasing trend in the test of time.

Objective Activated platelets serve as a catalyst for thrombin generation. Furthermore, oral MHT may carry greater thrombotic risk than transdermal products. This study compared effects of oral and transdermal MHT on platelet characteristics including platelet‐derived microvesicles (MV) in recently menopausal women. Methods Platelets and MV were prepared from blood of a subset of women (n=117) enrolled in the Kronos Early Estrogen Prevention Study prior to and after 4 years of treatment with either oral conjugated equine estrogen (0.45 mg, oCEE), transdermal 17β estradiol (50 µg/day, tE2), each with intermittent progesterone (200 mg/day for 12 days a month), or placebo pills and patch. Results Platelet count, and activated platelet P‐selectin and fibrinogen‐binding receptor expression were similar across groups. Numbers of tissue factor positive and platelet‐derived MV increased significantly in the tE2 compared to placebo. Conclusions Four years of MHT did not increase thrombogenic characteristics of platelets. Thrombotic risk associated with oral MHT most likely involves liver‐derived proteins than platelets per se. Differential effects of oCEE and tE2 on circulating MV may reflect the hormonal composition of the two formulations on non‐genomic pathways in circulating platelets. Funding This work was supported by grants from the Aurora Foundation to the Kronos Longevity Research Institute, NIH HL90639, UL1TR00013 1 , American Heart Association‐ Scientist Development Grant, AHA 08‐30503Z, American Heart Association, Grant‐in‐Aid, 12GRNT12050147, and the Mayo Foundation.

Background Break down of the blood brain barrier and activation of brain cells are implicated in progression of deposition of β‐amyloid that is associated with the pathophysiology of Alzheimer's disease. A previous study from our group indicated that deposition of β‐amyloid may be reduced in the brains of menopausal women treated with transdermal 17β‐estradiol. This study aimed to determine the association of peripheral microvesicles carrying markers of cells of the neurovascular unit with β‐amyloid in the brains of menopausal women and if the association was affected by prior menopausal hormone treatments (MHT). Methods Menopausal women previously enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic underwent β‐amyloid positron emission tomography (PET) imaging of their brains 3 years following treatment with either placebo (PL, n=29), transdermal 17β‐estradiol (tE2; n=21), or oral conjugated equine estrogen (oCEE; n=17) for 4 years. Microvesicles (MV) were isolated from peripheral venous blood by differential centrifugation and analyzed by flow cytometry using fluorophore conjugated antibodies directed toward total tau, β‐amyloid 1‐42 (Ab1‐42), neuron specific class III β‐tubulin (Tuj1), microglia ionized calcium adaptor molecule 1(Iab‐1), glial fibrillar acid protein (GFAP), and low density lipoprotein receptor‐related protein 1. Principal components analysis was used to reduce the dimensionality of the 6 brain markers to 2 principal components (PCs). Proportional odds ordinal logistic regression analysis was used to regress deposition of β‐amyloid on the 2 PCs with and without adjustment for MHT group. Results Number of blood MV positive for Ab1‐42 differed significantly among MHT groups (median [IQR]: 6.06 [2.11, 12.55] in the PL; 2.49 [0.73, 3.59] in the tE2 and 4.96 [0.83, 10.31] in the oCEE; P=0.036). The first 2 PCs explain 58% of the variance of the 6 markers. PC#1 represented a contrast between MV‐Iab‐1 and the MV‐GFAP and MV‐Tuj1. In multivariable models, brain β‐amyloid load positively associated with the first PC after adjustment for MHT (P= 0.006). Conclusion MV derived from cells of the neurovascular unit can be detected in peripheral blood, and, when combined into summary scores, showed an association with deposition of β‐amyloid in the brain that is independent of MHT. Support or Funding Information Supported by grants from NIH P50 AG044170 and the Mayo Foundation This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Cerebrovascular reactivity to hypercapnia, an estimate of microvascular responses in the brain, is increased during menopausal hormone treatment (MHT) in postmenopausal women. It is unclear whether this effect of MHT continues beyond the treatment period. We hypothesized that prior MHT use would not affect cerebrovascular reactivity 3 years after treatment. In addition, we have previously shown that cerebrovascular reactivity is associated with vascular activation in postmenopausal women with elevated cardiovascular risk. We hypothesized that cerebrovascular reactivity is not associated with markers of intravascular cellular activation in postmenopausal women with low cardiovascular risk who are within 10 years of menopause. Cerebrovascular reactivity to hypercapnia was measured in 58 postmenopausal women from the Kronos Early Estrogen Prevention Study at Mayo Clinic 3 years after the cessation of MHT [oral conjugated equine estrogen (oCEE), n=15; transdermal 17β‐estradiol (tE2, n=22); or placebo (PLA, n=23)]. Cerebrovascular reactivity was estimated from the middle cerebral artery flow velocity (MCAv) response to hypercapnia. Mean arterial blood pressure (MAP) was measured continuously throughout the protocol. Fasting blood was analyzed for a set of 14 activation markers of platelet and endothelial cells, inflammation and thrombogenicity. Principal components (PC) analysis was used to reduce these measures to fewer dimensions on which the associations of intravascular cellular activation with cerebrovascular reactivity could be based. Women were 60±3 years of age with a body mass index of 28±4 Kg/m 2 . MAP (99±14 mmHg in PLA, 97±7 mmHg in tE2, 98±9 mmHg in oCEE; p>0.90) and MCAv (60±14 cm/s in PLA, 68±20 cm/s in tE2, 71±18cm/s in oCEE; p>0.16) did not differ among groups. Cerebrovascular reactivity did not differ among women based on previous MHT randomization (1.2±0.7 cm/s/mmHg in PLA, 1.4±1.0 cm/s/mmHg in tE2 and 1.7±1.0 cm/s/mmHg in oCEE; p>0.17). The 14 markers of intravascular cellular activation were reduced to five PC that did not differ based on prior MHT assignment. There was no overall association of cellular activation PC with cerebrovascular reactivity. Effects of MHT on cerebral microvascular reactivity do not extend beyond the time of menopausal hormone treatment. Intravascular cellular activation does not alter cerebrovascular reactivity to hypercapnia in postmenopausal women with low cardiovascular risk profiles 3 years after the cessation of MHT. Support or Funding Information NIH grant P50 AG44170 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Objective Blood thrombogenicity and vascular inflammation may influence development of white matter hyperintensities (WMH) in the brain. This study aimed to determine if menopausal hormone treatments (MHT) modified that association in recently menopausal women who were enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) at Mayo Clinic. Methods Women (n=95) underwent MRI prior to and at 18, 36 and 48 months after randomization to either transdermal 17β‐estradiol (tE2, n=30), conjugated equine estrogen (oCEE, n=29) both with progesterone for 12 days per month or placebo pills and patch (PBO, n=36). Fasting blood was analyzed for a set of 14 activation markers of platelets and endothelial cells, inflammation, and thrombogenicity. Principal components (PC) analysis was used to reduce dimensionality of these markers, and the first 5 PC identified were then assessed for association with treatment and changes in WMH. Results WMH increased in all groups over the 48 months of treatment with greater increases in the oCEE compared to tE2 and PBO (P=0.015). The 5 PC explained 62% of the variation in cellular activation markers. A global test of these 5 PC revealed a borderline association with treatment group (P=0.059), with the PC reflecting total platelet count, platelet microaggregates and ATP secretion showing higher scores in the oCEE compared to the other groups (P=0.006). The change in WMH over the 48 months of MHT showed an overall association with the 5 PC (P=0.026), the most prominent of which was the first PC reflecting vascular inflammation by number of blood microveicles (MV) from activated monocytes and endothelial cells and MV positive for intercellular adhesion molecule 1 (P=0.001). There was no evidence that this association differed by MHT. Conclusion Markers of blood thrombogenicity and inflammation may influence development of WMH in the brain but this relationship may be influenced by factors other than the type of MHT used in the KEEPS study. Support or Funding Information NIH P50 AG44170 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

AbstractBackgroundOptimal timing of cardiovascular implantable electronic device (CIED) re‐implantation following device removal due to infection is undefined. Multinational guidelines reflect this and include no specific recommendation for this timing, while others have recommended waiting at least 14 days in cases of CIED related infective endocarditis (CIED‐IE). The current work seeks to clarify this issue.MethodsWe retrospectively reviewed institutional data at Mayo Clinic, Minnesota of patients aged ≥ 18 years who developed CIED‐IE from January 1, 1991 to February 1, 2016. CIED‐IE was defined as echocardiogram reported device lead or valvular vegetation. Regression analyses were used to relate the risk of clinical outcomes to the interval between CIED removal and re‐implantation and the location of vegetations.ResultsA total of 109 patients met study inclusion criteria. A majority (68.8%) of patients were men and the median age was 68.0 years. Transoesophageal echocardiogram (TEE) was performed in 95.4% of patients, with valve vegetations detected in 33.9% (n = 37). Survival analysis comparing patients in whom device re‐implantation was < 14 days vs. ≥14 days, and further categorized by those with and without valve vegetation, showed a significant difference (P = 0.028); patients with valve vegetation and reimplantation interval < 14 days had the lowest (58.7%) 12‐month survival. When adjusted for valve vegetation, longer time interval for reimplantation trended toward increased hospital length of stay (P = 0.079).ConclusionOur findings suggest that the recommended 14‐day delay between CIED extraction and re‐implantation in CIED‐IE patients is associated with a survival benefit, but longer length of hospital stay following re‐implantation.

Risk of CAD increases at menopause and platelets contribute to the etiology of CAD. We hypothesized that individual variation in platelet procoagulant activity at menopause correlates with the extent of CAD as reflected by coronary artery calcification ( CAC ). We developed several novel and global assays of platelet procoagulant activity: dense (ATP release) and alpha (P‐selectin expression) granule secretion and GPα IIb β 3 fibrinogen‐binding (PAC1 binding) to ADP stimulation, and prostaglandin E 1 (PEG 1 ) sensitivity as a surrogate for prostacyclin sensitivity. Platelets were prepared from venous blood collected from women screened for the Kronos Early Estrogen Prevention Study (n=125; mean±SD age=52.5±2.4 years) within 19.4±9.2 months of last menses. Baseline CAC score was determined. Of conventional CAD risk factors, only systolic blood pressure correlated with positive CAC score (n=23). ATP secretion tended to be less in women with positive CAC scores and was negatively correlated with blood glucose (P<0.001). P‐selectin expression and PAC1 binding increased with total cholesterol (P<0.05). PEG 1 sensitivity increased with increasing age and waist circumference (P<0.05). These results indicate that platelet functions change with age and in association with conventional risk factors for the disease in women at menopause. Supported by the Kronos Longevity Research Institute and NIH HL90639.

Introduction: Cardiovascular implantable electronic devices (CIED) infections are frequently complicated with bloodstream infection (BSI). Complete device removal and prolonged antimicrobial therapy is essential for cure. The frequency of persistent BSI after source control (device extraction) is not well described. This study aims to assess the utility of repeat blood cultures (BC) after device extraction as recommended by the American Heart Association (AHA) guidelines. Methods: We selected patients who presented with BSI in the setting of CIED infection and underwent device removal at Mayo Clinic Rochester between 2012 and 2017. Cases where BC were not drawn prior to extraction, or repeated within 72 hours of device extraction, or met criteria for contamination were excluded. Results: Of 656 patients who underwent CIED extraction for device infection, 190 with post-extraction BC met study criteria. Among the final study cohort (Table 1), 159 patients had negative BC, while 31 had positive BC following CIED extraction. Pre-extraction, the most common causative organism was Staphylococcus aureus (91/190, 48%) (Figure 1a). Post-extraction, 22 of the 31 (71%) cases of persistent BSI were due to S. aureus (Fig 1b). The median duration of BSI was not significantly different between negative and positive BC groups (3 versus 4 days, p=0.92). Conclusions: Majority of patients had resolution of BSI after CIED extraction. S. aureus was the most common cause of persistent BSI post-extraction. Our findings support the AHA guidelines of repeating BC after device extraction, especially for S aureus .

Abstract Background The use of extracorporeal membrane oxygenation (ECMO) in critically ill adults is increasing. There are currently no guidelines for antimicrobial prophylaxis. We analyzed 7 years of prophylactic antimicrobial use across 3 time series for patients on ECMO at our institution in the development, improvement, and streamlining of our ECMO antimicrobial prophylaxis protocol. Methods In this quasi-experimental interrupted time series analysis, we evaluated the impact of an initial ECMO antimicrobial prophylaxis protocol, implemented in 2014, on antimicrobial use and National Healthcare Safety Network–reportable infection rates. Then, following a revision and streamlining of the protocol in November 2018, we reevaluated the same metrics. Results Our study population included 338 intensive care unit patients who received ECMO between July 2011 and November 2019. After implementation of the first version of the protocol, we did not observe significant changes in antimicrobial use or infection rates in these patients; however, following revision and streamlining of the protocol, we demonstrated a significant reduction in broad-spectrum antimicrobial use for prophylaxis in patients on ECMO without any evidence of a compensatory increase in infection rates. Conclusions Our final protocol significantly reduces broad-spectrum antimicrobial use for prophylaxis in patients on ECMO. We propose a standard antimicrobial prophylaxis regimen for patients on ECMO based on current evidence and our experience. Summary: There are no guidelines for antimicrobial prophylaxis in patients on extracorporeal membrane oxygenation (ECMO). A rational approach employing concepts of antimicrobial stewardship can drive logical antimicrobial selection for prophylaxis in patients on ECMO without adversely impacting outcomes.

Background: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer’s disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers. Objective: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women. Methods: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17β-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1–42 (Aβ1–42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs. Results: Only the number of microvesicles positive for Aβ1–42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p = 0.045). Conclusion: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition.