Development Of Severe Hypertension Research Articles

Severe hypertension development significantly improves progression-free survival in regorafenib treatment for metastatic colorectal cancer.

Regorafenib is the first multikinase inhibitor used for metastatic colorectal cancer (mCRC) treatment. Reports regarding other multikinase inhibitors have suggested that the development of hypertension is associated with improved clinical benefits. We aimed to reveal the relationship between the development of severe hypertension and regorafenib efficacy in an mCRC real-world setting. Patients with mCRC (n = 100) who received regorafenib were assessed retrospectively. The primary endpoint was a comparison of progression-free survival (PFS) between patients with and without ≥ grade 3 hypertension. The secondary endpoints were overall survival (OS), disease control rate (DCR), and adverse effects. Patients developing ≥ grade 3 hypertension accounted for 30%, and obtained significantly longer PFS than control patients (median PFS of 53 and 56days, 95% confidence interval [CI] of 46-144 and 49-63days, respectively; P = 0.04). In contrast, OS and DCR were not statistically different between the groups (P = 0.13 and P = 0.46, respectively). The incidence and severity of adverse effects were not significantly different, except for hypertension. Treatment interruption was significantly more frequent in patients with hypertension (P = 0.04). Multivariate Cox hazard analysis suggested that the development of ≥ grade 3 severe hypertension was an independent factor for improved PFS (adjusted hazard ratio 0.57, 95% CI 0.35-0.93; P = 0.02). In contrast, baseline hypoalbuminemia was associated with a worse PFS (1.85, 1.14-3.01; P = 0.01). We have revealed that patients who develop severe hypertension after regorafenib treatment for mCRC have improved PFS. Management of hypertension is important for effective treatment with less burden; therefore, further evaluation is needed.

Timely treatment of severe hypertension and risk of severe maternal morbidity at an urban hospital

Hypertensive disorders of pregnancy have been identified as a leading contributor to severe maternal morbidity and mortality. Pregnant persons with hypertensive disorders who develop severe hypertension at delivery admission have been shown to experience higher rates of severe maternal morbidity relative to those without severe hypertension. Current guidelines recommend prompt treatment of severe hypertension given known associated maternal and fetal risks; however, only 1 previous study has described an association between timeliness of antihypertensive therapy and risk of severe maternal morbidity. This study aimed to characterize how development of severe intrapartum hypertension and its timely treatment affect the risk of severe maternal morbidity. We conducted a population cohort study of deliveries with and without hypertensive disorders of pregnancy at a single urban hospital between 2016 and 2018. Among deliveries of persons with hypertensive disorders of pregnancy, we identified those with persistent severe hypertension (defined as blood pressure ≥160/105 mm Hg sustained over ≥15 minutes) and further classified individuals with severe hypertension as having received timely (within 60 minutes) or delayed treatment. Severe maternal morbidity was identified using a composite measure developed by the Centers for Disease Control and Prevention. We calculated overall and indicator-specific rates of severe maternal morbidity for 4 categories of deliveries: without hypertensive disorder of pregnancy, with hypertensive disorder of pregnancy without severe hypertension, with severe hypertension and timely treatment, and with severe hypertension and delayed treatment. We assessed the association between hypertensive disorder of pregnancy, severe hypertension, timeliness of treatment, and severe maternal morbidity using multivariable robust Poisson regression, adjusting for demographic and clinical characteristics. Of 3723 delivery hospitalizations within the study time frame, 32.3% (1204/3723) were complicated by presence of a hypertensive disorder without severe hypertension and 5.7% (211/3723) by presence of a hypertensive disorder with severe hypertension. Among those with severe hypertension, 48.8% (103/211) received timely treatment. Compared with deliveries not complicated by a hypertensive disorder, severe maternal morbidity risk was increased for hypertensive disorder of pregnancy without severe hypertension (124.4/1000 vs 52.0/1000; adjusted risk ratio, 1.84; 95% confidence interval, 1.41-2.40), severe hypertension with timely treatment (233.0/1000; adjusted risk ratio, 3.81; 95% confidence interval, 2.45-5.92), and severe hypertension with delayed treatment (305.6/1000; adjusted risk ratio, 5.38; 95% confidence interval, 3.75-7.73). Patients with hypertensive disorders of pregnancy are at an elevated risk of severe maternal morbidity, and development of severe hypertension further increases this risk. Timely antihypertensive treatment is associated with lower risk of severe maternal morbidity among those with severe hypertension. These findings emphasize the importance of provider education and quality improvement efforts aimed at expediting treatment of severe hypertension.

INFLUENCE OF GENDER, AGE AND METABOLIC FACTORS ON THE COURSE OF ARTERIAL HYPERTENSION IN PATIENTS WITH METABOLIC SYNDROME

According to the World Health Organization, more than 2.1 billion adults are overweight, while about 600 million are obese. Arterial hypertension is a component of the complete metabolic syndrome, its severity, the possibility of effective correction depends on the severity of metabolic disorders in the patient.
 The aim of our study was to study age, sex and metabolic parameters affecting the course of AH in MS in order to optimize therapy for patients with MS.
 Material and methods. The study included 316 patients with hypertension and metabolic syndrome aged 35 to 65 years. The average age of the patients was 51.8 ± 6.4 years. In total, 154 (48.73%) women and 162 (51.27%) men were examined. The patients were divided into three age groups: group 1 – patients aged 35-44 years, group 2 – from 45 to 54 years old, group 3 – from 55 to 65 years old. Clinical examination of patients included a clinical-anamnestic method (collection of complaints and anamnesis, examination) and work with medical records.
 The diagnosis of metabolic syndrome was verified based on the recommendations of the All-Russian Scientific Society of Cardiology (VNOK, 2009) if the patient had one main and at least two additional criteria.
 The main criterion for MS was the “central” (abdominal) type of obesity; additional signs – arterial hypertension; increased TG levels; a decrease in the level of HDL cholesterol; an increase in the level of LDL cholesterol; an increase in fasting plasma glucose; impaired glucose tolerance.
 For statistical processing of the research results, the Statistica for «Windows 10.0» software package was used.
 Results. The development of hypertension in different age groups depends on a combination of various factors that are interrelated with age-related changes in the cardiovascular system and metabolic parameters, which in general characterizes the features of its clinical course. MS itself has a significant impact on the development of hypertension.
 Conclusion. The comorbidity of obesity and the development of severe hypertension was revealed: there is an increase in the severity of hypertension with an increase in the degree of obesity. Age and obesity are both predictors of severe hypertension in MS. According to the predictive model, the following factors: male gender, with increasing age and degree of obesity, increases the likelihood of developing severe hypertension in MS. A comprehensive analysis of the total significance of risk factors, symptoms of target organ damage, taking into account age and gender factors, will make it possible to verify the individual variant of hypertension in MS, which will optimize the therapy of such patients and ensure a decrease in cardiovascular risk.

Study protocol for the randomized controlled EVA (early vascular adjustments) trial: tailored treatment of mild hypertension in pregnancy to prevent severe hypertension and preeclampsia

BackgroundIn contrast to severe gestational hypertension, it is questioned whether antihypertensive medication for mild to moderate gestational hypertension prevents adverse maternal and offspring outcomes. Hypertensive drugs halve the risk of severe hypertension, but do not seem to prevent progression to preeclampsia or reduce the risk of complications in offspring. In fact, beta-blockers, a first line therapy option, are suspected to impair foetal growth. Disappointing effects of antihypertensive medication can be anticipated when the pharmacological mode of action does not match the underlying haemodynamic imbalance. Hypertension may result from 1) high cardiac output, low vascular resistance state, in which beta blockade is expected to be most effective, or 2) low cardiac output, high vascular resistance state where dihydropyridine calcium channel blockers or central-acting alpha agonists might be the best corrective medication. In the latter, beta-blockade might be maternally ineffective and even contribute to impaired foetal growth by keeping cardiac output low. We propose a randomized controlled trial to determine whether correcting the haemodynamic imbalance in women with mild to moderate hypertension reduces the development of severe hypertension and/or preeclampsia more than non-pharmacological treatment does, without alleged negative effects on foetal growth.MethodsWomen diagnosed with mild to moderate hypertension without proteinuria or signs of other organ damage before 37 weeks of pregnancy are invited to participate in this randomized controlled trial. Women randomized to the intervention group will be prescribed tailored antihypertensive medication, using a simple diagnostic and treatment algorithm based on the mean arterial pressure/heart rate ratio, which serves as an easy-to-determine proxy for maternal circulatory state. Women randomized to the control group will receive non-pharmacological standard care according to national and international guidelines. In total, 208 women will be randomized in a 1:1 ratio. The primary outcome is progression to severe hypertension and preeclampsia and the secondary outcomes are adverse maternal and neonatal outcomes.DiscussionThis trial will provide evidence of whether tailoring treatment of mild to moderate gestational hypertension to the individual haemodynamic profile prevents maternal disease progression.Trial registrationNCT02531490, registered on 24 August 2015.

Response to the Time

Response to the Time

Transient neurologic deficit with complete recovery due to cervical spinal cord infarction after preoperative embolization for metastatic lesion of malignant pheochromocytoma at proximal thoracic spine

Spinal cord infarction after preoperative transarterial embolization for metastatic spinal lesions is uncommon and usually leads to complete paralysis. Transient neurologic deficit due to spinal cord infarction after preoperative embolization for spinal metastases has never been reported in the literature. A 30-year-old female patient was diseased with malignant pheochromocytoma and multiple metastases to lung and bones. She suffered from refractory pain at upper back and numbness at her body below xiphoid process but no motor deficit was noted at extremities. Magnetic resonance imaging (MRI) revealed paraspinal and epidural lesions originating from T2 to T4 vertebrae with compression to spinal cord. Preoperative embolization was executed to the spinal metastases with the intent to reduce intraoperative bleeding. Embolization procedure was performed to bilateral costocervical trunk, 3rd and 4th intercostal arteries with 400 μm Embozene® microsphere under local anesthesia. The procedure was discontinued immediately after development of severe hypertension that might be related to the pheochromocytoma and was treated with intravenous antihypertensive drug. There was no neurologic deficit until 6.5 hours after the procedure when weakness at right lower extremity and hypesthesia at left arm developed. Emergent MRI showed focal infarcts in spinal cord at right aspect of C5 and left C4 levels. With adequate hydration but no administration of steroid, muscle power gradually recovered in a few hours. Posterior instrumentation, neural decompression and tumor debulking were performed 2 days after embolization as scheduled. One week after the event of spinal cord infarction, she could stand up and walk without aid. Even though it is rare, spinal cord infarction is an important differential diagnosis for sudden decrease of muscle power after preoperative embolization for spinal metastases. Although complete paralysis is more common, transient neurologic deficit with complete recovery could happen in patients with minor infarcts in the spinal cord.

Transient neurologic deficit with complete recovery due to cervical spinal cord infarction after preoperative embolization for metastatic lesion of malignant pheochromocytoma at proximal thoracic spine

Spinal cord infarction after preoperative transarterial embolization for metastatic spinal lesions is uncommon and usually leads to complete paralysis. Transient neurologic deficit due to spinal cord infarction after preoperative embolization for spinal metastases has never been reported in the literature. A 30-year-old female patient was diseased with malignant pheochromocytoma and multiple metastases to lung and bones. She suffered from refractory pain at upper back and numbness at her body below xiphoid process but no motor deficit was noted at extremities. Magnetic resonance imaging (MRI) revealed paraspinal and epidural lesions originating from T2-4 vertebrae with compression to spinal cord. Preoperative embolization was executed to the spinal metastases with the intent to reduce intraoperative bleeding. Embolization procedure was performed to bilateral costocervical trunk, 3rd and 4th intercostal arteries with 400 μm Embozene® microsphere under local anesthesia. The procedure was discontinued immediately after development of severe hypertension that might be related to the pheochromocytoma and was treated with intravenous antihypertensive drug. There was no neurologic deficit until 6.5 hours after the procedure when weakness at right lower extremity and hypesthesia at left arm developed. Emergent MRI showed focal infarcts in spinal cord at right aspect of C5 and left C4 levels. With adequate hydration but no administration of steroid, muscle power gradually recovered in a few hours. Posterior instrumentation, neural decompression and tumor debulking were performed 2 days after embolization as scheduled. One week after the event of spinal cord infarction, she could stand up and walk without aid. Even though it is rare, spinal cord infarction is an important differential diagnosis for sudden decrease of muscle power after preoperative embolization for spinal metastases. Although complete paralysis is more common, transient neurologic deficit with complete recovery could happen in patients with minor infarcts in the spinal cord.

Batter Up.

Batter Up.

Abstract 034: Remote Patient Monitoring for Postpartum Hypertension: A Pilot Study

Background: Postpartum hypertension is a leading indication for hospital readmission and maternal mortality. Objective: To conduct a pilot intervention to establish the feasibility of telehealth monitoring/treatment after hospital discharge for women with or at risk of developing severe postpartum hypertension (SBP > 150 or DBP > 105 mmHg). Methods: This prospective intervention at a Midwestern academic group practice included adult women with a hypertension-related diagnosis in the antenatal and/or postpartum period. Prior to discharge, patients received a tablet computer and blue tooth equipment (scale, blood pressure, oxygen saturation and heart rate monitor) to transmit home vital signs daily to a nurse. Patients had a nurse telehealth visit 48 hours and 7 days post-discharge. A nurse-driven outpatient treatment algorithm was developed and utilized for initiation and/or cessation of antihypertensive medications. Study follow-up was 6 weeks postpartum, followed by transfer to routine clinical care. Results: Among the 121 women with a hypertension-related disorder of pregnancy; 32 of the intended 55 have been enrolled to date (26%). [HJ2] Among the study patients, 6/32 (19%) were discharged on antihypertensive medication, of which 4/6 (67%) required an increase in the dose after discharge. After discharge, 10/32 (31%) required antihypertensive initiation after discharge due to development of severe hypertension. Overall, postpartum blood pressures became severe on day 4.9 (mean SBP was 158mmHg and DBP was 96mmHg). Among enrolled participants, there were two emergency room visits, however no hospital readmissions; 3/32 (9%) discontinued the study prior to study completion due to social situations. Conclusions: The preliminary results of our pilot intervention demonstrate feasibility and patient acceptability with telehealth monitoring for postpartum hypertension-related disorders. Furthermore, we demonstrated important temporal trends in the natural history of postpartum hypertension from discharge through 6 weeks postpartum which will guide larger clinical trials. Telehealth monitoring is a promising outpatient treatment strategy for postpartum hypertension to reduce readmissions and decrease maternal morbidity.

Blood pressure patterns in women with gestational hypertension or mild preeclampsia at term

ObjectiveGestational hypertension (GH) and mild preeclampsia (PE) represent the most common medical complications of pregnancy, with the majority of cases developing at or near term. There is little knowledge of the course of blood pressure over time in these women. We explored the pattern of systolic and diastolic blood pressure over time in women with GH or mild PE at term participating in the HYPITAT trial, and we attempted to identify clinical factors influencing these blood pressure patterns and the impact of severe hypertension on clinical management. Study designWe used data from the HYPITAT trial, that included women with a singleton pregnancy with a fetus in cephalic position between 36 and 41 weeks of gestation with the diagnosis of GH or mild PE. Blood pressure measurements were performed from randomization or admission until delivery or discharge from the hospital. We included the highest blood pressure of each day.We evaluated systolic and diastolic blood pressure change over time, as well as the influence of clinical characteristics and laboratory findings on the course of blood pressure. We used univariate and multivariate regression analysis with a backward stepwise algorithm for the selection of variables. The model with the best fit (lowest AIC) was selected as the final model. We also compared mode of delivery for women with and without severe hypertension. ResultsWe studied 1076 women who had 4188 blood pressure measurements done. The systolic blood pressure showed a significant non-linear increase over time and for the diastolic blood pressure the pattern was also non-linear. In the multivariable model of systolic blood pressure change over time, nulliparity, ethnicity, systolic blood pressure (at baseline), BMI and LDH at randomization influenced the course of blood pressure. In the diastolic blood pressure model ALT and the baseline diastolic blood pressure had a significant influence. When we explored the association between blood pressure and mode of delivery, it appeared that development of severe hypertension was a risk factor for Caesarean section. ConclusionThe blood pressure in patients with GH or PE at term showed a non-linear increase with time, which was aggravated by clinical characteristics. Development of severe hypertension was a risk factor for Caesarean section, which may explain the elevated Caesarean section rates in the expectant monitoring group in the HYPITAT trial.

Maternal and fetal morbidity following discontinuation of antihypertensive drugs in mild to moderate chronic hypertension: A 4-year observational study.

To assess maternal and fetal morbidity in women with mild to moderate chronic hypertension on antihypertensive drug therapy compared to cessation of therapy. This was a prospective observational study included 222 women with mild to moderate chronic hypertension (systolic blood pressure of 140-159mmHg or diastolic blood pressure of 90-109mmHg) who were divided into two groups based on antihypertensive drug intake, treatment group (n=104) who received methyl dopa, and non-treatment group (n=118) who used only low dose aspirin. Patients were followed to assess maternal and fetal outcome. There were significant differences between the two groups regarding the development of severe hypertension (p<0.001), renal impairment (p<0.001), ECG changes (p<0.001), placental abruption (p<0.05), repeated hospital admissions (p<0.001), preterm delivery (p<0.05) and neonatal ICU admission (p<0.05) with higher occurrence in the non-treatment group. There were no significant differences between the two groups in terms of the development of preeclampsia, hepatic impairment, mode of delivery, venous thromboembolism, small for gestational age, intrauterine fetal demise or neonatal mortality (p>0.05). Maternal and fetal morbidity is increased following cessation of antihypertensive drug use in patients with mild to moderate chronic hypertension. Further larger studies are warranted to confirm or refute our findings.

Severe maternal morbidity in a large cohort of women with acute severe intrapartum hypertension

Hypertensive diseases of pregnancy are associated with severe maternal morbidity and remain common causes of maternal death. Recently, national guidelines have become available to aid in recognition and management of hypertension in pregnancy to reduce morbidity and mortality. The increased morbidity related to hypertensive disorders of pregnancy is presumed to be associated with the development of severe hypertension. However, there are few data on specific treatment or severe maternal morbidity in women with acute severe intrapartum hypertension as opposed to severe preeclampsia. The study aimed to characterize maternal morbidity associated with women with acute severe intrapartum hypertension, and to determine whether there was an association between various first-line antihypertensive agents and posttreatment blood pressure. This retrospective cohort study of women delivering between July 2012 and August 2014 at 15 hospitals participating in the California Maternal Quality Care Collaborative compared women with severe intrapartum hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >105 mm Hg) to women without severe hypertension. Hospital Patient Discharge Data and State of California Birth Certificate Data were used. Severe maternal morbidity using the Centers for Disease Control and Prevention criteria based on International Classification of Diseases-9 codes was compared between groups. The efficacy of different antihypertensive medications in meeting the 1-hour posttreatment goal was determined. Statistical methods included distribution appropriate univariate analyses and multivariate logistic regression. There were 2252 women with acute severe intrapartum hypertension and 93,650 women without severe hypertension. Severe maternal morbidity was significantly more frequent in the women withsevere hypertension (8.8%) compared to the control women (2.3%) (P< .0001). Severe maternal morbidity rates did not increase with increasing severity of blood pressures (P= .90 for systolic and .42 for diastolic). There was no difference in severe maternal morbidity between women treated (8.6%) and women not treated (9.5%) (P= .56). Antihypertensive treatment rates were significantly higher in hospitals with a level IV neonatal intensive care unit (85.8%) compared to a level III neonatal intensive care unit (80.2%) (P < .001), and in higher-volume hospitals (84.5%) compared to lower-volume hospitals (69.1%) (P < .001). Severe maternal morbidity rates among severely hypertensive women were significantly higher in hospitals with level III neonatal intensive care unit level compared to hospitals with a level IV neonatal intensive care unit (10.6% vs 5.7%, respectively; P < .001), and significantly higher in low-delivery volume hospitals compared to high-delivery volume hospitals (15.5% vs 7.6%, respectively; P < .001). Only 53% of women treated with oral labetalol as first-line medication met the posttreatment goal of nonsevere hypertension, significantly less than those treated with intravenous hydralazine, intravenous labetalol, or oral nifedipine (68%, 71%, and 82%, respectively) (P= .001). Severe intrapartum hypertension remained untreated in 17% of women. Women with acute severe intrapartum hypertension had a significantly higher risk of severe maternal morbidity compared to women without severe hypertension. Significantly lower antihypertensive treatment rates and higher severe maternal morbidity rates were seen in lower-delivery volume hospitals.

Incomplete Restoration of Angiotensin II-Induced Renal Extracellular Matrix Deposition and Inflammation Despite Complete Functional Recovery in Rats.

Some diseases associated with a temporary deterioration in kidney function and/or development of proteinuria show an apparently complete functional remission once the initiating trigger is removed. While it was earlier thought that a transient impairment of kidney function is harmless, accumulating evidence now suggests that these patients are more prone to developing renal failure later in life. We therefore sought to investigate to what extent renal functional changes, inflammation and collagen deposition are reversible after cessation of disease induction, potentially explaining residual sensitivity to damage. Using a rat model of Angiotensin II (Ang II)-induced hypertensive renal disease we show the development of severe hypertension (212 ± 10.43 vs. 146 ± 1.4 mmHg, p<0.001) and proteinuria (51.4 ± 6.3 vs. 14.7 ± 2.0 mg/24h, p<0.01) with declined creatinine clearance (2.0 ± 0.5 vs. 4.9 ± 0.6 mL/min, p<0.001) to occur after 3 weeks of Ang II infusion. At the structural level, Ang II infusion resulted in interstitial inflammation (18.8 ± 4.8 vs. 3.6 ± 0.5 number of macrophages, p<0.001), renal interstitial collagen deposition and lymphangiogenesis (4.1 ± 0.4 vs. 2.2 ± 0.4 number of lymph vessels, p<0.01). Eight weeks after cessation of Ang II, all clinical parameters, pre-fibrotic changes such as myofibroblast transformation and increase in lymph vessel number (lymphangiogenesis) returned to control values. However, glomerular desmin expression, glomerular and periglomerular macrophages and interstitial collagens remained elevated. These dormant abnormalities indicate that after transient renal function decline, inflammation and collagen deposition may persist despite normalization of the initiating pathophysiological stimulus perhaps rendering the kidney more vulnerable to further damage.

Abstract 340: Novel Molecular Mechanisms Involved In VEGFR Inhibition In Human Endothelial Cells

VEGF/VEGFR inhibitors are increasingly being used as anti-angiogenic drugs to treat cancer. However these drugs are limited by the development of severe hypertension. Molecular mechanisms whereby VEGF inhibitors cause hypertension are unclear, but nitric oxide (NO) signalling may be involved. We questioned whether reactive oxygen species (ROS) and Ang II, important regulators of vascular function in hypertension, also play a role in VEGF inhibitor-induced vascular dysfunction. Human microvascular endothelial cells (HMECs) were stimulated with vatalanib (VAT-VEGFR inhibitor) and gefitinib (GEF-EGFR inhibitor) in the absence/presence of Ang II. Activation of eNOS and MAPKs were assessed by immunoblotting. Antioxidant enzyme mRNA was analyzed by qPCR. Phosphorylation of eNOS activation site (Ser1177) (28.3% ± 7.1) and p38 MAPK (55.4% ± 2.4) was decreased by VAT, while no changes were observed after exposure of HMECs to GEF (p&lt;0.05). VAT also decreased mRNA expression of Nox4 (0.5 ± 0.2), and H2O2-related antioxidants enzymes such as catalase (0.4 ± 0.1) and glutathione peroxidase (0.4 ± 0.1). Ang II stimulation increased eNOS (171.2% ± 17.4), ERK1/2 (177.5% ± 38.5), p38 MAPK (186.9% ± 36.6) activation (p&lt;0.05); an effect blocked by VAT and GEF. Inhibition of VEGFR also blocked Ang II effects on SOD1 (1.33 ± 0.1), HO-1 (1.6 ± 0.3) and NQO1 (1.6 ± 0.3) mRNA levels (p&lt;0.05). In addition, Ang II increased Nox4 mRNA expression through VEGFR-dependent mechanisms. Interestingly, VEGFR1/2 and AT2R were expressed in HMEC, but not AT1R. Ang II effects on eNOS phosphorylation were inhibited by PDE123 (AT2R antagonist) but not by losartan (AT1R antagonist). In conclusion, our data elucidate novel mechanisms whereby AngII, possibly through AT2R-dependent VEGFR transactivation, regulates eNOS activation, MAPK signalling and H2O2-related antioxidant enzymes. In addition to changes in NO availability, VEGFR inhibition may interfere with the redox status of endothelial cells, leading to vascular dysfunction and hypertension.

Polymorphisms in Endothelial Nitric Oxide Synthase (eNOS) and Vascular Endothelial Growth Factor (VEGF) Predict Sunitinib-Induced Hypertension

Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)-2, endothelin-1 (ET-1), and endothelium-derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib-induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib-treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.

Inhibition of soluble epoxide hydrolase improves the impaired pressure–natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats

In the present study, we compared the effects of treatment with the novel soluble epoxide hydrolase (sEH) inhibitor (c-AUCB) with those of the AT1 receptor antagonist losartan on blood pressure (BP), autoregulation of renal blood flow (RBF) and on glomerular filtration rate (GFR) and the pressure-natriuresis relationship in response to stepwise reduction in renal arterial pressure (RAP) in Cyp1a1-Ren-2 transgenic rats. Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration for 11 days of the natural xenobiotic indole-3-carbinol (I3C) which activates the renin gene. Treatment with c-AUCB and losartan was started 48 h before initiating administration of the diet containing I3C. Rats were prepared for renal functional studies to evaluate in-vivo renal autoregulatory efficiency when RAP was gradually decreased by an aortic clamp. I3C administration resulted in the development of severe hypertension which was associated with markedly lower basal RBF and GFR and substantially impaired autoregulatory efficiency as well as a suppression of the pressure-natriuresis relationship when compared with noninduced rats. Treatment with c-AUCB significantly decreased BP, improved autoregulatory efficiency of RBF and GFR and the slope of pressure-natriuresis relationship. Treatment with losartan completely prevented the impaired autoregulation and pressure-natriuresis relationship as well as the development of hypertension in I3C-induced rats. Our present findings indicate that chronic treatment with the sEH inhibitor c-AUCB substantially attenuates the development of malignant hypertension in I3C-induced rats likely via improvement of the renal autoregulatory efficiency and the pressure-natriuresis relationship.

Single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (NOS3) and vascular endothelial growth factor (VEGF) and its relationship to sunitinib-induced hypertension.

4611 Background: Hypertension is a common side-effect in patients treated with sunitinib and is likely associated with inhibition of the VEGF/VEGF receptor(R)-2 pathway. SNPs in VEGF-A, VEGFR-2, but also in NOS3and endothelin-1 (EDN1) have been mentioned as possible candidates associated with a higher risk on development of hypertension. METHODS: A retrospective multicenter study was performed in 255 patients with advanced renal cell cancer and gastrointestinal stromal tumor treated with sunitinib 50 mg/day in a 4 weeks on 2 weeks off or 37.5 mg/day continuous schedule. Office systolic (SBP) and diastolic blood pressure (DBP) were measured at baseline and on days 14 and 28 of the first treatment cycle. Hypertension was graded according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE). Seven SNPs in genes encoding for VEGF-A (rs2010963, rs833061, rs3025039, rs699947), VEGFR-2 (rs1870377), EDN1 (rs5370) and NOS3 (rs2070744) were selected. SNPs were univariately tested against hypertension grades according to CTCAE. RESULTS: During the first treatment cycle, sunitinib induced a mean increase of 13 ± 23 mmHg and 10 ± 12 mmHg in SBP and DBP (t-test, P < 0.001), respectively. According to CTCAE, 36.5 % of patients developed hypertension. Among these patients, 10.6%, 12.9% and 12.9% had hypertension grade 1, 2, and 3, respectively. Development of grade 3 hypertension was associated with two copies of the C-allele in VEGF-A (rs833061; Chi-square, P = 0.048), two copies of the A-allele in VEGF-A(rs699947; P = 0.053) and a C-allele in NOS3 (rs2070744; P = 0.051). CONCLUSIONS: SNPs in genes of NOS3 and VEGF-A are associated with the development of severe hypertension in patients treated with sunitinib. In particular, the association between the NOS3 pathway and hypertension induced by an inhibitor of the VEGF/VEGFR-2 pathway is a new finding. Hence, SNPs in VEGF-A and NOS3 genes may identify patients predisposed to develop hypertension on sunitinib treatment.

A randomized trial of tight vs. less tight control of mild essential and gestational hypertension in pregnancy

To assess the effects of applying a tight vs. a less tight control of mild chronic essential or gestational non-proteinuric hypertension in pregnancy. A randomized trial was conducted in 2006-2007 in the University of Ain Shams, Egypt. Eligible participants (n=125) were randomly assigned to either tight or less tight control of mild chronic (essential) or gestational (non-proteinuric) hypertension. The primary outcome measure was the development of severe hypertension during follow-up. Analysis was by intention-to-treat. In the tight target group, adjustment of the dose with an increment of 191 mg yielded a mean dose of methyldopa of 1267+/-406 mg. Both systolic and diastolic BP levels were significantly less than in the tight target group. More women in the less tight group had severe hypertension during follow up (RR 3.167 and 95% CI 1.36-7.37). The rate of antenatal hospitalization was significantly higher in the less tight target group with a relative risk of 2.57 and 95% CI 1.16-5.70. The gestational age at delivery was significantly better in the tight target group. Preterm delivery and birth weight were not significantly different between the study groups. Tight control of blood pressure reduces the rate of antenatal hospitalization and does not adversely affect perinatal outcomes in women with mild essential or gestational hypertension.

Loss of taste-induced hypertension — caveat for taste modulation as a therapeutic option in obesity

Effective treatment of obesity is extremely difficult, and taste modulation has been suggested as a feasible option. We aim at presenting dangers associated with stroke-induced taste impairment. A case report is presented with clinical and laboratory findings. We review literature on the effect of taste modulation on body weight. Eight months after suffering stroke, a 63-year old obese woman with a nine year-old history of type 2 diabetes reported headache and poor general feeling. Physical examination revealed significantly elevated blood pressure of 190/110 mmHg. The patient had never had elevated blood pressure before nor ever been taking any antihypertensive medication. However, stroke resulted in severe persisting dysgeusia. We found out that she had been using up to 110 g of salt daily to make her meals palatable. Standard gustatory tests confirmed severe taste impairment, reflecting the lesion of the glossopharyngeal nerve. Taste loss was not associated with body weight reduction. Limiting daily salt intake to 5 g within 4 weeks resulted in lowering blood pressure to 120/70 mmHg. Stroke-induced dysgeusia may lead to increased salt intake in a type 2 diabetes patient, which caused development of severe hypertension. The taste loss did not yield any weight reduction. We suggest that aiming at reducing body weight by means of taste modulation should be done with caution. Physicians must be aware that patients may try to overcome dysgeusia by additional salt intake, if not adequately informed of the risk thereof.

AT1 receptor blockade is superior to conventional triple therapy in protecting against end-organ damage in Cyp1a1-Ren-2 transgenic rats with inducible hypertension

In the present study we compared the effects of treatment with the AT1 receptor antagonist candesartan and of 'triple therapy' (hydralazine, hydrochlorothiazide, reserpine) on the course of blood pressure, cardiac hypertrophy and angiotensin II concentrations after induction of hypertension in transgenic rats with inducible expression of the mouse renin gene (Cyp1a1-Ren-2 rats). Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration of the natural xenobiotic indole-3-carbinol (I3C, 0.3%) for 4 days. Starting on the day before administration of I3C, rats were treated either with candesartan or received triple therapy for 9 days. Systolic blood pressure was measured in conscious animals. Rats were decapitated and angiotensin II levels in plasma and in whole kidney and left ventricular tissues were determined by radioimmunoassay. Administration of I3C resulted in the development of severe hypertension and cardiac hypertrophy that was accompanied by marked elevations of plasma and tissue angiotensin II concentrations. Candesartan treatment prevented the development of hypertension and cardiac hypertrophy and was associated with a reduction of tissue angiotensin II concentrations. In contrast, triple therapy, despite maintaining systolic blood pressure in the normotensive range, did not prevent the development of cardiac hypertrophy and tissue angiotensin II augmentations. Our findings indicate that hypertension in Cyp1a1-Ren-2 rats is a clearly angiotensin II-dependent model of hypertension with elevated circulating and tissue angiotensin II concentrations, and that antihypertensive treatment with AT1 receptor blockade is superior to conventional triple therapy in effective protection against hypertension-induced end-organ damage in this rat model.