Kiran Tam

Hypertension in Response to AT1-AA: Role of Reactive Oxygen Species in Pregnancy-Induced Hypertension

BACKGROUND Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) and reactive oxygen species (ROS) are implicated in the pathophysiology of preeclampsia. The objective of this study was to determine the role of AT1-AA to stimulate placental oxidative stress in vivo and role ROS in mediating hypertension in response to AT1-AA during pregnancy. METHODS To achieve these goals, blood pressure (mean arterial pressure (MAP)) and ROS were analyzed in AT1-AA-induced hypertensive pregnant rats in the presence and absence of a superoxide dismutase mimetic, tempol. Rat AT1-AA (1:50) and tempol (30 mg/kg/day) were administered to pregnant rats beginning on day 12 of gestation. On day 19, MAP was analyzed and tissues collected for ROS analysis via lucigenin chemiluminescence. RESULTS MAP increased from 101 ± 2 normal pregnant (NP) rats to 116 ± 2 mm Hg in chronic AT1-AA infused rats (P = 0.002). Placental basal and NADPH oxidase stimulated ROS was 29 ± 6 and 92 ± 10 relative light units (RLUs) in NP rats. These levels increased to 159 ± 29 (P < 0.0001) and 287 ± 60 RLUs (P < 0.006) in AT1-AA infused rats. MAP in AT1-AA + tempol rats was 109 ± 2 mm Hg, no difference than tempol-treated controls (109 ± 3 mm Hg). Administration of tempol decreased basal and NADPH-stimulated placental ROS in AT1-AA-treated rats (121 ± 13; 262 ± 21 RLUs). Basal and NADPH-stimulated ROS in tempol-treated controls were 69 ± 24; 141 ± 33 RLUs. CONCLUSION This study indicates that AT1-AAs contribute to placental oxidative stress; one mechanism whereby the AT1-AA mediates hypertension during pregnancy.

Endothelin type A receptor antagonist attenuates placental ischemia–induced hypertension and uterine vascular resistance

OBJECTIVE We sought to determine the effect of an endothelin type A receptor antagonist (ETA) on uterine artery resistive index (UARI) and mean arterial pressure (MAP) in a placental ischemia rat model of preeclampsia produced by reduction in uterine perfusion pressure (RUPP). STUDY DESIGN UARI was assessed by Doppler velocimetry in RUPP and normal pregnant controls (NP) on gestational days (GD) 12, 15, and 18. UARI was also determined on GD 18 in NP and RUPP pregnant dams after pretreatment with ETA. MAP was recorded on GD 19. RESULTS The RUPP group had a higher MAP and UARI on GD 15 and 18 than the NP group. Pretreatment with ETA attenuated both the MAP and GD-18 UARI in the RUPP group without affecting these parameters in the NP group. CONCLUSION The improvement in UARI could be one potential mechanism for the reduction in MAP in response to ETA in pregnant dams with ischemic placentas.

Standardized Mississippi Protocol Treatment of 190 Patients with HELLP Syndrome: Slowing Disease Progression and Preventing New Major Maternal Morbidity

Objective. To evaluate the effectiveness of the Mississippi Protocol (MP) to treat HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Methods. Uniform early initiation of MP (corticosteroids, magnesium sulfate, systolic blood pressure control) was studied prospectively in patients admitted with severe preeclampsia/class 1 or class 2 HELLP syndrome. Results. One hundred and ninety patients between 2000 and 2007 received MP without suffering maternal death, stroke, or liver rupture. Only 39 of 163 patients (24%) not class 1 when MP began progressed to class 1 disease; only 18.2% of class 1 and 2.4% of class 2 subsequently developed major maternal morbidity. Conclusion. Early initiation of MP inhibits HELLP syndrome disease progression and severity.

Role of reactive oxygen species during hypertension in response to chronic antiangiogenic factor (sFlt-1) excess in pregnant rats.

BACKGROUND Preeclampsia is associated with increased levels of reactive oxygen species (ROS) and the antiangiogenic factor, soluble fms-like tyrosine kinase-1 (sFlt-1). Moreover, recent studies have indicated that chronic sFlt-1 excess causes hypertension in pregnant animals. The purpose of this study was to evaluate the role of ROS in mediating sFlt-1-induced hypertension in the pregnant rat. METHODS Mean arterial pressure (MAP), and plasma sFlt-1 and tissue ROS levels were measured in the following groups: (i) pregnant controls; (ii) sFlt-1-treated pregnant rats; (iii) Tempol-treated pregnant rats; (iv) sFlt-1- and Tempol-treated pregnant rats. RESULTS MAP increased from 104 ± 2 mm Hg in pregnant control rats to 118 ± 3 mm Hg (P = 0.002) in sFlt-1-infused rats. Basal and nicotinamide adenine dinucleotide phosphate (NADPH)-stimulated levels of tissue ROS were increased in response to excess sFlt-1 during pregnancy. Pretreatment with Tempol attenuated oxidative stress and hypertension in response to sFlt-1. CONCLUSIONS ROS play an important role in mediating hypertension in response to chronic sFlt-1 excess during pregnancy.

Approaches to reduce urinary tract injury during management of placenta accreta, increta, and percreta: a systematic review

Objective. A systematic review of the literature was conducted to answer the following question: are there enhancements to standard peripartum hysterectomy technique that minimize unintentional urinary tract (UT) injury in pregnancies complicated by invasive placental attachment (INPLAT)? Methods. A PubMed search of English language articles on INPLAT published by June 2010 was conducted. Data regarding the following parameters was required for inclusion in the quantitative analysis of the review’s objective: (1) type of INPLAT, (2) details pertaining to medical and surgical management of INPLAT, and (3) complications, if any, associated with management. An attempt was made to identify approaches that may lower the risk of unintentional UT injury. Results. Most cases (285 of 292) were managed by hysterectomy. There were 83 (29%) cases of unintentional UT injury. Antenatal diagnosis of INPLAT lowered the rate of UT injury (39% vs. 63%; P = 0.04). Information regarding surgical technique or medical management was available for 90 cases; 14 of these underwent a standard hysterectomy technique. Methotrexate treatment and 11 modifications of the surgical technique were associated with 16% unintentional UT injury rate as opposed to 57% for standard hysterectomy (P = 0.002). The use of ureteral stents reduced risk of urologic injury (P = 0.01). Multiple logistic regression analysis identified antenatal diagnosis as the significant predictor of an intact UT. Conclusions. Antenatal diagnosis of INPLAT is paramount to minimize UT injury. Utilization of management modifications identified in this review may reduce urologic injury due to INPLAT.

Seeking the mechanism(s) of action for corticosteroids in HELLP syndrome: SMASH study

INTRODUCTION Administration of dexamethasone to the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome patients (10 mg intravenously [IV] every 12 hours) shortens the disease course and reduces maternal morbidity in patients treated at the University of Mississippi Medical Center (UMMC), associated with this severe form of preeclampsia. However, the pathophysiological mechanisms involved with this intervention remain unclear. OBJECTIVE We sought to investigate the potential role of IV dexamethasone to restore the imbalance among antiangiogenic and inflammatory factors known to be significantly elevated in women with HELLP syndrome. STUDY DESIGN This was a single-center prospective study of women diagnosed with HELLP syndrome who were treated for IV dexamethasone at UMMC. Blood was drawn prior to dexamethasone administration and again 12 and 24 hours after the initial dexamethasone administration. Enzyme-linked immune assays were used to measure circulating inflammatory cytokines and antiangiogenic factors. A repeated-measures analysis of variance was used to analyze the data collected before, after, and during dexamethasone administration. RESULTS Seventeen women with HELLP syndrome were enrolled in this study. Dexamethasone significantly decreased evidence of hemolysis (P = .002) and liver enzymes (P = .003), and significantly increased platelets (P = .0001) within 24 hours of administration. Circulating interleukin-6 levels after 24 hours were decreased (P < .001); soluble fms-like tyrosine kinase-1 and soluble endoglin were also significantly decreased by 24 hours after dexamethasone administration (P < .002 and P < .004, respectively). There were no significant differences in circulating levels of placental growth factor (P = .886) due to dexamethasone administration. Angiotensin II receptor autoantibody levels were unchanged by dexamethasone administration. CONCLUSION We conclude that 1 important mechanism of dexamethasone administration is to blunt the release of both antiangiogenic and inflammatory factors suggested to play role in the pathophysiology of HELLP syndrome.

Postpartum thrombotic microangiopathic syndrome.

OBJECTIVE Characterization of syndromes for patients with life-threatening, progressively worsening hemolysis-elevated-liver-enzymes-and-platelet (HELLP) syndrome-like diseases and with thrombotic microangiopathies. RETROSPECTIVE STUDY DESIGN: Patients who underwent postpartum plasma-exchange (PPEX) for preeclampsia-related, and microangiopathy/coagulopathy illnesses unresponsive to medical therapy between 1994 and 2008 in our center and elsewhere. RESULTS Nine patients were treated with PPEX in our center with 78% maternal survival. Treatment with PPEX increased platelet levels (p=0.048), decreased serum lactic dehydrogenase (p=0.0012) and aspartate aminotransferase (p=0.0001). CONCLUSION Nineteen patients from publications combined with our patients suggest five categories of postpartum thrombotic microangiopathy syndrome that exhibit HELLP syndrome criteria and respond to PPEX.

Fetal gastroschisis: epidemiological characteristics and pregnancy outcomes in Mississippi.

We describe the epidemiological characteristics and identify maternal-fetal outcomes in pregnancies complicated by gastroschisis. We retrospectively reviewed 115 cases of gastroschisis at the University of Mississippi Medical Center. The incidence of gastroschisis trended upward between 2000 and 2008. Significant proportions of mothers were nonobese, nulliparous, teenagers, smokers, and nonconsumers of alcohol. Infants delivered at > 36 weeks or without sepsis had shorter hospital stay (HS) and interval to full enteral feeding (FEF). The rates of low birth weight (LBW), fetal growth restriction, and spontaneous preterm birth (PTB) were 63%, 45%, and 24%, respectively. Bowel atresia was noted in 9%. Rates of primary closure (25%), neonatal sepsis (29%), fetal death (2%), and infant mortality (4%) were notable. Median HS and interval to FEF were 40 and 30 days, respectively. The incidence of gastroschisis is increasing in Mississippi. Sepsis, LBW, and PTB are key determinants of poor infant outcomes.