Development Of End-organ Damage Research Articles

Diagnostic and Prognostic Value of PACAP in Multiple Myeloma

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional neuropeptide with well-known anti-inflammatory, antioxidant, antitumor, and immunomodulatory effects. PACAP regulates the production of various proinflammatory factors and may influence the complex cytokine network of the bone marrow microenvironment altered by plasma cells, affecting the progression of multiple myeloma (MM) and the development of end-organ damage. The aim of our study was to investigate the changes in PACAP-38 levels in patients with MM to explore its value as a potential biomarker in this disease. We compared the plasma PACAP-38 levels of MM patients with healthy individuals by ELISA method and examined its relationship with various MM-related clinical and laboratory parameters. Lower PACAP-38 levels were measured in MM patients compared with the healthy controls, however, this difference vanished if the patient achieved any response better than partial response. In addition, lower peptide levels were found in elderly patients. Significantly higher PACAP-38 levels were seen in patients with lower stage, lower plasma cell infiltration in bone marrow, lower markers of tumor burden in serum, lower total urinary and Bence-Jones protein levels, and in patients after lenalidomide therapy. Higher PACAP-38 levels in newly diagnosed MM patients predicted longer survival and a higher probability of complete response to treatment. Our findings confirm the hypothesis that PACAP plays an important role in the pathomechanism of MM. Furthermore, our results suggest that PACAP might be used as a valuable, non-invasive, complementary biomarker in diagnosis, and may be utilized for prognosis prediction and response monitoring.

Homozygous whole body Cbs knockout in adult mice features minimal pathology during ageing despite severe homocysteinemia.

Deficiencies in Cystathionine-β-synthase (CBS) lead to hyperhomocysteinemia (HHCy), which is considered a risk factor for cardiovascular, bone and neurological disease. Moreover, CBS is important for the production of cysteine, hydrogen sulfide (H2 S) and glutathione. Studying the biological role of CBS in adult mice has been severely hampered by embryological disturbances and perinatal mortality. To overcome these issues and assess the effects of whole-body CBS deficiency in adult mice, we engineered and characterized a Cre-inducible Cbs knockout model during ageing. No perinatal mortality occurred before Cbs-/- induction at 10weeks of age. Mice were followed until 90weeks of age and ablation of Cbs was confirmed in liver and kidney but not in brain. Severe HHCy was observed in Cbs-/- (289 ± 58µM) but not in Cbs+/- or control mice (<10µM). Cbs-/- showed impaired growth, facial alopecia, endothelial dysfunction in absence of increased mortality, and signs of liver or kidney damage. CBS expression in skin localized to sebaceous glands and epidermis, suggesting local effects of Cbs-/- on alopecia. Cbs-/- showed increased markers of oxidative stress and senescence but expression of other H2 S producing enzymes (CSE and 3-MST) was not affected. CBS deficiency severely impaired H2 S production capacity in liver, but not in brain or kidney. In summary, Cbs-/- mice presented a mild phenotype without mortality despite severe HHCy. The findings demonstrate that HHCy is not directly linked to development of end organ damage.

P-138: Frequent magnetic resonance imaging partially reduces the development of end organ damage in patients with smoldering myeloma

Background Osteolytic lesions are a hallmark of multiple myeloma (MM) and are present in 80% of patients at first diagnosis. Since they can lead to instabilities, fractures, and pain they go along with a significant impact on the quality of life of patients. By definition, patients with smoldering multiple myeloma (SMM) don’t have osteolytic lesions yet. Modern diagnostic technologies like magnetic resonance imaging (MRI) or positron emission tomography with computed tomography (PET/CT) allow for detection of focal accumulations of myeloma cells before the actual bone has been destroyed. In SMM the presence of these lesions has been identified as risk factor for progression into symptomatic disease and has together with a free light chain ratio of ≥100 and a plasma cell infiltration of the bone marrow of >/=60% been identified as “biomarkers of malignancy” indicating necessity of systemic treatment. Methods To investigate if frequent, longitudinal whole body (WB) MRI helps to predict the development of MM in general and osteolytic lesions in particular the current prospective study has enrolled 96 evaluable patients with SMM and has followed them with WBMRI every 6 months and clinical and serological markers every 3 months. Bone marrow biopsies were only performed when clinically indicated. Results The 1-, 2-, and 3-year progression rates with application of the current diagnostic criteria were 10%, 19% and 25%, respectively. Of 22 patients progressing into MM, 7 showed biomarkers of malignancy only without associated end organ damage. Four of those progressed with >1 focal lesion (FL) in MRI or a growing FL without osteolytic lesion (OL), and 3 due to a serum free light-chain ratio ≥100. The remaining 15 patients (68%) who progressed into MM still suffered from end-organ damage at progression. In all but 1 patient, OL showed a corresponding FL in WBMRI at time of diagnosis of the respective OL. The time between first appearance of a FL and the diagnosis of the OL was highly variable. Conclusion Applying biomarkers of malignancy and frequent WBMRIs reduced the proportion of patients suffering from end-organ damage at progression to 68%. This supports the current development to initiate therapeutic or preventive treatment in patients with high risk SMM identified by markers beyond the biomarkers of malignancy in the current disease definition. Osteolytic lesions are a hallmark of multiple myeloma (MM) and are present in 80% of patients at first diagnosis. Since they can lead to instabilities, fractures, and pain they go along with a significant impact on the quality of life of patients. By definition, patients with smoldering multiple myeloma (SMM) don’t have osteolytic lesions yet. Modern diagnostic technologies like magnetic resonance imaging (MRI) or positron emission tomography with computed tomography (PET/CT) allow for detection of focal accumulations of myeloma cells before the actual bone has been destroyed. In SMM the presence of these lesions has been identified as risk factor for progression into symptomatic disease and has together with a free light chain ratio of ≥100 and a plasma cell infiltration of the bone marrow of >/=60% been identified as “biomarkers of malignancy” indicating necessity of systemic treatment. To investigate if frequent, longitudinal whole body (WB) MRI helps to predict the development of MM in general and osteolytic lesions in particular the current prospective study has enrolled 96 evaluable patients with SMM and has followed them with WBMRI every 6 months and clinical and serological markers every 3 months. Bone marrow biopsies were only performed when clinically indicated. The 1-, 2-, and 3-year progression rates with application of the current diagnostic criteria were 10%, 19% and 25%, respectively. Of 22 patients progressing into MM, 7 showed biomarkers of malignancy only without associated end organ damage. Four of those progressed with >1 focal lesion (FL) in MRI or a growing FL without osteolytic lesion (OL), and 3 due to a serum free light-chain ratio ≥100. The remaining 15 patients (68%) who progressed into MM still suffered from end-organ damage at progression. In all but 1 patient, OL showed a corresponding FL in WBMRI at time of diagnosis of the respective OL. The time between first appearance of a FL and the diagnosis of the OL was highly variable. Applying biomarkers of malignancy and frequent WBMRIs reduced the proportion of patients suffering from end-organ damage at progression to 68%. This supports the current development to initiate therapeutic or preventive treatment in patients with high risk SMM identified by markers beyond the biomarkers of malignancy in the current disease definition.

Smoldering Myeloma Treatment: Who, What, and When.

Smoldering multiple myeloma (MM) is a clonal plasma cell disorder characterized by excess marrow involvement and immunoglobulin production. It is the precursor of MM, differing by the lack of end-organ damage. Smoldering MM encompasses a heterogeneous group of patients, with a median risk of progression to active disease of 50% in the first 5 years. Until recently, the standard of care would dictate observation off therapy until the development of end-organ damage. The recognition of high-risk and ultrahigh-risk subgroups of smoldering MM, with more likely evolution to MM, has led to earlier initiation of therapy in the disease course. Ongoing studies to define the ideal timing and patient population are underway, as well as identification of which agents would be of greatest benefit, as the armamentarium for MM continues to grow.

Assessing the utility of monitoring IgA multiple myeloma patients with quantitative serum IgA levels.

e20515 Background: IgA monoclonal proteins (MCPs), unlike IgG MCPs, often migrate in the beta region on serum protein electrophoresis (SPEP) which can lead to underestimation of their size due to the co-migration with physiologic proteins. In IgA multiple myeloma (MM), the utility of quantitative IgA levels in assessing disease response in comparison to SPEP is not well studied. Methods: We retrospectively analyzed 304 IgA MM patients, diagnosed between 2004 and 2018, with available serial MCP and quantitative IgA levels. Kaplan Meier analysis was used to estimate the median progression free survival (mPFS) using the IMWG criteria and our study definition of IgA progression (2 consecutive IgA values that are &gt; 25% above the nadir IgA value and above upper limit of normal (ULN) of 356 mg/dL, and a detectable IgA MCP on serum immunofixation). The mPFS was defined as the time from treatment initiation until disease progression or death. Results: IgA MCP migrated in the beta region in 134 (44%) patients, and in the gamma region in 150 (56%) patients. At diagnosis the median MCP was 3 (IQR 1.9-4) g/dL and the median IgA was 3240 (IQR 2008-4420) mg/dL. The median time from treatment initiation to MCP nadir was 80 (IQR 42-144) days and median time to IgA nadir was 154 (IQR 90-238) days. At MCP nadir 40% of patients had an IgA above the ULN. All complete responders (n = 104) had normal IgA levels, with a median IgA of 54 (IQR 27-88) g/dL. A ≥90% decrease in IgA between treatment initiation and IgA nadir, compared to a &lt; 90% decrease, was associated with a longer mPFS (34 vs. 20 months, p = 0.006) and overall survival (97 vs. 33 months, p = 0.003). Patients with serial MCP and IgA levels available prior to progression (n = 195) were used to compare the mPFS using the IMWG and IgA progression criteria. The mPFS using the IgA criteria was 32 (95% CI 29-39) months, versus 39 (95% CI 33-45) months using IMWG criteria. Overall, 92 (47%) patients progressed by both IMWG and IgA criteria. At the time of progression using the IgA criteria compared to at IMWG progression, the median hemoglobin was higher (13.3 vs. 11.6 g/dL, respectively, p &lt; 0.001) and fewer patients had new symptomatic bone lesions (2% vs. 33%, respectively, p &lt; 0.001). Conclusions: In IgA MM patients, monitoring quantitative IgA levels predicts disease response and allows for earlier detection of disease progression, prior to the development of end organ damage.

Immune mechanisms of salt-sensitive hypertension and renal end-organ damage.

Immune mechanisms have been recognized to have a role in the pathogenesis of hypertension, vascular disease and kidney damage in humans and animals for many decades. Contemporary advances in experimentation have permitted a deeper understanding of the mechanisms by which inflammation and immunity participate in cardiovascular disease, and multiple observations have demonstrated strong correlations between the discoveries made in animals and those made in patients with hypertension. Of note, striking phenotypic similarities have been observed in the infiltration of immune cells in the kidney and the development of end-organ damage in patients and animal models with sodium-sensitive hypertension. The available data suggest that an initial salt-induced increase in renal perfusion pressure, which is likely independent of immune mechanisms, induces the infiltration of immune cells into the kidney. The mechanisms mediating immune cell infiltration in the kidney are not well understood but likely involve tissue damage, the direct influence of salt to stimulate immune cell activation, sympathetic nerve stimulation or other factors. The infiltrating cells then release cytokines, free radicals and other factors that contribute to renal damage as well as increased retention of sodium and water and vascular resistance, which lead to the further development of hypertension.

Aorto-Hepatic By-Pass Grafting as Treatment Option After Acute Thrombosis of a Celiac Trunk Stenting. Report of a Case

Celiac trunk thrombosis is a rare event after percutaneous stenting. Treatment options include surgery or endovascular approach. We report the case of a diabetic female patient of 56 years old with a recurrent chronic mesenteric ischemia related to celiac trunk stenosis. We choose endovascular approach and we performed a stenting of this lesion with a ballon expendable stent of 6 × 29 mm. Acute abdomen occurred at the first postoperative day. Acute mesenteric ischemia was suspected. CT scan objectified a stent thrombosis and beginning of intestinal distress. Because of doubt of intestinal viability, we performed urgently a laparotomy and an anterograde aorto-hepatic bypass. Post-operative course was satisfactory. We put the patient on platelet antiaggregant therapy. One year after, CT scan confirms graft patency. Acute thrombosis of a celiac trunk stenting is an emergency and diagnosis must be performed before the development of end-organ damage. Aorto hepatic bypass can be a good alternative.

Role of lipids and free radicals in diabetic with hypertension and smokers for causation of coronary heart disease

Introduction: The major independent risk factors for the development of atherosclerosis are the plasma cholesterol concentration, triglyceride, cigarette smoking, hypertension and diabetes, which are by them self’s risk factor for coronary heart disease. Cardiovascular disease (CVD) threatens to cripple India’s workforce and stunt India’s growth if timely and appropriate public health measures are not instituted. Hyperglycemia, hypertension and cigarette smoking depletes natural antioxidants and facilitates the production of reactive oxygen species (ROS) which has the ability to react with all biological molecules and exert cytotoxic effects on cellular components that promotes and accelerate atherosclerosis. Hence the present study was aimed to find out collective effect of NIDDM, hypertension and cigarette smoking on lipid profile and oxidative stress in progression of CHD events. Materials and methods: We studied 50 healthy and 50 diabetes with hypertension and or smokers patients (i. e. had two or more CHD risk factors) patients with matched for age and body mass index. Blood samples were drawn after an overnight fast. W e estimated serum triglycerides,total cholesterol, HDL-c and LDL-c and VLDL- c values were calculated by Friedwald’s equation. We also estimated the total serum lipid peroxides by reaction with thiobarbituric acid. Results: In the control group I mean values of total cholesterol were 180.21 ± 18.13 mg %, LDL-c 106.60 ±18.2 mg%, serum triglycerides were 99.90 ± 16.14 mg %, HDL-c were 53.83 ± 16.42mg% and in the group II serum triglycerides 217.9 ± 19.1 mg% and were significantly increased as compared to group I. The serum HDL-c group II 29.6 ± 8.07mg % were significantly decreased as compared to group I (P is<0.05). The serum lipid peroxides in the group 2nd (296.9.±60.10) were significantly increased as compared to group 1st (180.96±35.16). Conclusion: It can be concluded that patients of NIDDM with hypertension, smoking have higher total serum cholesterol, serum triglycerides, serum lipid peroxides (MDA), LDL- c and VLDL-c with lower HDL- c. These can be corrected, treated by dietary and life style modification before the development of end organ damage. For realization of exact role of lipid profile and oxidative stress further higher level studies should be done.

Receptor-associated prorenin system contributes to development of inflammation and angiogenesis in proliferative diabetic retinopathy.

The renin-angiotensin system (RAS) plays a potential role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor of several diseases including diabetes. So far, using animal disease models, we have shown molecular mechanisms, in which tissue RAS stimulates retinal angiogenesis, and the critical roles of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction, referred to as the receptor-associated prorenin system (RAPS). Moreover, we recently reported that the protein levels of prorenin and soluble (P)RR increased in the vitreous fluids obtained from patients with proliferative diabetic retinopathy (PDR), suggesting the association of (P)RR with vascular endothelial growth factor (VEGF)-driven angiogenic activity in human PDR, and also showed a close relationship between the vitreous renin activity and VEGF-induced pathogenesis of diabetic retinopathy. Our data using animal disease models and human clinical samples suggest that both vitreous RAS and retinal RAPS play critical roles in the molecular pathogenesis of diabetic retinopathy.

Serelaxin for the treatment of acute heart failure: a review with a focus on end-organ protection.

Acute heart failure (AHF) is a complex clinical syndrome characterized by fluid overload and haemodynamic abnormalities (short-term clinical consequences) and the development of end-organ damage (long-term consequences). Current therapies for the treatment of AHF, such as loop diuretics and vasodilators, help to relieve haemodynamic imbalance and congestion, but have not been shown to prevent (and may even contribute to) end-organ damage, or to provide long-term clinical benefit. Serelaxin is the recombinant form of human relaxin-2, a naturally occurring hormone involved in mediating haemodynamic changes during pregnancy. Preclinical and clinical studies have investigated the effects mediated by serelaxin and the suitability of this agent for the treatment of patients with AHF. Data suggest that serelaxin acts via multiple pathways to improve haemodynamics at the vascular, cardiac, and renal level and provide effective congestion relief. In addition, this novel agent may protect the heart, kidneys, and liver from damage by inhibiting inflammation, oxidative stress, cell death, and tissue fibrosis, and stimulating angiogenesis. Serelaxin may therefore improve both short- and long-term outcomes in patients with AHF. In this review, we examine the unique mechanisms underlying the potential benefits of serelaxin for the treatment of AHF, in particular, those involved in mediating end-organ protection.

Autonomic Dysfunction, Sympathetic Hyperactivity and the Development of End-Organ Damage in Hypertension: Multiple Benefits of Exercise Training

Autonomic dysfunction is closely related to the development of hypertension, which is characterized by increased sympathetic activity, decreased vagal tonus and baroreflex dys - function. The hypertension-induced maladaptive changes progressively lead to heart failure, myocardial infarction and stroke. Hypertrophic remodeling of brain arterioles, chemoreceptors activation, blood-brain barrier abnormalities, oxidative stress and pro-inflammatory cytokines production in autonomic brain areas increase neuronal activity and sympathetic outflow. These responses, together with increased baroreflex dysfunction-induced pressure variability, renin- angiotensin system hyperactivation and capillary rarefaction, increase blood pressure levels and act as a positive feedback mechanism to perpetuate hypertension and development of end- organ damage. Exercise training, a non-pharmacological tool, has been used as an adjuvant therapy to treat hypertension. Our recent data showed that moderate aerobic training in adult SHR completely normalizes oxidative stress and inflammation in autonomic brain areas in - volved in cardiovascular control and promptly corrects baroreflex dysfunction and increases cardiac vagal activity. The early (2-weeks) training-induced beneficial responses improve auto - nomic control even in the persistence of hypertension, since a partial reduction of pressure lev- els was observed after 8 weeks of exercise training, which was related to reversion of arteriolar hypertrophic remodeling and consequent decrease of peripheral vascular resistance.

Propylthiouracil-associated rapidly progressive crescentic glomerulonephritis with double positive anti-glomerular basement membrane and antineutrophil cytoplasmic antibody: the first case report.

We report a case of propylthiouracil (PTU)-induced double antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody (anti-GBM antibody) disease causing pulmonary-renal syndrome in a 35-year-old Thai woman with 10-year history of PTU treatment for thyrotoxicosis. She developed clinical symptoms of vasculitis upon receiving long-term PTU treatment. Prednisolone treatment and the switching from PTU to methimazole resulted to short-term clinical improvement. Nevertheless following termination of steroid treatment, she developed recurrent pulmonary hemorrhage and rapidly progressive glomerulonephritis. The kidney biopsy showed crescentic glomerulonephritis with linear IgG deposit on the glomerular basement membrane although transbronchial lung biopsy showed no immune deposit along the alveolar basement membrane. Serum testing for p-ANCA was positive and western blot showed positive antibody to the alpha-3 chain of collagen type IV. Both ANCA and anti-GBM antibody may play a role in the development of end organ damage. To facilitate early and specific intervention, clinicians should be aware of the propensity of PTU to cause lupus-like syndromes with renal involvement. In patients with PTU-induced ANCA-associated glomerulonephritis, serum anti-GBM antibody test may be useful in the early diagnosis of double positive antibodies disease and plasmapheresis should be performed without delay.

Developmental conditioning of the vasculature.

There is increasing evidence from epidemiological and experimental animal studies that the early life environment, of which nutrition is a key component, acts through developmental adaptive responses to set the capacity of cardiovascular and metabolic pathways to respond to physiological and pathophysiological challenges in later life. One finding that is consistent to both population studies and animal models is the propensity for such effects to induce endothelial dysfunction throughout the vascular tree, including the microvasculature. Obesity, type 2 diabetes and hypertension are associated with changes in microvascular function affecting multiple tissues and organs. These changes may be detected early, often before the onset of macrovascular disease and the development of end organ damage. Suboptimal maternal nutrition and fetal growth result in reduced microvascular perfusion and functional dilator capacity in the offspring, which together with microvascular rarefaction and remodeling serve to limit capillary recruitment, reduce exchange capacity and increase diffusion distances of metabolic substrates; they also increase local and overall peripheral resistance. This article explores how a developmentally conditioned disadvantageous microvascular phenotype may represent an important and additional risk factor for increased susceptibility to the development of cardio-metabolic disease in adult life and considers the cell signaling pathways associated with microvascular dysfunction that may be "primed" by the maternal environment. As the microvasculature has been shown to be a potential target for early therapeutic and lifestyle intervention, this article also considers evidence for the efficacy of such strategies in humans and in animal models of the developmental origins of health and disease.

Improving outcomes in children with sickle cell disease: treatment considerations and strategies.

Over the past decades there has been a significant improvement in the care of patients with sickle cell disease (SCD) in high-income countries. However, more needs to be learned about the complex pathophysiology and the factors that contribute to the development of end organ damage from the disease. While antibiotic prophylaxis and appropriate treatment of infections have resulted in a significant reduction of early mortality, management of the painful episodes and prevention of organ damage remain a challenge. Hydroxyurea is the only medication approved as disease-modifying therapy, and bone marrow transplant as curative treatment is not available to most patients. In low-income countries with the highest disease burden, early mortality is high due to limited resources for systematic screening, early diagnosis, and disease management. In order to improve outcomes in patients with SCD in high-income countries, better and widespread implementation of known disease-modifying therapies and the development of newer therapies targeting key pathophysiologic pathways are required. In low-income countries with high disease burden, innovative approaches to develop low-cost diagnostic devices and treatments that can be implemented to scale are needed to combat early mortality from the disease. Sustainable solutions in low-resource settings require evidence-based affordable interventions that can be integrated into primary and secondary healthcare systems.

C-reactive protein and Hypertension

C-reactive protein (CRP), the prototypical acute-phase reactant, is one of the most widely known biomarkers of cardiovascular disease. Circulating levels of CRP are clinically used to predict the occurrence of cardiovascular events and to aide in the selection of therapies based on more accurate risk assessment in individuals who are at intermediate risk. This paper reviews the role of CRP in hypertension. In hypertensive individuals, CRP levels associate with vascular stiffness, atherosclerosis and the development of end-organ damage and cardiovascular events. Data suggest that some anti-hypertensive medications may lower CRP levels in a manner independent of their effect on blood pressure. In individuals who are normotensive at baseline, CRP levels have been shown in multiple cohorts to foretell the development of hypertension on follow-up. Whether genetic variability that influences circulating levels of CRP independent of environmental and behavioral factors can also be used in a similar manner to predict the change in blood pressure and development of hypertension is controversial. In addition to its role as a biomarker, experimental studies have unraveled an active direct participation of CRP in the development of endothelial dysfunction, vascular stiffness and elevated blood pressure. CRP has also been implicated as a mediator of vascular remodeling in response to injury and cardiac remodeling in response to pressure overload. Emerging data may reveal novel vascular inflammatory pathways and identify new targets for treatment of vascular pathology.

The microvasculature: a target for nutritional programming and later risk of cardio‐metabolic disease

There is compelling evidence that microvascular deficits affecting multiple tissues and organs play an important role in the aetiopathogenesis of cardio-metabolic disease. Furthermore, both in humans and animal models, deficits in small vessel structure and function can be detected early, often before the onset of macrovascular disease and the development of end-organ damage that is common to hypertension and obesity-associated clinical disorders. This article considers the growing evidence for the negative impact of an adverse maternal diet on the long-term health of her child, and how this can result in a disadvantageous vascular phenotype that extends to the microvascular bed. We describe how structural and functional modifications in the offspring microcirculation during development may represent an important and additional risk determinant to increase susceptibility to the development of cardio-metabolic disease in adult life and consider the cell-signalling pathways associated with endothelial dysfunction that may be 'primed' by the maternal environment. Published studies were identified that reported outcomes related to the microcirculation, endothelium, maternal diet and vascular programming using NCBI PubMed.gov, MEDLINE and ISI Web of Science databases from 1980 until April 2013 using pre-specified search terms. Information extracted from over 230 original reports and review articles was critically evaluated by the authors for inclusion in this review.

Effects of obesity and race on left ventricular geometry in hypertensive children

Like left ventricular hypertrophy (LVH), abnormal left ventricular (LV) geometry increases cardiovascular risk, but little data utilizing age and sex-specific norms are currently available on LV geometry in hypertensive children. This was a cross-sectional study of 141 hypertensive children aimed at determining the prevalence of LVH and abnormal LV geometry in the patient population and whether clinical characteristics associated with these findings differ by race. LVH was defined as an LV mass index of ≥95th percentile or cardiologist diagnosis. Abnormal geometry was defined as the presence of LVH or a relative wall thickness of >0.41. The prevalence of LVH was 35 % overall. According to race, LVH prevalence was 49 % among African-Americans (AA) versus 30 % among non-AA (p < 0.05). Overweight/obesity was also highly prevalent among AA compared to non-AA (87 vs. 71 %, respectively; p = 0.03). After multivariable adjustment, the body mass index (BMI) z-score and 95 % diastolic blood pressure (BP) index were the sole independent predictors of LVH. Of the 141 hypertensive children, 40 % had abnormal LV geometry; 63 % among AA vs. 32 % among non-AA (p = 0.001). Multivariable analyses revealed a 3.8-fold increased odds of abnormal geometry among AA (p = 0.002). While LVH, abnormal geometry and overweight/obesity are more prevalent among AA hypertensive children, after multivariable adjustment, BMI and race were independently associated with LVH and abnormal geometry, respectively. This result suggests that both race and obesity have important roles in the development of end-organ damage among children with primary hypertension.

Tissue specific regulation of CB1/CB2 gene receptors in salt sensitive hypertension of SHR

A growing body of evidence suggests that endogenous cannabinoids participate in the regulation of blood pressure in salt‐sensitive hypertension. However, there is limited information on the role of cannabinoids in the development of cardiac and renal abnormalities associated with high dietary salt intake. Therefore, the present study evaluated gene expression of the two major cannabinoid receptors (CB1 and CB2) in the heart and kidneys of the spontaneously hypertensive rat (SHR) fed a high salt diet. Male SHRs were given an 8% salt diet (HS; n=7), while their age‐matched controls (C; n=7) received standard chow for 5 weeks. CB1 and CB2 mRNA was measured using reverse transcriptase, real‐time polymerase chain reaction. After 5 weeks, the HS exacerbated hypertension (C: 208 ± 13; HS: 260 ± 11 mmHg, p&lt;0.05) and increased left ventricular weight (C: 980 ± 12; HS: 1163 ± 38 mg, p&lt;0.05), cardiac fibrosis [C: 3.41 ± 0.48; HS: 13.58 ± 3.29 %; p&lt;0.05] and urinary protein excretion (C: 20 ± 2; HS: 160 ± 38 mg/day; p&lt;0.05). CB1 receptor mRNA was 2.4‐fold (p&lt;0.05) and 1.4‐fold (p&lt;0.05) reduced in the heart and kidneys of salt‐loaded SHR, respectively. In contrast, CB2 mRNA was increased 1.8‐fold in kidney (p&lt;0.05), but not in the heart. These results suggest that CB1/CB2 gene receptors are regulated in a tissue‐specific manner in salt‐loaded SHRs and may play a role in the development of end organ damage due to high dietary salt intake.

(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

Aims/hypothesis The renin–angiotensin system (RAS) potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of (pro)renin receptor ([P]RR) in retinal inflammation in a rodent model of early diabetes. In this study we aim to elucidate the (P)RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy.

Interplay of neutrophils and type I interferons in the development of end-organ damage in SLE

Patients with systemic lupus erythematosus (SLE) have up to a 50-fold increased risk of developing atherosclerotic cardiovascular disease that cannot be explained by the Framingham risk equation. While both SLE-specific and nonspecific mechanisms have been proposed to play a prominent role in the induction of premature vascular damage in this disease, the exact etiology remains unclear. We have proposed that an imbalance between vascular damage and repair probably induced by IFNα and other type I interferons could play a prominent role in the induction of accelerated atherosclerosis in SLE. Our group and others have recently elucidated the potential role that these cytokines play in the development and progression of premature atherosclerotic disease in SLE and, potentially, in other autoimmune diseases. More recently, a novel role for aberrant neutrophils in the development of autoimmune responses and vascular damage in SLE and other diseases has emerged; in particular, the role that neutrophil extracellular traps may play in the development of this disease and its vascular complications such as endothelial dysfunction and atherothrombosis. The recent description of a distinct subset of proinflammatory neutrophils isolated from lupus patients that induces vascular damage and synthesizes type I interferons has shed new light into a potentially important cell subset implicated in endothelial damage. Finally, novel discoveries pertaining to the interactions of lipoproteins and the immune system may prove quite informative in understanding how premature atherosclerotic plaque develops in lupus.