Pathophysiology Of Cardiovascular Disease Research Articles

MO757: Prevention of Vascular Calcification by the Endogenous Chromogranin a-Derived Mediator that Inhibits Osteogenic Transdifferentiation

Abstract BACKGROUND AND AIMS The adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. METHOD In this study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. RESULTS This peptide was named the ‘calcification blocking factor’ (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-κB activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. CONCLUSION In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short-active sites may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification.

Sex Differences in Vascular Endothelial Function After Liver Transplant

INTRODUCTIONLiver transplant (LT) recipients have an increased risk of developing cardiovascular disease (CVD) after transplant. Sex differences may be a significant determinant in the pathophysiology of CVD. However, sex‐differences in vascular dysfunction, an established precursor to CVD, have not been explored in LT recipients. The purpose of this study was to investigate the sex differences in vascular function and cardiometabolic risk‐factors to CVD among LT patients.METHODSConduit artery endothelial function was measured via flow‐mediated dilation of the brachial artery (FMDBA) with duplex ultrasound in 23 age‐matched LT patients (11 Male, 12 Female; Mean ± SEM: Age 55 ± 2 years). Aortic pressure waves were synthesized from radial artery waveforms acquired by applanation tonometry and the use of a generalized transfer function. Novel plasma based cardiometabolic risk factors were assessed with nuclear magnetic resonance spectroscopy. Lipoprotein insulin resistance index (LPIR) was calculated as a weighted combination of concentrations and particle sizes of very low‐density, low‐density, and high‐density lipoproteins. Diabetes risk index (DRI) factors LPIR and branched‐chain amino acid levels to predict the risk of type 2 diabetes. Metabolic inflammation index (INFX) combines concentrations of the inflammation biomarker GlycA and high‐density lipoprotein particle subspecies.RESULTSMales had lower FMDBA than females (3.98 ± 0.63 vs 6.27 ± 0.43%, p < 0.01). There were no sex differences in aortic systolic pressure (Male vs Female; 129 ± 3 vs 118 ± 5 mmHg, p = 0.09), body mass index (38 ± 2 vs 36 ± 2 kg/m2, p = 0.61), LPIR (57 ± 7 vs 55 ± 7, p = 0.89), DRI (53 ± 7 vs 44 ± 6, p = 0.38), or INFX (47 ± 2 vs 54 ± 3, p = 0.13).CONCLUSIONSMales had poorer vascular endothelial function compared to females following LT, suggesting that males may be more susceptible to the development of CVD after LT. However, this increased risk cannot be explained by differences in traditional cardiometabolic risk factors. Future research should identify non‐traditional CVD risk factors that contribute to sex differences in vascular function towards implementing precision medicine for the prevention and management of CVD in LT patients.

The good, the bad and the ugly: the impact of extracellular vesicles on the cardiovascular system.

Cardiovascular diseases (CVDs), which encompass a myriad of pathological conditions that affect the heart and/or the blood vessels, remain the major cause of morbidity and mortality worldwide. By transferring a wide variety of bioactive molecules, including proteins and microRNAs (miRNAs), extracellular vesicles (EVs) are recognized as key players in long-range communication across the cardiovascular system. It has been demonstrated that these highly heterogeneous nanosized vesicles participate both in the maintenance of homeostasis of the heart and vessels, and contribute to the pathophysiology of CVDs, thus emerging as promising tools for diagnosis, prognosis and treatment of multiple CVDs. In this review, we highlight the beneficial roles of EV-mediated communication in regulating vascular homeostasis, and inter-organ crosstalk as a potential mechanism controlling systemic metabolic fitness. In addition, the impact of EV secretion in disease development is described, particularly focusing on cardiac remodelling following ischaemia, atherogenesis and atrial fibrillation progression. Finally, we discuss the potential of endogenous and bioengineered EVs as therapeutic tools for CVDs, as well as the suitability of assessing the molecular signature of circulating EVs as a non-invasive predictive marker of CVD onset and progression. This rapidly expanding field of research has established the role of EVs as key conveyors of both cardioprotective and detrimental signals, which might be of relevance in uncovering novel therapeutic targets and biomarkers of CVDs.

Glucosamine regulates macrophage function in heart failure.

Glucosamine regulates macrophage function in heart failure.

Effect of oxidative stress on telomere maintenance in aortic smooth muscle cells

Reactive oxygen species (ROS) and telomere dysfunction are both associated with aging and the development of age-related diseases. Although there is evidence for a direct relationship between ROS and telomere dysfunction as well as an independent association of oxidative stress and telomere attrition with age-related disorders, there has not been sufficient exploration of how the interaction between oxidative stress and telomere function may contribute to the pathophysiology of cardiovascular diseases (CVD). To better understand the complex relationships between oxidative stress, telomerase biology and pathophysiology, we examined the telomere biology of aortic smooth muscle cells (ASMCs) isolated from mutant mouse models of oxidative stress. We discovered that telomere lengths were significantly shorter in ASMCs isolated from superoxide dismutase 2 heterozygous (Sod2+/−) mice, which exhibit increased arterial stiffness with aging, and the observed telomere attrition occurred over time. Furthermore, the telomere erosion occurred even though telomerase activity increased. In contrast, telomeres remained stable in wild-type and superoxide dismutase 1 heterozygous (Sod1+/−) mice, which do not exhibit CVD phenotypes. The data indicate that mitochondrial oxidative stress, in particular elevated superoxide levels and decreased hydrogen peroxide levels, induces telomere erosion in the ASMCs of the Sod2+/− mice. This reduction in telomere length occurs despite an increase in telomerase activity and correlates with the onset of disease phenotype. Our results suggest that the oxidative stress caused by imbalance in mitochondrial ROS, from deficient SOD2 activity as a model for mitochondrial dysfunction results in telomere dysfunction, which may contribute to pathogenesis of CVD.

The Case for, and Challenges of, Human Cardiac Tissue in Advancing Phosphoprotein Research.

Cardiovascular disease (CVD) and stroke affect over 92 million Americans and account for nearly 1 out of 3 deaths in the US. The use of animal models in cardiovascular research has led to considerable advances in treatment and in our understanding of the pathophysiology of many CVDs. Still, animals may not fully recapitulate human disease states; species differences have long been postulated to be one of the main reasons for a failure of translation between animals and humans in drug discovery and development. Indeed, it has become increasingly clear over the past few decades that to answer certain biomedical questions, like the physiological mechanisms that go awry in many human CVDs, animal tissues may not always be the best option to use. While human cardiac tissue has long been used for laboratory research, published findings often contradict each other, leading to difficulties in interpretation. Current difficulties in utilizing human cardiac tissue include differences in acquisition time, varying tissue procurement protocols, and the struggle to define a human “control” sample. With the tremendous emphasis on translational research that continues to grow, research studies using human tissues are becoming more common. This mini review will discuss advantages, disadvantages, and considerations of using human cardiac tissue in the study of CVDs, paying specific attention to the study of phosphoproteins.

Integrated metabolomic and transcriptomic analysis identifies benzo[a]pyrene-induced characteristic metabolic reprogramming during accumulation of lipids and reactive oxygen species in macrophages

Polycyclic aromatic hydrocarbon exposure is a major risk factor for cardiovascular diseases. Macrophage lipid accumulation is a characteristic molecular event in the pathophysiology of cardiovascular diseases. Metabolic reprogramming is an intervention target for diseases and toxic effects of environmental pollutants. However, comprehensive metabolic reprogramming related to BaP-induced macrophage lipid accumulation is currently unexplored. Therefore, metabolomics and transcriptomics were conducted to unveil relevant metabolic reprogramming in BaP-exposed macrophages, and to discover potential intervention targets. Metabolomics revealed that most amino acids, nucleotides, monosaccharides, and organic acids were significantly decreased, while most fatty acids and steroids accumulated in BaP-exposed macrophages. Transcriptomics showed that fatty acid synthesis and oxidation, and steroid synthesis and export were decreased, while import of fatty acids and steroids was increased, indicating potential roles of lipid transport in macrophage lipid accumulation following BaP exposure. Meanwhile, alanine, aspartate and glutamate metabolism, branched-chain amino acid degradation, nucleotide synthesis, monosaccharide import, pentose phosphate pathway, citrate synthesis, and glycolysis were decreased, while nucleotide degradation was increased, thus inducing decreases in most amino acids, nucleotides, monosaccharides, and organic acids in BaP-exposed macrophages. Additionally, increases in oxidative stress and the activation of antioxidant systems were observed in BaP-exposed macrophages, which was evinced by increases in reactive oxygen species, and the activation of Fenton reaction, Vdac2/3, Sod2, and Nrf2. Moreover, BaP-induced accumulation of reactive oxygen species and lipids in macrophages could be abolished by epigallocatechin-3-gallate. Quantitative PCR showed that BaP exposure activated aryl hydrocarbon receptor signaling and promoted the proinflammatory phenotype in macrophages, and these effects were inhibited or even abolished by the separate treatment with epigallocatechin-3-gallate or CH-223191, suggesting the regulatory role of aryl hydrocarbon receptor signaling in BaP-induced toxic effects. This study provides novel insights into the toxic effects of polycyclic aromatic hydrocarbons on macrophage metabolism and potential intervention targets.

Experimental models of pulmonary embolism

Pulmonary embolism (PE) ranks third in the structure of acute cardiovascular diseases. Every year there is a rapid increase in morbidity and mortality from PE. Laboratory biomarkers for PE diagnosis do not have the necessary specificity, and therefore are ineffective. PE requires timely active treatment, in particular for the prevention of serious complications. In this regard, further research is needed to study and search for novel promising biomarkers for the early detection of PE, pathophysiological mechanisms and targets for therapeutic effects. To a large extent, novel data on the pathophysiology of cardiovascular diseases, including PE, scientists receive from experimental studies using animal models. In this review, we summarize the main existing experimental models of PE, describe the principles and methods for modeling this disease. There are following models of PE: intravenous thrombin infusion, adenosine diphosphate-induced PE, PE induction by thromboplastin, recombinant human tissue factor or high molecular weight polyphosphates, collagen/adrenaline-induced PE, ex vivo thrombus intravenous administration, surgical model. This publication also presents our own experience in creating an artificial model of PE in animals using an intravenous thrombus. In our model, confirmation of PE was obtained during pathological examination and an increase in the level of following biomarkers: troponin, N-terminal pro-brain natriuretic peptide, and D-dimer. In this pilot study, a PE model was created to study the pathogenesis and novel treatment options for this disease. To confirm the effectiveness of the model, future studies are required.

The Role of Inflammation as a Preponderant Risk Factor in Cardiovascular Diseases.

Cardiovascular diseases cause considerable health and economic burden, as they are the leading cause of disability and death in the western world. Inactivity, hypertension, obesity, diabetes, and smoking are among the classic risk factors for cardiovascular disease. From a pathophysiological point of view, the arteries of our body bear the harmful stimuli produced by these factors and respond to them with a series of intricate adaptive mechanisms. Vascular remodeling constitutes an adaptive response to hemodynamic and inflammatory alterations associated with hypertension, diabetes, and other illnesses. Thickening of the arterial walls leads to endothelial dysfunction and increases the risk of cerebrovascular and coronary events. During the last decades, antiplatelet, lipid-lowering, and antihypertensive therapies have been the cornerstone of primary and secondary prevention of cardiovascular events. However, it is still unknown whether their efficacy is strictly associated with the control of the classical risk factors or their additive effects on vascular inflammation. Since inflammation of arterial walls is related to the pathogenesis of atherosclerosis, it has been hypothesized that anti-inflammatory therapies could prevent and treat vascular remodeling. Clinical trials based on canakinumab or hydroxychloroquine provide further insight into the role of inflammation in the pathophysiology of cardiovascular diseases. In this review, we have analyzed evidence and suggested that inflammation may play an important role in the final pathway of many cardiovascular risk factors.

Abstract P182: Large Scale Analyses Of Gene-by-smoking Interaction On Cardiovascular Disease

Introduction: Cardiovascular disease risk is determined by both genetic susceptibility and lifestyle factors such as smoking. However, gene-by-smoking interactions have been understudied in this context. The objective of this study was to leverage large-scale individual level data to carry out a genome-wide gene-by-smoking interaction analysis on cardiovascular outcomes including coronary heart disease (CHD), stroke and peripheral artery disease (PAD). Methods: Our study sample included 401,384 unrelated, European-ancestry participants of the UK Biobank study. CHD, stroke, and PAD outcomes were based on data from baseline questionnaires and linked data from inpatient admissions and death registries. Smoking status (ever vs never) was based on self-report at baseline. Gene-environment interaction analyses were carried out using GEM (https://github.com/large-scale-gxe-methods/GEM), a new, computationally efficient software tool developed for biobank scale data. Using generalized linear models, we carried out a test of the genetic main effect adjusted for smoking status, a formal test for gene-by-smoking interaction, and a joint test of the main genetic and interaction effects. Single nucleotide polymorphisms with a minor allele frequency less than 1% were excluded from analyses. Results: The formal interaction test revealed a novel genome-wide significant (GWS) gene-by-smoking signal for PAD within the IREB2 gene (p=2.0x10 -8 ), which has been previously associated with smoking intensity and lung disease. The joint test has been shown to increase power for genetic discovery, which we observed here. The joint test for PAD identified 10 additional loci reaching genome-wide significance (p<5x10 -8 ) that were not revealed in the main effect analyses. Several of these loci are in genes linked with measures of body composition in earlier studies ( PNLIP, CDH4, STAT5A, PRKCE ). We did not detect any GWS gene-by-smoking interactions for CHD or stroke. However, for CHD, two novel loci within the ARSG and SARS1 genes were identified using the joint test but had no GWS main effects. Both genes have been associated with LDL-cholesterol levels in prior genome-wide studies. Although our analyses did not yield any signals that exceeded the GWS threshold for stroke, we did identify 25 and 47 independent loci that reached genome-wide suggestive significance (p<1x10 -5 ) for the formal interaction and joint tests, respectively. We are augmenting the current analyses to include additional data from approximately 120,000 trans-ethnic ancestry individuals. Conclusion: The analysis of gene-by-smoking interactions can provide novel insights into the genetic architecture and pathophysiology of cardiovascular disease.

Antirheumatic therapy is associated with reduced complement activation in rheumatoid arthritis.

BackgroundThe complement system plays an important role in pathophysiology of cardiovascular disease (CVD), and might be involved in accelerated atherogenesis in rheumatoid arthritis (RA). The role of complement activation in response to treatment, and in development of premature CVD in RA, is limited. Therefore, we examined the effects of methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi) on complement activation using soluble terminal complement complex (TCC) levels in RA; and assessed associations between TCC and inflammatory and cardiovascular biomarkers.MethodsWe assessed 64 RA patients starting with MTX monotherapy (n = 34) or TNFi with or without MTX co-medication (TNFi±MTX, n = 30). ELISA was used to measure TCC in EDTA plasma. The patients were examined at baseline, after 6 weeks and 6 months of treatment.ResultsMedian TCC was 1.10 CAU/mL, and 57 (89%) patients had TCC above the estimated upper reference limit (<0.70). Compared to baseline, TCC levels were significantly lower at 6-week visit (0.85 CAU/mL, p<0.0001), without significant differences between the two treatment regimens. Notably, sustained reduction in TCC was only achieved after 6 months on TNFi±MTX (0.80 CAU/mL, p = 0.006). Reductions in TCC after treatment were related to decreased C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and interleukin 6, and increased levels of total, high and low-density lipoprotein cholesterol. Similarly, baseline TCC was significantly related to baseline CRP, ESR and interleukin 6. Patients with endothelial dysfunction had higher baseline TCC than those without (median 1.4 versus 1.0 CAU/mL, p = 0.023).ConclusionsPatients with active RA had elevated TCC, indicating increased complement activation. TCC decreased with antirheumatic treatment already after 6 weeks. However, only treatment with TNFi±MTX led to sustained reduction in TCC during the 6-month follow-up period. RA patients with endothelial dysfunction had higher baseline TCC compared to those without, possibly reflecting involvement of complement in the atherosclerotic process in RA.

The role of the mineralocorticoid receptor in immune cells in cardiovascular disease.

Chronic low-grade inflammation and immune cell activation are important mechanisms in the pathophysiology of cardiovascular disease (CVD). Therefore, targeted immunosuppression is a promising novel therapy to reduce cardiovascular risk. In this review, we identify the mineralocorticoid receptor (MR) on immune cells as a potential target to modulate inflammation. The MR is present in almost all cells of the cardiovascular system, including immune cells. Activation of the MRs in innate and adaptive immune cells induces inflammation which can contribute to CVD, by inducing endothelial dysfunction and hypertension. Moreover, it accelerates atherosclerotic plaque formation and destabilization and impairs tissue regeneration after ischaemic events. Identifying the molecular targets for these non-renal actions of the MR provides promising novel cardiovascular drug targets for mineralocorticoid receptor antagonists (MRAs), which are currently mainly applied in hypertension and heart failure. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.

POS-411 A NOVEL ADRENAL PEPTIDE THAT PREVENTS VASCULAR CALCIFICATION BY INHIBITING OSTEOGENIC TRANSDIFFERENTIATION

Vascular calcification is an important component of cardiovascular (CV) pathology that is highly prevalent in the general population, increases with ageing and is associated with increased mortality in patients with hypertension, chronic kidney disease (CKD), and atherosclerosis. The pathogenesis of vascular calcification is complex and involves an imbalance of enhancers and inhibitors of the underlying processes. The adrenal glands participate in CV physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function.In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification.

The Role of Neutrophil Lymphocyte Ratio , Vitamin D, and NGAL as Cardiovascular Disease Marker in Chronic Kidney Disease

Chronic kidney disease (CKD) patients have higher risk to develop cardiovascular disease (CVD) than non-CKD patients. Neutrophil lymphocyte ratio (NLR) in CKD patients reflects inflammation status and role as complementary prognostic marker to evaluate cardiovascular risk in stage 3 to 5 CKD. High prevalence of vitamin D deficiency commonly found in CKD patients, leads to endothelial dysfunction and increase inflammation. NGAL is used as renal injury biomarker but nowadays NGAL has been known plays important role in CVD pathophysiology. CVD identification in CKD patients is necessary to obtain CVD risk and to stratify mortality earlier in CKD patients. This study aimed to obtain the differences and continued to obtain cut off of NLR, vitamin D and NGAL in CKD patients undergoing hemodialysis (HD) with and without CVD if the differences was significantly. A cross-sectional study was conducted in dr. Cipto Mangunkusumo National Hospital Jakarta, in December- February 2020. Total subjects were 83, consists of two groups with and without the CVD. There were no significant differences of NLR and vitamin D in CKD patients undergoing hemodialysis (HD) with and without CVD. The significant difference was found only in NGAL with cut off 5.64 ng/ml. NLR was lower, meanwhile vitamin D and NGAL were higher in CKD patients undergoing HD with and without CVD.

Tempol Preserves Endothelial Progenitor Cells in Male Mice with Ambient Fine Particulate Matter Exposure.

Ambient fine particulate matter (PM) exposure associates with an increased risk of cardiovascular diseases (CVDs). Major sex differences between males and females exist in epidemiology, pathophysiology, and outcome of CVDs. Endothelial progenitor cells (EPCs) play a vital role in the development and progression of CVDs. PM exposure-induced reduction of EPCs is observed in male, not female, mice with increased reactive oxygen species (ROS) production and oxidative stress. The lung is considered an important source of ROS in mice with PM exposure. The aim of the present study was to investigate the sex differences in pulmonary superoxide dismutase (SOD) expression and ROS production, and to test the effect of SOD mimic Tempol on the populations of EPCs in mice with PM exposure. Both male and female C57BL/6 mice (8–10 weeks) were exposed to intranasal PM or vehicle for 6 weeks. Flow cytometry analysis demonstrated that PM exposure significantly decreased the levels of EPCs (CD34+/CD133+) in both blood and bone marrow with increased ROS production in males, but not in females. ELISA analysis showed higher levels of serum IL-6 and IL-1βin males than in females. Pulmonary expression of the antioxidant enzyme SOD1 was significantly decreased in males after PM exposure, but not in females. Administration of the SOD mimic Tempol in male mice with PM exposure attenuated the production of ROS and inflammatory cytokines, and preserved EPC levels. These data indicated that PM exposure-induced reduction of EPC population in male mice may be due to decreased expression of pulmonary SOD1 in male mice.

Increased expression of six-large extracellular vesicle-derived miRNAs signature for nonvalvular atrial fibrillation

BackgroundsNon-valvular atrial fibrillation (AF) is the most common type of cardiac arrhythmia. AF is caused by electrophysiological abnormalities and alteration of atrial tissues, which leads to the generation of abnormal electrical impulses. Extracellular vesicles (EVs) are membrane-bound vesicles released by all cell types. Large EVs (lEVs) are secreted by the outward budding of the plasma membrane during cell activation or cell stress. lEVs are thought to act as vehicles for miRNAs to modulate cardiovascular function, and to be involved in the pathophysiology of cardiovascular diseases (CVDs), including AF. This study identified lEV-miRNAs that were differentially expressed between AF patients and non-AF controls.MethodslEVs were isolated by differential centrifugation and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM), flow cytometry and Western blot analysis. For the discovery phase, 12 AF patients and 12 non-AF controls were enrolled to determine lEV-miRNA profile using quantitative reverse transcription polymerase chain reaction array. The candidate miRNAs were confirmed their expression in a validation cohort using droplet digital PCR (30 AF, 30 controls). Bioinformatics analysis was used to predict their target genes and functional pathways.ResultsTEM, NTA and flow cytometry demonstrated that lEVs presented as cup shape vesicles with a size ranging from 100 to 1000 nm. AF patients had significantly higher levels of lEVs at the size of 101–200 nm than non-AF controls. Western blot analysis was used to confirm EV markers and showed the high level of cardiomyocyte expression (Caveolin-3) in lEVs from AF patients. Nineteen miRNAs were significantly higher (> twofold, p < 0.05) in AF patients compared to non-AF controls. Six highly expressed miRNAs (miR-106b-3p, miR-590-5p, miR-339-3p, miR-378-3p, miR-328-3p, and miR-532-3p) were selected to confirm their expression. Logistic regression analysis showed that increases in the levels of these 6 highly expressed miRNAs associated with AF. The possible functional roles of these lEV-miRNAs may involve in arrhythmogenesis, cell apoptosis, cell proliferation, oxygen hemostasis, and structural remodeling in AF.ConclusionIncreased expression of six lEV-miRNAs reflects the pathophysiology of AF that may provide fundamental knowledge to develop the novel biomarkers for diagnosis or monitoring the patients with the high risk of AF.

Underrepresentation of women in cardiac imaging trials: A review

Inclusion and equal representation of women in cardiovascular imaging trials are essential to provide insight into the factors impacting women's heart health and outcomes. Despite heart disease being the leading cause of mortality for women in the United States, women have been underrepresented in cardiovascular clinical trials, including imaging trials. Research demonstrates that women have key sex-specific differences in the pathophysiology of cardiovascular disease, the evolution of disease state, and disease manifestation (Solimene, 2010; Nevsky et al., 2011 [1,2]). This understanding and acknowledgment come decades after clinical providers have extrapolated data from cardiovascular disease clinical trials conducted primarily on Caucasian men, assuming the data were generalizable to sex, race, and ethnicity. The current cardiology society guidelines, which recommend optimal medical therapies for various cardiovascular diseases, are based on trials predominantly focused on men rather than women.Sex-based research, governmental and institutional task forces, and policies on gender equity have made inroads into the disproportionate number of women's enrollment in clinical research. The National Institutes of Health in the 1990s set forth requirements on incorporating women and minorities in research, including clinical trials (Mastroianni et al., 1994; Mieres et al., 2014 [3,4]). Continued progress is imperative to improve the gap in the number of women enrolled in clinical research trials.

Effect of Angiotensin receptor blockade on Plasma Osmolality and Neurohumoral Responses to High Environmental Temperature in Rats Fed a High Salt Diet

Plasma osmolality (pOsmol) and neurohumoral signals play important roles in the pathophysiology of cardiovascular diseases. Our study investigated the effect of high environmental temperature (HET) on neurohumoral responses and pOsmol in rats fed a high salt diet (HSD), with and without angiotensin II receptor blockade (ARB), using telmisartan. Fifty-six male 8-week old Sprague-Dawley rats (95-110g) were randomly assigned into seven groups of 8 rats. These included control rats (I) fed with 0.3% NaCl diet (normal diet, ND); salt-loaded rats (II) fed with 8% NaCl (high salt) diet; ND rats (III) exposed to HET (38.5±0.5oC ) 4 hours daily per week; rats (IV) fed with 8% NaCl diet and exposed to HET daily. Others included rats (V) fed with 8% NaCl diet and treated with telmisartan (30mg/kg); ND rats (VI) exposed to HET and treated with telmisartan; rats (VI) fed with 8% NaCl diet, exposed to HET and treated with telmisartan. Plasma angiotensin II, aldosterone, vasopressin and norepinephrine (NE) concentrations were determined by ELISA technique; pOsmol from plasma K+, Na+ and Urea. HSD combined with HET in rats synergistically increased pOsmol (P&lt;0.001) with an associated non-synergistic rise in fluid intake (P&lt;0.001), fluid balance (P&lt;0.001), plasma angiotensin II (P&lt;0.01) and aldosterone (P&lt;0.05), NE (P&lt;0.001) and vasopressin (P&lt;0.05) concentrations compared to control. Telmisartan did not alter pOsmol in all the treated-rats, but normalized fluid intake levels and plasma vasopressin in the rats exposed to either HSD or HEt alone. Prolonged exposure of rats to hot environment exacerbated the effect of excess dietary salt on pOsmol, with no effect on angiotensin II-mediated neurohumoral responses

Effect of Angiotensin receptor blockade on Plasma Osmolality and Neurohumoral Responses to High Environmental Temperature in Rats Fed a High Salt Diet.

Plasma osmolality (pOsmol) and neurohumoral signals play important roles in the pathophysiology of cardiovascular diseases. Our study investigated the effect of high environmental temperature (HET) on neurohumoral responses and pOsmol in rats fed a high salt diet (HSD), with and without angiotensin II receptor blockade (ARB), using telmisartan. Fifty-six male 8-week old Sprague-Dawley rats (95-110g) were randomly assigned into seven groups of 8 rats. These included control rats (I) fed with 0.3% NaCl diet (normal diet, ND); salt-loaded rats (II) fed with 8% NaCl (high salt) diet; ND rats (III) exposed to HET (38.5±0.5oC ) 4 hours daily per week; rats (IV) fed with 8% NaCl diet and exposed to HET daily. Others included rats (V) fed with 8% NaCl diet and treated with telmisartan (30mg/kg); ND rats (VI) exposed to HET and treated with telmisartan; rats (VI) fed with 8% NaCl diet, exposed to HET and treated with telmisartan. Plasma angiotensin II, aldosterone, vasopressin and norepinephrine (NE) concentrations were determined by ELISA technique; pOsmol from plasma K+, Na+ and Urea. HSD combined with HET in rats synergistically increased pOsmol (P<0.001) with an associated non-synergistic rise in fluid intake (P<0.001), fluid balance (P<0.001), plasma angiotensin II (P<0.01) and aldosterone (P<0.05), NE (P<0.001) and vasopressin (P<0.05) concentrations compared to control. Telmisartan did not alter pOsmol in all the treated-rats, but normalized fluid intake levels and plasma vasopressin in the rats exposed to either HSD or HEt alone. Prolonged exposure of rats to hot environment exacerbated the effect of excess dietary salt on pOsmol, with no effect on angiotensin II-mediated neurohumoral responses.

Energy metabolism homeostasis in cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the general population. Energy metabolism disturbance is one of the early abnormalities in CVDs, such as coronary heart disease, diabetic cardiomyopathy, and heart failure. To explore the role of myocardial energy homeostasis disturbance in CVDs, it is important to understand myocardial metabolism in the normal heart and their function in the complex pathophysiology of CVDs. In this article, we summarized lipid metabolism/lipotoxicity and glucose metabolism/insulin resistance in the heart, focused on the metabolic regulation during neonatal and ageing heart, proposed potential metabolic mechanisms for cardiac regeneration and degeneration. We provided an overview of emerging molecular network among cardiac proliferation, regeneration, and metabolic disturbance. These novel targets promise a new era for the treatment of CVDs.