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Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure–regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT1R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.

Background: Stroke commonly affects cognition and, by definition, much vascular dementia follows stroke. However, there are fundamental limitations in our understanding of vascular cognitive impairment, restricting understanding of prevalence, trajectories, mechanisms, prevention, treatment, and patient service needs. Aims: Rates, Risks and Routes to Reduce Vascular Dementia (R4VaD) is an observational cohort study of post-stroke cognition. We aim to recruit a wide range of patients with stroke, presenting to geographically diverse UK hospitals, into a longitudinal study to determine rates of, and risk factors for, cognitive and related impairments after stroke, to assess potential mechanisms and improve prediction models. Methods: We will recruit at least 2000 patients within six weeks of stroke with or without capacity to consent, and collect baseline demographic, clinical, socioeconomic, lifestyle, cognitive, neuropsychiatric and informant data using streamlined patient centred methods appropriate to the stage after stroke. We will obtain more detailed assessments at 4-8 weeks after the baseline assessment and follow-up by phone and post yearly to at least 2 years. We will assess diagnostic neuroimaging in all, and high-sensitivity inflammatory markers, genetics, blood pressure (BP) and diffusion tensor imaging in mechanistic sub-studies. Planned Outputs: R4VaD will provide reliable data on long-term cognitive function after stroke, stratified by prior cognition, stroke- and patient-related variables, and improved risk prediction. It will create a platform enabling sharing of data, imaging and samples. Participants will be consented for re-contact, facilitating future clinical trials, and providing a resource for the stroke and dementia research communities.

AIMS: Interferon-stimulated gene 15 (ISG15) encodes an ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defense response to microbial infection; however, its contribution to vascular damage associated to hypertension is unknown. METHODS AND RESULTS: Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensinII (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodeling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodeling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodeling. CONCLUSION: ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation. TRANSLATIONAL PERSPECTIVE: Recent evidence from randomized clinical trials demonstrate the effectiveness of specific anti-inflammatory treatments in cardiovascular prevention. In this study we have identified a new inflammatory mediator involved in vascular damage in experimental and human hypertension and aneurysms. We found that interferon stimulated gene 15 (ISG15) is increased at the vascular level in animal models of hypertension and aneurysms. More importantly, ISG15 correlates with human hypertension, vascular remodeling, and aneurysms presence. Underlying mechanisms responsible for vascular damage induced by ISG15 include oxidative and inflammation. Our results further support the role of inflammation in vascular damage in different cardiovascular pathologies.

To provide updated, evidence-based recommendations for the management of hypertension in adults.For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. While changes in cardiovascular morbidity and mortality were the primary outcomes of interest, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity/mortality data in this field, and for certain comorbid conditions, other relevant outcomes, such as development of proteinuria or worsening of kidney function, were considered.MEDLINE searches were conducted from November 2003 to October 2004 to update the 2004 recommendations. Reference lists were scanned, experts were contacted, and the personal files of the subgroup members and authors were used to identify additional published studies. All relevant articles were reviewed and appraised independently, using prespecified levels of evidence, by content and methodology experts. As per previous years, only studies that had been published in the peer-reviewed literature were included; evidence from abstracts, conference presentations and unpublished personal communications was not included.Lifestyle modifications to prevent and/or treat hypertension include the following: perform 30 min to 60 min of aerobic exercise on four to seven days of the week; maintain a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a reduced fat, low cholesterol diet with an adequate intake of potassium, magnesium and calcium; restrict salt intake; and consider stress management (in selected individuals). Treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and any comorbid conditions. Blood pressure should be lowered to 140/90 mmHg or less in all patients, and to 130/80 mmHg or less in those with diabetes mellitus or chronic kidney disease. Most adults with hypertension require more than one agent to achieve target blood pressures. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic hypertension with or without systolic hypertension include beta-blockers (in those younger than 60 years), angiotensin-converting enzyme (ACE) inhibitors (except in black patients), long-acting calcium channel blockers and angiotensin receptor antagonists. Other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine calcium channel blockers and angiotensin receptor antagonists. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with diabetes mellitus, ACE inhibitors or angiotensin receptor antagonists (or thiazides in patients with diabetes mellitus without albuminuria) are appropriate first-line therapies; and in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended. All hypertensive patients should have their fasting lipids screened, and those with dyslipidemia should be treated using the thresholds, targets and agents recommended by the Canadian Hypertension Education Program Working Group on the management of dyslipidemia and the prevention of cardiovascular disease. Selected patients with hypertension, but without dyslipidemia, should also receive statin therapy and/or acetylsalicylic acid therapy.All recommendations were graded according to the strength of the evidence and voted on by the 43 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.