Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms

Hypertension and type 2 diabetes are common comorbidities. Hypertension is twice as frequent in patients with diabetes compared with those who do not have diabetes. Moreover, patients with hypertension often exhibit insulin resistance and are at greater risk of diabetes developing than are normotensive individuals. The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by hypertension. Accordingly, diabetes and hypertension are closely interlinked because of similar risk factors, such as endothelial dysfunction, vascular inflammation, arterial remodelling, atherosclerosis, dyslipidemia, and obesity. There is also substantial overlap in the cardiovascular complications of diabetes and hypertension related primarily to microvascular and macrovascular disease. Common mechanisms, such as upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system likely contribute to the close relationship between diabetes and hypertension. In this article we discuss diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions. We also highlight some vascular mechanisms that predispose to both conditions, focusing on advanced glycation end products, oxidative stress, inflammation, the immune system, and microRNAs. Finally, we provide some insights into current therapies targeting diabetes and cardiovascular complications and introduce some new agents that may have vasoprotective therapeutic potential in diabetes

Progenitor cells, bone marrow–derived fibrocytes and endothelial-to-mesenchymal transition: new players in vascular fibrosis

No abstract available

Factor analysis of treatment outcomes from a UK specialist addiction service:relationship between the Leeds Dependence Questionnaire, Social Satisfaction Questionnaire and 10-item Clinical Outcomes in Routine Evaluation

INTRODUCTION AND AIMS: To examine the relationship between three outcome measures used by a specialist addiction service (UK): the Leeds Dependence Questionnaire (LDQ), the Social Satisfaction Questionnaire (SSQ) and the 10-item Clinical Outcomes in Routine Evaluation (CORE-10). DESIGN AND METHOD: A clinical sample of 715 service user records was extracted from a specialist addiction service (2011) database. The LDQ (dependence), SSQ (social satisfaction) and CORE-10 (psychological distress) were routinely administered at the start of treatment and again between 3 and 12 months post-treatment. A mixed pre/post-treatment dataset of 526 service users was subjected to exploratory factor analysis. Parallel Analysis and the Hull method were used to suggest the most parsimonious factor solution. RESULTS: Exploratory factor analysis with three factors accounted for 66.2% of the total variance but Parallel Analysis supported two factors as sufficient to account for observed correlations among items. In the two-factor solution, LDQ items and nine of the 10 CORE-10 items loaded on the first factor >0.41, and the SSQ items on factor 2 with loadings >0.63. A two dimensional summary appears sufficient and clinically meaningful. DISCUSSION AND CONCLUSIONS: Among specialist addiction service users, social satisfaction appears to be a unique construct of addiction and is not the same as variation due to psychological distress or dependence. Our interpretation of the findings is that dependence is best thought of as a specific psychological condition subsumed under the construct psychological distress. [Fairhurst C, Böhnke JR, Gabe R, Croudace TJ, Tober G, Raistrick D. Factor analysis of treatment outcomes from a UK specialist addiction service: Relationship between the Leeds Dependence Questionnaire, Social Satisfaction Questionnaire and 10-item Clinical Outcomes in Routine Evaluation. Drug Alcohol Rev 2014;33:643–650

Complex zoning behavior in pyroxene in FeO-rich chondrules in the Semarkona ordinary chondrite

A detailed understanding of the properties of silicate minerals in chondrules is essential to the interpretation of chondrule formation conditions. This study is further work in a series of petrologic studies of chondrules in the least equilibrated LL chondrite, Semarkona (LL3.0). The objectives of this work are as follows: (1) to understand chondrule formation conditions and nebular processes; and (2) to use the data as a basis for understanding the effects of metamorphism in more equilibrated chondrites. FeO-rich pyroxene in the chondrules described shows complex zoning behavior. Low-Ca clinopyroxene, orthopyroxene, pigeonite, and augite are all observed, in various associations with one another. Coexisting olivine phenocrysts are also FeO-rich and strongly zoned. Compositional and zoning properties are similar to those observed in boninites and are interpreted as resulting from rapid cooling of individual chondrules

Toxicity of cancer therapy: what the cardiologist needs to know about angiogenesis inhibitors

Clinical outcomes for patients with a wide range of malignancies have improved substantially over the last two decades. Tyrosine kinase inhibitors (TKIs) are potent signalling cascade inhibitors and have been responsible for significant advances in cancer therapy. By inhibiting vascular endothelial growth factor receptor (VEGFR)-mediated tumour blood vessel growth, VEGFR-TKIs have become a mainstay of treatment for a number of solid malignancies. However, the incidence of VEGFR-TKI-associated cardiovascular toxicity is substantial and previously under-recognised. Almost all patients have an acute rise in blood pressure, and the majority develop hypertension. They are associated with the development of left ventricular systolic dysfunction (LVSD), heart failure and myocardial ischaemia and can have effects on myocardial repolarisation. Attention should be given to rigorous baseline assessment of patients prior to commencing VEGFR-TKIs, with careful consideration of baseline cardiovascular risk factors. Baseline blood pressure measurement, ECG and cardiac imaging should be performed routinely. Hypertension management currently follows national guidelines, but there may be a future role forendothelin-1 antagonism in the prevention or treatment of VEGFR-TKI-associated hypertension. VEGFR-TKI-associated LVSD appears to be independent of dose and is reversible. Patients who develop LVSD and heart failure should be managed with conventional heart failure therapies, but the role of prophylactic therapy is yet to be defined. Serial monitoring of left ventricular function and QT interval require better standardisation and coordinated care. Management of these complex patients requires collaborative, cardio-oncology care to allow the true therapeutic potential from cancer treatment while minimising competing cardiovascular effects

The Lymphoedema Genitourinary Cancer Questionnaire in urology follow‐up clinics

Is the Lymphoedema Genitourinary Cancer Questionnaire (LGUCQ) useful to men treated for genitourinary cancer through facilitating symptom disclosure? Lymphoedema can be debilitating and progressive and its association with bladder, prostate, testicular and penile cancer, either as a consequence of treatment or progressive disease is well recognized. However, lymphoedema is generally unrecognized during follow‐up. Research on genitourinary cancer‐related lymphoedema is sparse with a lack of reliable prevalence figures. A lack of empirical understanding of the experiences of these men led to the development of the LGUCQ, a simple two‐sided tool to facilitate self‐reporting of symptoms and difficulties associated with lymphoedema. Related pilot work suggests that written self‐report tools enable men to disclose more sensitive information than they would verbally. However, the LGUCQ had not been formally evaluated in an uro‐oncology department to identify the benefits from the perspective of the patients and health professionals. Thematic analysis of completed LGUCQs and interviews with patients and staff were performed. Emergent themes included the perceived barriers to symptom disclosure, the LGUCQ as facilitator and pragmatic addition, the support needs of patients and health professionals and refinements required for roll out. Issues limiting identification of lymphoedema within uro‐oncology services existed. Findings suggest the inclusion of the LGUCQ within uro‐oncology clinics could lead to earlier identification of lymphoedema. Patients could identify genital oedema problems with the LGUCQ increasing prompt and accurate disclosure and normalizing the experience

Monotherapy with major antihypertensive drug classes and risk of hospital admissions for mood disorders

Major depressive and bipolar disorders predispose to atherosclerosis, and there is accruing data from animal model, epidemiological, and genomic studies that commonly used antihypertensive drugs may have a role in the pathogenesis or course of mood disorders. In this study, we propose to determine whether antihypertensive drugs have an impact on mood disorders through the analysis of patients on monotherapy with different classes of antihypertensive drugs from a large hospital database of 525 046 patients with follow-up for 5 years. There were 144 066 eligible patients fulfilling the inclusion criteria: age 40 to 80 years old at time of antihypertensive prescription and medication exposure >90 days. The burden of comorbidity assessed by Charlson and Elixhauser scores showed an independent linear association with mood disorder diagnosis. The median time to hospital admission with mood disorder was 847 days for the 299 admissions (641 685 person-years of follow-up). Patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had the lowest risk for mood disorder admissions, and compared with this group, those on β-blockers (hazard ratio=2.11; [95% confidence interval, 1.12–3.98]; P=0.02) and calcium antagonists (2.28 [95% confidence interval, 1.13–4.58]; P=0.02) showed higher risk, whereas those on no antihypertensives (1.63 [95% confidence interval, 0.94–2.82]; P=0.08) and thiazide diuretics (1.56 [95% confidence interval, 0.65–3.73]; P=0.32) showed no significant difference. Overall, our exploratory findings suggest possible differential effects of antihypertensive medications on mood that merits further study: calcium antagonists and β-blockers may be associated with increased risk, whereas angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be associated with a decreased risk of mood disorders

Proteins involved in endocytosis are upregulated by ageing in the normal human brain: Implications for the development of Alzheimer's Disease

© The Author(s) 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. The greatest risk factor for Alzheimer's disease (AD) is advanced age, but the reason for this association remains unclear. Amyloid-β (Aβ) is produced from amyloid precursor protein (APP) primarily after APP is internalized by clathrin-mediated or clathrin-independent endocytosis. Changes in endocytosis in AD have been identified. We hypothesized that endocytic protein expression is altered during ageing, thus influencing the likelihood of developing AD by increasing Aβ production. We explored how levels of endocytic proteins, APP, its metabolites, secretase enzymes, and tau varied with age in cortical brain samples from men of three age ranges (young [20-30], middle aged [45-55], and old [70-90]) with no symptoms of dementia. Aβ40 and Aβ42 were significantly increased in old brains, while APP and secretase expression was unaffected by age. Phosphorylated GSK3β increased significantly with age, a possible precursor for neurofibrillary tangle production, although phosphorylated tau was undetectable. Significant increases in clathrin, dynamin-1, AP180, Rab-5, caveolin-2, and flotillin-2 were seen in old brains. Rab-5 also increased in middle-aged brains prior to changes in Aβ levels. This age-related increase in endocytic protein expression, not described previously, suggests an age-related upregulation of endocytosis which could predispose older individuals to develop AD by increasing APP internalization and Aβ generation

Vascular smooth muscle contraction in hypertension

Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, vascular dementia and chronic kidney disease. Pathophysiological mechanisms contributing to the development of hypertension include increased vascular resistance, determined in large part by reduced vascular diameter due to increased vascular contraction and arterial remodelling. These processes are regulated by complex interacting systems such as the renin angiotensin aldosterone system (RAAS), sympathetic nervous system, immune activation and oxidative stress, which influence vascular smooth muscle function. Vascular smooth muscle cells are highly plastic and in pathological conditions undergo phenotypic changes from a contractile to a proliferative state. Vascular smooth muscle contraction is triggered by an increase in intracellular free calcium concentration ([Ca2+]i), promoting actin-myosin cross-bridge formation. Growing evidence indicates that contraction is also regulated by calcium-independent mechanisms involving RhoA-Rho kinase (ROCK), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signaling, reactive oxygen species and reorganization of the actin cytoskeleton. Activation of immune/inflammatory pathways and noncoding RNAs are also emerging as important regulators of vascular function. Vascular smooth muscle cell [Ca2+]i, not only determines the contractile state but also influences activity of many calcium-dependent transcription factors and proteins thereby impacting the cellular phenotype and function. Perturbations in vascular smooth muscle cell signaling and altered function influence vascular reactivity and tone, important determinants of vascular resistance and blood pressure. Here we discuss mechanisms regulating vascular reactivity and contraction in physiological and pathophysiological conditions and highlight some new advances in the field, focusing specifically on hypertension

Transgender adults, gender-affirming hormone therapy and blood pressure: a systematic review

Objectives: Gender-affirming hormone therapy (GHT) is utilized by people who are transgender to align their secondary sex characteristics with their sex identity. Data relating to cardiovascular outcomes in this population are limited. We aimed to review the impact of GHT on the blood pressure (BP) of transgender individuals. Methods: We searched PubMed/MEDLINE, SCOPUS and Cochrane Library databases for articles published relating to the BP of transgender adults commencing GHT. Methodological quality was assessed via the ‘Quality Assessment Tool for Before–After (Pre–Post) Studies with No Control Group’. Results: Six hundred articles were screened, of which 14 studies were included in this systematic review encompassing 1309 individuals (∼50% transgender men and women) treated with GHT between 1989 and 2019. These articles were all pre–post observational studies without control groups. Mean ages ranged between 23.0–36.7 years (transgender men) and 25.2–34.8 years (transgender women). Interventions were diverse and included oral, transdermal and injectable hormonal preparations with 4 months to 5 years follow-up. Most studies in transgender men did not demonstrate a change in BP, whereas transgender women on GHT demonstrated an increase in SBP but not DBP. These studies were heterogenous with significant methodological limitations and only two were determined to have a good quality rating. Conclusion: There is currently insufficient data to advise the impact of GHT on BP in transgender individuals. Better quality research is essential to elucidate whether exogenous sex hormones modulate BP in transgender people and whether this putative alteration infers poorer cardiovascular outcomes