To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

Executive Summary Non-communicable disease currently accounts for 59% of global deaths and 46% of the global burden of disease. In 2000, 38% of all male deaths and 43% of all female deaths, in South Africa, were due to non-communicable disease. Like all health systems, the South African health system is not adequately equipped to deal with these types of diseases. The burden of chronic disease will grow over time due to factors such as urbanisation and associated behaviours regarding food consumption and physical activity. The World Health Organisation has developed the Innovative Care for Chronic Conditions (ICCC) framework for resource-constrained settings. The ICCC framework is structured into three levels: macro (positive policy environment), meso (community and health care organisation) and micro (health care interactions) levels. Using diabetes and hypertension as examples of chronic disease, this research drew upon portions of this framework to examine service provision for chronic diseases in the Gauteng Province. The overall aim of the study was to document the resources available to manage chronic disease in the Gauteng Province by investigating primary health care clinics, community organisations, and provincial and district support. The objectives were to describe the following: health services offered by primary health care clinics in the city of iv Johannesburg for the management of patients with diabetes and hypertension; the role of district and provincial management in chronic disease care; and the role of community based organisations within the city of Johannesburg in promoting good health, preventing chronic illness, and providing curative and rehabilitative services. The micro level is represented by primary health care (PHC) clinics, the meso level is represented by community-based organisations (CBOs), and the macro level is represented by provincial and regional managers. This is a qualitative, cross-sectional descriptive study. The study population is PHC clinics, associated CBOs, and managers operating in Metropolitan Johannesburg, which is managed by the provincial government. One Gauteng province sub-district was selected by simple random sampling from a list of sub-districts containing at least five provincial PHC clinics. The selected sub-district was located in Soweto and the four PHC clinics and two community health centres were included in the study. Snowball sampling was used to select the CBOs after contacting the PHC clinics. Chronic disease managers at the regional and provincial level were also selected for the study. Data was collected entirely through interviews. One key respondent was selected at each site after contacting the site via telephone. The interview was in-depth and guided by a pre-determined list of questions. The issues probed included topics common to all three levels such as: challenges in chronic disease management, goals for chronic disease management, financial and human resource issues and patient information. Interviews were tape recorded, transcribed and analysed thematically. Ethics approval for the study was obtained from the University of the Witwatersrand’s Human Research Ethics Committee and authorisation to conduct the research was acquired from the Gauteng Provincial Department of Health. A total of 13 people were interviewed. At the micro level (PHC clinics), health care workers believed there was an adequate skill mix for chronic disease care but felt unsupported and understaffed. They did not feel motivated by the incentives currently offered. No health information was maintained at the clinic and all patient information was kept on cards. These cards were used to track patients’ progress, clinic attendance and compliance. The only information collected, and sent for analysis, was a patient headcount. Clinics primarily focused on curative treatment. Patients were deemed to be ‘controlled’ or ‘uncontrolled’ based on their ability to return to the clinic for monthly check-ups and consistently achieve acceptable clinical indicators such as blood pressure and/or blood glucose level. Medical doctors, the only health care workers permitted to initiate insulin therapy, are present only at the community health centres. Patients at PHC clinics must therefore receive referrals and travel to CHC to receive such treatment. PHC sisters did not express an interest in being able to begin insulin therapy, suggesting it is too dangerous and should only be performed by a medical doctor. Five CBO representatives were interviewed. Only two community-based organisations could be identified as having dealt specifically with chronic disease. Both of which focused on diabetes but were inclusive of hypertension due to the number of patients with both conditions. These organisations operated with no budget, paid staff or dedicated office space. They maintained close relationships with clinic staff and ran support groups at the clinic, many times with the help of sisters at the clinic. The other CBOs included in the study were home-based care in nature and dealt primarily with HIV/AIDS. They began treating these chronic disease patients when they realised the stigma of HIV/AIDS was ultimately affecting their outreach. In contrast to the two chronic disease CBOs, the AIDS related organisations all received government training and funding, which included stipends. It was felt that the government training did not provide enough information regarding noncommunicable chronic disease such as hypertension, and instead focused almost exclusively on HIV/AIDS. A monthly meeting was held for all Soweto-based CBOs to discuss issues and receive information from government representatives. There exist dedicated chronic disease programme managers at both regional (covering two districts) and provincial levels. Both levels support one another as they work with the PHC clinics in managing chronic disease. Managers felt free to communicate ‘upwards’ from region to province and province to the national level on an as-needed basis. With respect to PHC services, they saw their role largely as conduits. They provided guidelines to the clinics that were created at the national level and then subsequently monitored their guideline implementation by conducting random site visits. Managers felt that health care worker support was to be accomplished at the clinic level, rather than being their personal responsibility. Chronic disease services, in the study area, held the primarily focus on curative care rather than on health promotion, prevention and early diagnosis through screening. Nearly all patient education was delivered to individuals who had already developed one or more chronic conditions. Community-based organisations motivated those with chronic disease to adhere to treatment protocols, make positive lifestyle choices, and provide patients with a forum to discuss their conditions and learn from one another. They also worked with the government to implement awareness campaigns each month. These campaigns included the community and provided education to those whom had not yet developed a chronic disease. All three levels of the ICCC are functional and communicate with each other, though to varying degrees. While communication between levels is present, there exists a top-down management style where workers feel unsupported. The government is heavily involved in all three levels of chronic disease management. They train and pay PHC clinic staff and CBO workers. The government produces and disseminates all guidelines and protocols and monitor their implementation. The government accomplishes all these tasks while collecting only monthly patient headcounts from each clinic. Patients retain all clinical data and managers see no need to collect any data other than a monthly headcount from each clinic. Nurses are unable to initiate insulin therapy and are unhappy with the current incentive program. There are only two CBOs dedicated to chronic disease, all the rest focus primarily on HIV/AIDS. CBO workers do not feel there is enough training regarding chronic diseases. Each level cite various challenges to successfully managing chronic disease. These include, but are not limited to, low patient compliance, finances, lack of family support, and human resource issues. The research applied only a portion of the ICCC framework to one group of government clinics - provincial PHC clinics and CHCs. Examining a larger number of clinics and managers and applying a greater portion of the ICCC framework would be valuable further research. The following recommendations are a partial list of those generated by this research: • Increase the amount of chronic disease information presented in the mandatory government training of all CBO health care workers. • Construct a comprehensive list of all CBOs that includes: contact information, where they operate, services provided, current client addresses, etc. This will strengthen their ability to partner with one another and reduce overlap in patient care. • Educate patients better regarding how insulin works. This will decrease the usage of herbal medicines that mask health problems and lessen patients’ fear of insulin. • PHC nurses could be trained and permitted to administer and/or initiate insulin therapy. • Enable managers to realise they can affect change in clinic staff, rather than feeling this responsibility belongs solely to the clinic manager.

0107750D Masters Research - Faculty of Health sciences / The prescription habits of general practitioners are continually under the scrutiny of ethical critics. There are numerous factors that influence a practitioner’s decision as to which antihypertensive agents to prescribe for the treatment of hypertension. As outlined in various international and national guidelines for the management of hypertension, the recommended treatment depends on ethnicity, current life-style, diet, smoking, age, gender, family history and possible underlying or secondary conditions such as diabetes mellitus, heart failure, isolated systolic hypertension, myocardial infarction, pregnancy, and evidence of coronary artery disease (CAD), stroke or peripheral vascular disease. Currently the control of blood pressure in patients with hypertension is far from optimal with over 70% of hypertensive patients being reported as having imperfect control. A number of factors related to the patient, the practitioner or the medication may explain the high incidence of inadequate blood pressure control. One possible explanation for the poor control of blood pressure may be that practitioners fail to comply with the guidelines. Hence the aim of my study was firstly to determine whether a practitioner’s decision as to which medication to prescribe in the treatment of hypertension is influenced by the Southern African Hypertension Society Guidelines. Secondly, in an attempt to assess the validity of the results of the primary analysis, the actual prescription habits (MediCross® database) were assessed and compared to the general practitioner’s recall of their prescription habits. Questionnaires were distributed to 320 MediCross® practitioners and prescription habits were identified and substantiated by the screening of an existing MediCross® database. I chose as my sample MediCross® general practitioners, as they are demographically representative of all major urban areas in South Africa; likely to be open-minded to supporting research and answering questionnaires (as MediCross® is part of a Clinical Research Site Management Organisation); and I had access to the database of the prescriptions made by MediCross® practitioners hence enabling me to fulfil my second objective. However, it must be kept in mind that these practitioners are representative of general practitioners in urban areas only (as the title of my research report indicates). My results show that 33.1% adhere to the guidelines (when a non-conservative definition of diuretics is used); 27% have heard of the guidelines and have a copy of them. When asked to give their own opinion however, 39% thought they adhered to the guidelines. The results also show that ACE inhibitors are the most commonly prescribed drug class for uncomplicated hypertension but a comparison to a MediCross® database, of which the quality is questionable, does not support this. As the response rate to the questionnaires was only 24.7%, these results are only a pilot study; however they suggest that few general practitioners use the guidelines or even have a copy of the guidelines. This pilot study suggests that the guidelines need to be distributed more widely. Furthermore the general practitioners that responded to the questionnaire indicated that the management of hypertension is difficult in that there is no single treatment regimen appropriate for all populations and each different - 5 - patient. It was also their view that clinical guidelines for the management of hypertension should more accurately reflect the uncertainty of when to initiate treatment and individual variation if they are going to take these guidelines seriously and comply with them.

Thesis (Ph.D.)--Boston University / This investigation studied the mode of hostility management in persons with essential hypertension. The mode of adjustment to hostile impulses of hypertensive persons was viewed as a defensive adaptation which was different from the normal mode. The hypothesized differences between these groups were to be observed under two conditions, one with and one without hostility arousal. Under both conditions it was predicted that the hypertensive would be over-inhibited with respect to expressions of hostility. In the first condition a higher level of inhibition and tension was expected to characterize the hypertensive group. Under the second condition greater change from the earlier levels of inhibition and tension were also expected to characterize the hypertensive group. The independent variable of essential hypertension was defined on the basis of presence or absence of a medical diagnosis of essential hypertension. The second independent variable was hostility arousal. The method employed was an adaptation of the Wisconsin card sort that involved punishment for failure [TRUNCATED]

Primary aldosteronism (PA) accounts for 5-10% of all hypertension. One of the major causes of PA is sporadic formation of aldosterone-producing adenomas (APAs). These benign tumours develop in the cortical region of adrenal glands and autonomously secrete excessive amounts of aldosterone. This hormone increases sodium retention and water reabsorption by the kidneys, leading to high blood pressure. Landmark discoveries of somatic mutations in APAs led to better understanding of molecular mechanisms causing autonomous aldosterone secretion. The first mutations were found in KCNJ5, followed by ATP1A1, ATP2B3 and CACNA1D, all encoding cation-channels or transporters. Several in vitro studies showed disruption of cellular ion-balance leading to the phenotype of hyper-aldosterone secretion from APAs. Following our lab's discovery of initial four somatic mutations by whole exome sequencing, over 30 single-base change mutations have been reported in the CACNA1D gene, which encodes the a1 subunit of an L-type Ca2+ channel (LTCC), CaV1.3. Initial and several subsequent mutations cause electrophysiological gain-of-function with increased activation and/or slowed inactivation of CaV1.3. Prior to the discovery of these mutations, L-type Ca2+ channels were not considered important in regulation of aldosterone production. In the first part of my thesis, I investigated two of the mutations and showed that the gain-of-function results in increased aldosterone secretion from an adrenocortical carcinoma cell line, H295R, when transiently transfected with the mutants. I also showed that CaV1.3 can play a role in physiological aldosterone secretion, finding that CYP11B2 expression is reduced by 50% in the adrenals of CaV1.3 knockout mice. The discovery of mutations in CACNA1D led to a drug discovery challenge award from a pharmaceutical company in which high-throughput screening of CaV1.3-expressing cells was undertaken against the company's 1.8M compound library. I identified the adrenal isoforms of the channel's alpha and beta subunits (CACNA1D and CACNB2), and helped development of the stable HEK293 cell line used for screening. This led to 3 tool compounds (A, B & C) that were selective antagonists for CaV1.3 over another family member of the ion channels in high-throughput electrophysiological experiments using IonWorks Barracuda and QPatch platforms. I showed compound B to effectively inhibit aldosterone secretion in both H295R and primary adrenal cells isolated from a normal adrenal. This finding is a significant step in developing compound B further into a CaV1.3-selective drug for treating PA patients without cardiovascular side effects as in the case of existing dihydropyridine class of Ca2+ channel blockers. The second part of my thesis focused on genotyping and whole exome sequencing of 59 APAs from 52 patients, in order to identify further genes underlying primary aldosteronism. Mutations in previously reported genes were identified in 34 of the APAs (57.6%). CACNA1D was the most commonly mutated gene (20.3%) in this cohort, but not KCNJ5 (16.9%) as previously reported. This variation in the frequencies observed is perhaps due to the different methods used for screening PA. For example, many of our patients were detected by renin measurement in resistant hypertension, and their APA identified by a unique PET-CT (using C11 metomidate), in place of adrenal vein sampling. In addition to this, novel somatic mutation was found in a gene not encoding an ion channel, however, this protein was previously linked to cell-cell adhesion and tumour suppression. The gene identified is CADM1, a cell adhesion molecule 1, and the mutation found leads to substitution of uncharged by negatively charged amino acid in the single transmembrane domain of this cell surface protein. The likely significance of this discovery was greatly enhanced when we ascertained that one of the 'private' somatic mutations found on whole exome sequencing of APAs in Munich was in fact a similar substitution in the adjacent amino acid of the membrane-spanning domain. High expression of CADM1 in zona glomerulosa (ZG) was found, the site of aldosterone synthesis in the adrenal cortex and in the APAs, as well as the aldosterone producing cell clusters (APCCs) within the ZG. In vitro experiments using H295R cells showed both mutations in CADM1 lead to 10-20 fold upregulation of CYP11B2 transcription, on qPCR, resulting in 2-4-fold increase of aldosterone secretion, compared to the wild-type CADM1. Despite the introduction of a negative charge into the transmembrane domain, both mutants could translocate to the cell surface. The evidence to date, points to the loss of cell-cell adhesion in the presence of mutant CADM1 as the cause of uncontrolled aldosterone synthesis. Silencing of CADM1 in H295R cells revealed downregulation of aldosterone synthesis and secretion. Transcriptome analysis by RNAseq, of H295R cells expressing wild-type or mutant CADM1 or silenced CADM1 showed a large number of differentially expressed genes. Mutant CADM1 upregulated genes involved in steroidogenesis and ACTH response pathways. A possible role of CADM1 was found to be in the regulation of inter-cell communication via gap junction protein, connexin-43 (Cx43). This was upregulated with higher expression on plasma membrane in the CADM1 silenced cells. TSG101, a protein involved in lysosomal degradation of Cx43 was downregulated in the absence of CADM1 and possibly the mechanism for increased Cx43 expression. Also, immunostaining of adrenal sections showed internalised para-nuclear staining localisation of Cx43 in the ZG, APAs and APCCs, regions with high CADM1 expression compared to membranous localisation of Cx43 in ZF. In contrast to the common and numerous mutations in CACNA1D, mutations in CADM1 are rare. Nonetheless, they may enhance our understanding of the functional significance of glomerular structure of the outer zone of adrenal cortex, where cell-cell adhesion and intercellular communication appear critical for the regulation of aldosterone secretion.

Orientador: Roberta Okamoto / Coorientador: Leonardo Perez Faverani / Banca: Idelmo Rangel Garcia Junior / Banca: Paulo Roberto Botacin / Banca: Claudio Maldonado Pastori / Banca: Ana Cláudia Rossi / Resumo: Objetivo: O presente estudo objetivou avaliar as características morfométicas, histológicas e imunoistoquímicas do tecido ósseo coletado de pacientes portadores de hipertensão arterial sistêmica compensada pelo uso de medicamentos antagonistas do sistema renina-angiotensina-aldoesterona (SRAA). Materiais e Métodos: Trinta pacientes com indicação para reabilitação por meio de implantes instalados na região posterior de mandíbula foram divididos em dois grupos, seguindo os critérios de inclusão e exclusão previamente estabelecidos. O primeiro grupo não apresentava alterações sistêmicas (GSA) e não fazia uso de qualquer medicação e, o segundo grupo foi composto por pacientes hipertensos diagnosticados e medicados por antagonistas do SRAA (GAS). Durante o procedimento cirúrgico para instalação dos implantes osseointegráveis com superfície texturizada, foram coletados blocos ósseos por meio de biópsia com broca trefina de 3,0mm de diâmetro nos locais de instalação dos implantes. As biópsias coletadas foram separadas para avaliação por microtomografia computadorizada, sendo avaliados os seguintes parâmetros: volume ósseo (BV/TV), percentual de volume ósseo (BV/TV), espessura de trabéculas (Tb.Th), número de trabéculas (Tb.N), separação entre as trabéculas (Tb.S) e porosidade total (Po-tot). Também foi realizada a análise dos cortes histológicos corados por hematoxilina e eosina, bem como a avaliação imunoistoquímica de proteínas que caracterizam as células da linhagem osteoblástica...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Objectives: This study aimed to evaluate the morphometric characteristics, histological and immunohistochemical bone tissue collected from patients with hypertension offset by the use of drugs antagonists of the renin angiotensin system. Material and Methods: 30 patients referred for rehabilitation with implants placed in the posterior mandible were divided into two groups, following the criteria of inclusion and exclusion previously established. The first group showed no systemic changes (GSA) and did not use any medication and the second group was composed of diagnosed hypertensive patients treated by RAAS (GAS) antagonists. During the procedure for installation of dental implants with textured surface, they were collected bone blocks through biopsy trephine drill 3.0mm diameter implants in the installation sites. The collected biopsies were separated fo evaluatio by microtomography, being evaluated the following parameters: bone volume (BV / TV), trabecular thickness(Tb.Th), trabecular number (Tb.N), separation of the trabecular (Tb.S) and total porosity (Po-tot). Also the analysis of histological sections stained with hematoxylin and eosin staining was performed as well a the immunohistochemical evaluation of proteins that characterize the cells of osteoblast lineage: Runx2, osteopontin and osteocalcin. Results: For all parameters (BV, BV / TV, Tb.Th, Tb.N, Tb.S and E-tot) were similar in the comparison between GAS and GSA (p> 0.05, t test). The biology of bone tissue to ... (Complete abstract click electronic access below) / Doutor

The nuclear hormone receptor peroxisome proliferator-activated receptor Γ (PPARΓ) is a ligand-dependent transcription factor of increasing importance in cardiovascular physiology. Treatment of type II diabetes patients with thiazolidinediones (TZD), synthetic ligands of PPARΓ, improves insulin sensitivity and also lowers blood pressure despite increased water and salt retention by the kidneys. In 1999, Stephen O'Rahilly's group reported that patients carrying mutations in PPARΓ exhibit severe type II diabetes and early-onset hypertension. The missense mutations in PPARΓ (e.g. V290M, P467L) affect the ligand-binding domain and render the transcription factor dominant negative (DN). These findings suggested that the PPARΓ activation plays a vital role in cardiovascular regulation but they did not differentiate whether the cardiovascular protective effects of TZDs result from systemic metabolic changes or direct actions of PPARΓ in the vasculature. To answer this, our group generated transgenic mice that express DN PPARΓ specifically in vascular endothelial or vascular smooth muscle cell types. Herein we are reporting the molecular and physiological mechanism linking mutation of PPARΓ to impaired vascular function leading to hypertension. Smooth muscle-specific expression of DN PPARΓ in transgenic mice causes increased arterial pressure and enhanced agonist-mediated contraction and blunting of nitric oxide-mediated relaxation in aorta via a RhoA/Rho-kinase-dependent mechanism. Our results demonstrate that interference with PPARΓ in smooth muscle impairs Cullin-3 RING E3 ubiquitin ligase-mediated regulation of RhoA/Rho-kinase signaling and identify Cullin-3 as a novel regulator of vascular function. Hypertension, insulin resistance and atherosclerosis are major targets for therapeutic intervention against morbidity and mortality caused by coronary artery disease. In addition to the beneficial blood-pressure lowering and insulin-sensitizing effects of treatment with TZD PPARΓ agonists, they also have potent inhibitory effects on atherosclerosis progression. Given the concerns over TZD use including weight gain and edema, it is essential to understand the fundamental mechanisms by which vascular PPARΓ affects atherosclerosis lesion development. We tested this by crossing our transgenic mice onto the apolipoprotein E-deficient (ApoE-/-) mouse model of hypercholesterolemia. Either endothelial- or smooth muscle-specific expression of DN PPARΓ on the ApoE-/- background led to enhanced atherosclerotic lesion formation in aorta without altering levels of plasma cholesterol and triglycerides. Furthermore, endothelial- or smooth muscle-specific DN PPARΓ induced distinct alterations in the signature of genes related to atherogenesis when comparing aortic tissue from either model with its respective non-transgenic control. Our results obtained using PPARΓ-interfering mutations provide novel mechanistic insight into pathways critical to the pathogenesis of cardiovascular diseases.

Thesis (M Med.(Family Medicine & PHC))-- University of Limpopo, 2009. / A study on reasons why hypertensive patients seen at Natalspruit Hospital consult traditional healers whilst taking treatment from the hospital. Aim: To understand reasons given by patients receiving treatment for hypertension at Natalspruit Hospital for concurrently using traditional medicine. Design: Explorative descriptive qualitative study. Setting: Natalspruit Hospital, Gauteng – South Africa. Study population: All patients attending the researcher‟s practice suffering from hypertension and also consulted traditional healers. Results: The results of this study originated from the data collected from different interviews and their interpretations by the researcher. The respondents answered freely to the research question during a face to face conversation which was recorded with the purpose of exploring the topic in details. A certain number of information was obtained on why hypertensive patients despite their treatment from the researcher‟s practice were seeking help from the traditional healers. Number of answers derived from all respondents on the reasons why they combine the two types of medicine for their hypertension. This study focused on the ways the respondents felt about the service from the hospital/clinic, from the traditional healers and mainly on the reasons given by them when seeking help from traditional healers. Nine respondents were our group which was interviewed. The group consisted primarily of females than males, most of them were unemployed. Recommendations: Based on the results found, recommendations are that traditional medicine should be encouraged, especially in rural areas as it contributes substantially to primary health care. The government should primarily be using its resources in encouraging traditional healers to become a part of the health care delivery system through workshops involving both health professionals and traditional healers, training of modern doctors in the importance of cultural care and positive attitude towards the traditional healers. The government should consider integrating traditional medicine into the formal health system of the state. There is need to be education of patients on side-effects of anti-hypertensives at the time of dispensing, for instance ACE Inhibitors and the cough, to prevent patients seeking solutions for themselves, including taking traditional medication; education of staff in hospitals/clinics on care of patients to improve their attitudes. There is need for principles of Family Medicine to be taught and implemented in all levels of care. There is need for accessibility of modern medicine in remote areas where hospital facilities should be closer to all. A pilot referral system should be introduced and evaluated. If successful, a full-scale system should be introduced. This will ensure that the traditional healer feels both involved and committed. Traditional healers should come out into the open and be more assertive so that their work becomes transparent and this could further enhance their public image.

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Abstract not available