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Pulse pressure, wide [keywords]
- Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension. [JOURNAL ARTICLE]
- Hypertension 2013 Dec 9.
A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na(+) excretion and further Na(+) loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.
- Phenotypic Transformation of Smooth Muscle in Vasospasm after Aneurysmal Subarachnoid Hemorrhage. [JOURNAL ARTICLE]
- Transl Stroke Res 2013 Nov 20.
Differentiated smooth muscle cells (SMC) control vasoconstriction and vasodilation, but they can undergo transformation, proliferate, secret cytokines, and migrate into the subendotherial layer with adverse consequences. In this review, we discuss the phenotypic transformation of SMC in cerebral vasospasm after subarachnoid hemorrhage. Phenotypic transformation starts with an insult as caused by aneurysm rupture: Elevation of intracranial and blood pressure, secretion of norepinephrine, and mechanical force on an artery are factors that can cause aneurysm. The phenotypic transformation of SMC is accelerated by inflammation, thrombin, and growth factors. A wide variety of cytokines (e.g., interleukin (IL)-1β, IL-33, matrix metalloproteinases, nitric oxidase synthases, endothelins, thromboxane A2, mitogen-activated protein kinase, platelet-derived vascular growth factors, and vascular endothelial factor) all play roles in cerebral vasospasm (CVS). We summarize the correlations between various factors and the phenotypic transformation of SMC. A new target of this study is the transient receptor potential channel in CVS. Statin together with fasdil prevents phenotypic transformation of SMC in an animal model. Clazosentan prevents CVS and improves outcome in aneurysmal subarachnoid hemorrhage in a dose-dependent manner. Clinical trials of cilostazol for the prevention of phenotypic transformation of SMC have been reported, along with requisite experimental evidence. To conquer CVS in its complexity, we will ultimately need to elucidate its general, underlying mechanism.
- Genetics studies in ischaemic stroke. [Journal Article]
- Transl Stroke Res 2010 Dec; 1(4):238-45.
Conventional risk factors such as high blood pressure account for a significant proportion of stroke risk, but much stroke risk remains unexplained. Epidemiological evidence suggests genetic predisposition accounts for some of this unexplained risk. Many candidate genes association studies have been performed but have lead to largely disappointing results. The genome-wide association study (GWAS) approach allows novel associations to be identified with as many as one million polymorphisms (genetic variants) across the genome. It has been successfully applied to other complex diseases, including other cardiovascular diseases, but stroke has lagged behind. A number of GWAS projects in stroke are now underway. Genetic variants originally identified using the GWAS approach in atrial fibrillation and coronary artery disease have been shown to also confer an increased risk of stroke. These associations have been with specific subtypes of stroke, emphasising the importance of accurate stroke subtyping. The use of intermediate phenotypes for stroke, such as white matter hyperintensities on MRI and carotid intima-media thickness, is also discussed.
- Mapping eQTLs in the Norfolk Island Genetic Isolate Identifies Candidate Genes for CVD Risk Traits. [Journal Article]
- Am J Hum Genet 2013 Dec 5; 93(6):1087-99.
Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10(-7)) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations.
- Life experiences among obstructive sleep apnoea patients receiving continuous positive airway pressure therapy. [Journal Article]
- J Clin Nurs 2014 Jan; 23(1-2):268-78.
To generate a descriptive theoretical framework for experiences among obstructive sleep apnoea (OSA) patients undergoing continuous positive airway pressure (CPAP) therapy.Insufficient information is available about subjective experiences among OSA patients undergoing CPAP therapy. This study aims to address that lack of insight into patients' feelings.A qualitative study using the grounded theory method to establish a descriptive theory.Twenty-two Taiwanese OSA patients undergoing CPAP therapy participated in comprehensive interviews.The patients, aged 37-68 years, participated in wide-ranging interviews. 'Living with CPAP' was the core theme describing the life experiences of OSA patients undergoing CPAP. Health warnings were identified as the antecedent condition, with subcategories including the following: severe snoring, choking and feelings of a terrible death during sleep, day and night sleepiness, easy tiredness, decreased memory, poor sleep, dry mouth, dry throat, headache, high blood pressure, poor blood sugar level control and falling asleep while driving. Analyses indicated seven subcategories of OSA patients with CPAP: (1) seeking medical information, (2) difficulties with CPAP, (3) trial and error for the 'right' CPAP, (4) long scheduled waiting times, (5) wondering, (6) high expectations, and (7) getting back good health.The results will assist healthcare providers with references for OSA health care based on patients' subjective perspectives.After interpreting and analysing results, suggestions include the following: (1) provide medical resource education for outpatients and inpatients to access self-care knowledge regarding OSA; (2) institute professional personnel for providing OSA health education in sleep clinics or sleep centres; (3) develop hospital standards for sleep examination processes to shorten waiting times; (4) establish case management for pursuing OSA patients receiving CPAP; (5) arrange regular forums for patients to share their experiences; and (6) provide community health education to promote awareness of snoring issues.
- Direct Mass Spectrometry Analysis of Untreated Samples of Ultralow Amounts Using Extraction Nano-Electrospray. [JOURNAL ARTICLE]
- Anal Methods 2013 Dec 7; 5(23)
Direct mass spectrometry analysis of untreated samples of volumes as low as 0.2 µL were achieved using fast extraction and nanoESI (electrospray ionization) in a combined fashion. The analytes in dried samples on paper substrates were extracted by organic solvent in a nanoESI tube and ionized with a high voltage applied for generating a spray. The ionization source produced stable signals for different atmospheric pressure interfaces of triple quadrupole instruments. Analysis time more than 20 minutes were available with 10 µL solvent consumed for the entire analysis process. The performance in qualitative and quantitative analysis was characterized with a wide variety of samples. Limits of detection as low as 0.1 ng/mL (corresponding to an absolute amount of 0.05 pg) were obtained for analysis of atrazine in river water, thiabendazole in orange homogenate, and methamphetamine in blood.
- New Antiobesity Agents: Lorcaserin (Belviq) and Phentermine/Topiramate ER (Qsymia). [Journal Article]
- Cardiol Rev 2014 Jan-Feb; 22(1):43-50.
Obesity is a risk factor for a wide range of conditions, including cardiovascular disease. Although lifestyle modifications remain the cornerstone for the management of obesity, pharmacologic agents may be a helpful addition to patients who have comorbidities and do not respond adequately to diet and exercise. Lorcaserin and phentermine/topiramate ER are 2 long-awaited agents, approved in 2012 for obesity management, 13 years since orlistat received US Food and Drug Administration approval in 1999. Lorcaserin is a serotonin agonist, whereas phentermine/topiramate is a combination of a sympathomimetic agent and an antiepileptic drug; both these agents have been shown to reduce weight significantly and improve cardiovascular and metabolic parameters, such as blood pressure, lipids, and HbA1C. This article reviews the pharmacology and clinical efficacy and safety of each of these agents. The differences among the three available agents for long-term management of obesity will also be examined.
- Assessment of Central Blood Pressure in Patients With Type 2 Diabetes: A Comparison Between Sphygmocor and Invasively Measured Values. [JOURNAL ARTICLE]
- Am J Hypertens 2013 Dec 4.
The SphygmoCor is used for noninvasive assessment of ascending aortic blood pressure (BP). However, the validity of the SphygmoCor transfer function has not been tested in an exclusively type 2 diabetic patient sample. Calibration with systolic (SBP) and diastolic (DBP) brachial BP has previously been associated with substantial imprecision of central BP estimates. We hypothesized that different noninvasive calibration strategies might improve the accuracy of the estimated ascending aortic BPs.In 34 patients with type 2 diabetes we estimated ascending aortic SBP and DBP using the SphygmoCor device and compared these data with invasively recorded data. The validity of the transfer function was assessed by calibrating with invasively recorded DBP and mean BP (MBP). The influence of noninvasive calibration strategies was assessed by calibrating with brachial oscillometric SBP+DBP vs. DBP+MBP using a form factor (ff) of 0.33 and 0.40, respectively.When calibrating with invasive BP, the difference between estimated and invasively measured ascending aortic SBP and DBP was -2.3±5.6/1.0±0.9mm Hg. When calibrating with oscillometric brachial BPs, the differences were -9.6±8.1/14.1±6.2mm Hg (calibration with SBP and DBP), -8.3±11.7/13.9±6.1mm Hg (DBP and MBP; ff = 0.33), and 1.9±12.2/14.1±6.2mm Hg (DBP and MBP; ff = 0.40), respectively. Calibration with the average of 3 brachial BPs did not improve accuracy.The SphygmoCor transfer function seems valid in patients with type 2 diabetes. Noninvasive calibration with DBP and MBP (ff = 0.40) enables accurate estimation of mean ascending aortic SBP at the group level. However, the wide limits of agreement indicate limited accuracy in the individual patient.Clinical Trials No. NCT01538290.
- Coupling blood flow and neural function in the retina: a model for homeostatic responses to ocular perfusion pressure challenge. [JOURNAL ARTICLE]
- Physiol Rep 2013 Aug; 1(3):e00055.
Retinal function is known to be more resistant than blood flow to acute reduction of ocular perfusion pressure (OPP). To understand the mechanisms underlying the disconnect between blood flow and neural function, a mathematical model is developed in this study, which proposes that increased oxygen extraction ratio compensates for relative ischemia to sustain retinal function. In addition, the model incorporates a term to account for a pressure-related mechanical stress on neurons when OPP reduction is achieved by intraocular pressure (IOP) elevation. We show that this model, combining ocular blood flow, oxygen extraction ratio, and IOP mechanical stress on neurons, accounts for retinal function over a wide range of OPP manipulations. The robustness of the model is tested against experimental data where ocular blood flow, oxygen tension, and retinal function were simultaneously measured during acute OPP manipulation. The model provides a basis for understanding the retinal hemodynamic responses to short-term OPP challenge.
- DPP-IV inhibitors: Beyond glycaemic control? [JOURNAL ARTICLE]
- Trends Cardiovasc Med 2013 Oct 31.
Dipeptidyl-peptidase-IV (DPP-IV) inhibitors are a new class of oral hypoglycaemic agents recently approved for the management of type 2 diabetes mellitus. Early data suggested that they had a positive impact on the cardiovascular system: treatment appeared to result in improvements in cardiac performance, blood pressure and lipid levels. However, recent clinical findings bring this into question. Our understanding of the physiological actions of these agents is complicated by the fact that DPP-IV has a wide range of substrates in addition to glucagon-like peptide 1. Indeed, DPP-IV inhibition alters concentrations of a wide variety of cytokines and neuropeptides. A deeper understanding of the physiological effects of these drugs as well as their true impact on cardiovascular risk is needed before consideration can be given to extending their use beyond the treatment of diabetes.