Pathophysiologic correlates of exercise intolerance in adults with pulmonary hypertension and congenital heart disease

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The Role of Urban Morphology Design on Enhancing Physical Activities and Public Health

Along with environmental pollutions, urban planning has been connected to public health. The research indicates that the quality of built environments plays an important role in reducing mental disorders and overall health. The structure and shape of the city are considered as one of the factors influencing happiness and health in urban communities and the type of the daily activities of citizens. The aim of this study was to promote physical activity in the main structure of the city via urban design in a way that the main form and morphology of the city can encourage citizens to move around and have physical activity within the city. Functional, physical, cultural- social, and perceptual-visual features are regarded as the most important and effective criteria in increasing physical activities in urban spaces based on literature review. The environmental quality of urban spaces and their role in the physical activities of citizens in urban spaces were assessed by using the questionnaire tool and analytical network process (ANP) of structural equation modeling. Further, the space syntax method was utilized to evaluate the role of the spatial integration of urban spaces on improving physical activities. Based on the results, the consideration of functional diversity, spatial flexibility and integration, security, and the aesthetic and visual quality of urban spaces plays an important role in improving the physical health of citizens in urban spaces. Further, more physical activities, including motivation for walking and consequently, the sense of public health and happiness, were observed in the streets having higher linkage and space syntax indexes with their surrounding texture

Patient and Disease-Specific Induced Pluripotent Stem Cells for Discovery of Personalized Cardiovascular Drugs and Therapeutics.

Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. Despite significant advances, drug therapy and discovery for cardiovascular disease have lagged behind other fields such as oncology. We speculate that this paucity of drug discovery is due to a previous lack of efficient, reproducible, and translational model systems. Notably, existing drug discovery and testing platforms rely on animal studies and clinical trials, but investigations in animal models have inherent limitations due to interspecies differences. Moreover, clinical trials are inherently flawed by assuming that all individuals with a disease will respond identically to a therapy, ignoring the genetic and epigenomic variations that define our individuality. With ever-improving differentiation and phenotyping methods, patient-specific iPSC-derived cardiovascular cells allow unprecedented opportunities to discover new drug targets and screen compounds for cardiovascular disease. Imbued with the genetic information of an individual, iPSCs will vastly improve our ability to test drugs efficiently, as well as tailor and titrate drug therapy for each patient

Pharmacometabolomics reveals racial differences in response to atenolol treatment.

Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug

Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability

Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability. Am J Physiol Renal Physiol 313: F174 –F183, 2017. First published March 29, 2017; doi:10.1152/ajprenal.00482.2016.—The goals of this study were to 1) develop a computational model of solute transport and oxygenation in the kidney of the female spontaneously hypertensive rat (SHR), and 2) apply that model to investigate sex differences in nitric oxide (NO) levels in SHR and their effects on medullary oxygenation and oxidative stress. To accomplish these goals, we first measured NO synthase (NOS) 1 and NOS3 protein expression levels in total renal microvessels of male and female SHR. We found that the expression of both NOS1 and NOS3 is higher in the renal vasculature of females compared with males. To predict the implications of that finding on medullary oxygenation and oxidative stress levels, we developed a detailed computational model of the female SHR kidney. The model was based on a published male kidney model and represents solute transport and the biochemical reactions among O2, NO, and superoxide (O2 ) in the renal medulla. Model simulations conducted using both male and female SHR kidney models predicted significant radial gradients in interstitial fluid oxygen tension (PO2) and NO and O2 concentration in the outer medulla and upper inner medulla. The models also predicted that increases in endothelial NO-generating capacity, even when limited to specific vascular segments, may substantially raise medullary NO and PO2 levels. Other potential sex differences in SHR, including O2 production rate, are predicted to significantly impact oxidative stress levels, but effects on NO concentration and PO2 are limited.This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-106102 to A. T. Layton, and by American Heart Association Grant 14GRNT20480199 to J. C. Sullivan. (R01-DK-106102 - National Institute of Diabetes and Digestive and Kidney Diseases; 14GRNT20480199 - American Heart Association)Accepted manuscrip

Epigenetics and immunometabolism in diabetes and aging

Significance: A strong relationship between hyperglycemia, impaired insulin pathway and cardiovascular disease in type 2 diabetes (T2D) is linked to oxidative stress and inflammation. Immunometabolic pathways link these pathogenic processes and pose important potential therapeutic targets. Recent Advances: The link between immunity and metabolism is bi-directional and includes the role of inflammation in the pathogenesis of metabolic disorders such as T2D, obesity, metabolic syndrome and hypertension as well as the role of metabolic factors in regulation of immune cell functions. Low-grade inflammation, oxidative stress, balance between superoxide and nitric oxide, and the infiltration of macrophages, T cells, B cells in insulin-sensitive tissues, leads to metabolic impairment and accelerated ageing. Critical Issues: Inflammatory infiltrate and altered immune cell phenotype precede development of metabolic disorders. Inflammatory changes are tightly linked to alterations in metabolic status and energy expenditure and are controlled by epigenetic mechanisms. Future directions: A better comprehension of these mechanistic insights is of utmost importance to identify novel molecular targets. Here, we describe a complex scenario of epigenetic changes and immunometabolism linking to diabetes and aging-associated vascular disease

Cardiovascular and metabolic effects of long-term traffic noise exposure

Traffic noise is an increasingly common environmental exposure affecting large parts of the European population. Since the auditory system is directly linked to the sympathetic nervous and the endocrine systems, noise may induce a stress response, influencing several physiological, metabolic and immunological processes. Previous epidemiological studies suggest harmful effects of traffic noise on the cardiovascular system; however, the overall picture is inconclusive. The primary aim of this thesis was to investigate the long-term effects of traffic noise on cardiovascular and metabolic outcomes. A secondary aim was to apply and evaluate digital noise maps produced in Sweden in accordance with the European Environmental Noise Directive (END) for assessments of residential traffic noise exposure. The long-term effects of aircraft noise on hypertension, obesity and Type 2 diabetes were investigated using questionnaire and clinical data from a cohort within the Stockholm Diabetes Prevention Program. Aircraft noise exposure was assessed by Geographic Information Systems and based on the participants’ residential history. After exclusion of subjects who used tobacco prior to the clinical examinations, the risk of hypertension related to aircraft noise exposure was increased in males (RR per 5 dB(A) Lden 1.21; 95% CI 1.05-1.39) but not in females (RR 0.97; 0.83-1.13). Stronger associations were seen among noise annoyed (RR 1.42; 1.11-1.82). Regardless of sex, long-term exposure to aircraft noise also showed statistically significant associations with waist circumference: 0.62 cm (0.54-0.70) per 1 dB(A) Lden. Also, females exposed at ≥50 dB(A) Lden had a twofold increased risk of Type 2 diabetes, although adjustments for contextual confounding reduced the estimates. A sub-population of the National Environmental Health Survey 2007 (NEHS07) was used to evaluate the Swedish END maps of road traffic and railway noise. The observed proportion of annoyed subjects was plotted as a function of noise exposure and compared to already established exposure-response functions. Generally, there was a good agreement between observed and predicted proportions of annoyed, suggesting that the noise maps are useful for assessments of residential traffic noise exposure. The best agreement was found when the noise estimates derived from the maps were adjusted for how the dwellings were located within the buildings. Cross-sectional analyses were performed based on the NEHS07 of associations between neighborhood traffic load, Lden levels of road traffic and railway noise, respectively, and prevalence of self-reported hypertension and cardiovascular disease. Neither traffic load nor road traffic noise was associated with the cardiovascular outcomes; however, there was a borderline significant association between railway noise and cardiovascular disease. Methodological limitations make these results difficult to interpret. In conclusion, our findings suggest adverse effects of long-term traffic noise exposure on cardiovascular as well as metabolic outcomes. Thus, traffic noise may have detrimental public health effects and research in this area should be prioritized