Ambulatory blood pressure monitoring in clinical trials with antihypertensive agents

Ambulatory blood pressure monitoring (ABPM) is being used increasingly for the evaluation of antihypertensive agents in clinical trials. In this brief review several aspects of ABPM are discussed. In particular, attention is paid to the extent to which ABPM is subject to a placebo response and the extent to which the sample size of the study population can be reduced with this type of measurement. In addition, some remarks are made with regard to how selection of patients with this methodology can be improved and how it may be used as a tool to evaluate the duration of action of antihypertensive agents. Finally, some potential disadvantages of ABPM as compared to conventional clinic blood pressure measurements are discussed

Recent advances in hypertension and cardiovascular toxicities with vascular endothelial growth factor inhibition

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Semicarbazide-sensitive amine oxidase (SSAO): from cell to circulation

Semicarbazide-sensitive amine oxidase (SSAO) is a multi-functional enzyme widely present in nature. It converts primary amines into their corresponding aldehydes, while generating H(2)O(2) and NH(3). In mammals, SSAO circulates in plasma, while a membrane-bound form (often referred to as vascular adhesion protein-1, VAP-1) is found in many tissues and organs, especially in adipocytes and vascular endothelial and smooth muscle cells. In recent years, evidence has been accumulating that SSAO has a role in protein cross-linking, formation of advanced glycation end-products, atherogenesis, glucose regulation and leukocyte extravasation at inflammation sites. Plasma SSAO is quite stable in healthy adults, but is elevated in diabetes mellitus (both type 1 and type 2), congestive heart failure and liver cirrhosis. The origin of circulating SSAO remains unclear, but recent evidence from clinical studies and from (transgenic) animal studies suggests that adipocytes and vascular endothelial cells may be the most important source. Studies with cell cultures show evidence that the membrane-bound SSAO can be split off from the cells, thus giving rise to the (truncated) circulating form of SSAO. In some pathological conditions the diseased organ may be the main source of the elevated plasma SSAO. Little is known as yet about the regulation of plasma SSAO. Thyroid hormone appears to play a (modest) role in this respect. Further evidence from clinical, animal and cell-culture studies, helped by the new availability of selective SSAO inhibitors, is needed to shed more light on the question of the regulation of SSAO

Drug mechanisms to help in managing resistant hypertension in obesity

Obesity is a major risk factor for the development of hypertension. Because the prevalence of obesity is increasing worldwide, the prevalence of obesity hypertension is also increasing. Importantly, hypertension in obesity is commonly complicated by dyslipidemia and type 2 diabetes mellitus and hence imposes a high cardiovascular disease risk. Furthermore, obesity is strongly associated with resistant hypertension. Activation of the sympathetic nervous system and the renin-angiotensin system, leading to renal sodium and water retention, links obesity with hypertension. There is also evidence for the release of factors by visceral adipose tissue promoting excessive aldosterone production, and a more central role of aldosterone in obesity hypertension is emerging. Randomized studies evaluating the effect of different classes of antihypertensive agents in obesity hypertension are scarce, short-lasting, and small. Considering the emerging role of aldosterone in the pathogenesis of obesity hypertension, mineralocorticoid receptor antagonism may play a more central role in the pharmacologic treatment of obesity hypertension in the near future

Endothelin-1 and blood pressure after inhibition of nitric oxide synthesis in human septic shock

BACKGROUND: The systemic hypotension during human sepsis has been ascribed to increased production of nitric oxide (NO). Therefore, inhibitors of NO synthesis have been used in the treatment of hypotension in patients with septic shock. In addition, NO production may inhibit the synthesis and vasoconstrictor effects of endothelin-1 (ET-1). In this study, we tested whether ET-1 contributed to the vasopressor action of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock. METHODS AND RESULTS: Compared with healthy volunteers, patients with septic shock had increased plasma levels of nitrite/nitrate (37+/-5 [SEM] versus 12+/-5 mmol/L, P<0.01), the stable end products of NO metabolism, and ET-1 (45+/-7 versus 3+/-2 pg/mL, P<0.001). Plasma ET-1 concentration was not related to plasma nitrite/nitrate concentration or blood pressure. Continuous infusion of L-NAME (1 mg. kg-1. h-1 IV) for 12 hours increased mean arterial pressure by 43+/-5% and systemic vascular resistance by 64+/-10% (both P<0.01). The increase in blood pressure and systemic vascular resistance correlated positively with the level of ET-1 (both P<0. 005) but not with plasma nitrite/nitrate level. L-NAME infusion did not result in significant changes in the plasma concentrations of ET-1 or nitrite/nitrate. CONCLUSIONS: NO and ET-1 may both play a role in the cardiovascular derangements of human sepsis. Although L-NAME does not increase ET-1 concentration in patients with septic shock, the vasopressor response induced by L-NAME depends on the plasma level of ET-1. These findings may indicate that inhibitors of NO synthesis unmask a tonic pressor response of ET-1 in human septic shock

Hypertension: Renin-Angiotensin-Aldosterone System Alterations

Blockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension

The impact of implementing the WHO-2013 criteria for gestational diabetes mellitus on its prevalence and pregnancy outcomes: A comparison of the WHO-1999 and WHO-2013 diagnostic thresholds

Aims/hypothesis: To determine the impact of implementing the new WHO-2013 criteria on prevalence of gestational diabetes mellitus (GDM) and pregnancy outcomes compared to the WHO-1999 criteria. Methods: A retrospective study conducted in pregnant women who were referred to the Erasmus MC for an oral glucose tolerance test (OGTT) between 2010 and 2015. Results: Of 3089 women, 11.5 % (n = 354) were diagnosed with GDM based on the WHO-1999 criteria and 17.0 % (n = 524) based on the 2013–criteria, with 97 (3.1 %) reclassified as non-GDM and 267 (8.6 %) reclassified as GDM when shifting from the 1999 to 2013-criteria. In contrast to 60 % of patients in the WHO-2013 group, only 2 % of the WHO-1999 group was diagnosed with GDM because of an elevated fasting glucose only. Patients reclassified as GDM by WHO-2013 criteria had a higher body mass index (p < 0.001) and delivered babies with a higher birth weight (p = 0.01). Maternal and neonatal adverse outcomes were comparable between patients with GDM based on WHO-1999 criteria and patients newly included by WHO-2013 criteria. Conclusions: Implementing the new diagnostic criteria leads to a considerable increase of prevalence of GDM. The newly included patients were more frequently overweighed and delivered babies with a higher birth weight. The added diagnostic value of the fasting glucose threshold of the WHO-1999 criteria is very low compared to the 2-h post-OGTT threshold, supporting the use of a lower fasting glucose threshold value as advocated by the WHO-2013 criteria. Tweet: The new WHO-2013 criteria leads to a considerable increase of prevalence of GDM