The Role of Lipid-Lowering Therapy in Post-Stroke Patients: Update and Recommendations.

PURPOSE OF REVIEW: Stroke is the second leading cause of death and disability-adjusted life years worldwide, and the global lifetime risk of stroke is rising. Moreover, patients with a prior stroke are at high risk of recurrent events. We aimed at reviewing the evidence supporting aggressive secondary prevention strategies for lipid-lowering treatment in this population. RECENT FINDINGS: Statins are the key players in such aggressive management; however, stroke survivors remain at significant residual risk suggesting the need for both better implementation of statin use as well as additional lipid lowering therapies. Newer drugs have become available and represent important tools in the management of patients with prior ischemic stroke. The role of lipid lowering treatment in hemorrhagic stroke is more controversial, given epidemiological data linking low lipid levels with increased risk of first and recurrent events. Aggressive secondary prevention strategies, including lipid lowering treatments, have proven to mitigate the risk of recurrent events in post-stroke patients. The tools available for treating such high-risk population have expanded beyond statins, and clinicians should familiarize themselves with them.

Biology and postnatal development of organ systems of cynomolgus monkeys (Macaca fascicularis).

BACKGROUND: The cynomolgus macaque has become the most used non-human primate species in nonclinical safety assessment during the past decades. METHODS: This review summarizes the biological data and organ system development milestones of the cynomolgus macaque available in the literature. RESULTS: The cynomolgus macaque is born precocious relative to humans in some organ systems (e.g., nervous, skeletal, respiratory, and gastrointestinal). Organ systems develop, refine, and expand at different rates after birth. In general, the respiratory, gastrointestinal, renal, and hematopoietic systems mature at approximately 3 years of age. The female reproductive, cardiovascular and hepatobiliary systems mature at approximately 4 years of age. The central nervous, skeletal, immune, male reproductive, and endocrine systems complete their development at approximately 5 to 9 years of age. CONCLUSIONS: The cynomolgus macaque has no meaningful developmental differences in critical organ systems between 2 and 3 years of age for use in nonclinical safety assessment.

De novo Fc-based receptor dimerizers differentially modulate PlexinB1 function.

Signaling by single-pass transmembrane receptors often involves a formation of ligand-induced receptor dimers with particular conformation, and bivalent receptor binders can modulate receptor functions by inducing different receptor dimer conformations, although such agents are difficult to design. Here, we describe the generation of both antagonistic and agonistic receptor dimerizers toward PlexinB1 (PlxnB1), a receptor for semaphorin 4D (Sema4D), by grafting two different PlxnB1-binding peptides onto the human immunoglobulin G1 (IgG1) Fc protein. The function-modulating activity of a peptide Fc was strongly dependent on the type of the peptide as well as the grafting site, with the best variants showing activity at an nM concentration range. Structural analysis of each peptide-PlxnB1 complex revealed that the agonistic Fc dimerizes PlxnB1 in a face-to-face fashion similar to that induced by Sema4D, whereas antagonistic Fc would induce signaling-incompetent PlxnB1 dimer conformation, enforcing the idea that plexin activation is primarily controlled by the receptor orientation within the dimer.

Age- and sex-related changes in body weights and clinical pathology analytes in cynomolgus monkeys (Macaca Fascicularis) of Mauritius origin.

BACKGROUND: Clinical pathology and body weight information for the cynomolgus monkey in the literature is primarily derived from a small number of animals with limited age ranges, varying geographic origins, and mixed genders. OBJECTIVES: This study aimed to summarize the age- and sex-related changes in clinical pathology analytes and body weights in cynomolgus monkeys of Mauritian origin. METHODS: Pre-study age and body weight data were reviewed in 1819 animals, and pre-study hematologic, coagulation, and serum biochemical analytes were reviewed in 1664 animals. RESULTS: Body weights were statistically higher (P < 0.01) in males than females in all age groups (2-10 years). These measurements became prominent after 4 years of age and peaked at 7 to 8 years of age in both sexes. Sex-related differences were noted in reticulocyte (RETIC) counts, creatinine, cholesterol, and triglyceride concentrations, and alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) activities. Age-related differences were noted in RETIC and lymphocyte counts, creatinine, triglyceride, phosphorus, and globulin concentrations, and ALP and GGT activities. The youngest (2 to <3 year) age group had the fewest number of clinical pathologic analyte differences including ALP and GGT activity differences which occurred in all age groups from 2 to 10 years; they also had age-related lower globulin concentrations. There were no age- or sex-related differences in coagulation measurands. CONCLUSIONS: Sexual dimorphism in body weight was apparent for all ages from 2 to 10 years of age. The only difference in clinical pathology analytes unique to the 2 to <3 years of age group were age-related lower globulin levels.

Lasso-grafting of macrocyclic peptide pharmacophores yields multi-functional proteins.

Protein engineering has great potential for devising multifunctional recombinant proteins to serve as next-generation protein therapeutics, but it often requires drastic modifications of the parental protein scaffolds e.g., additional domains at the N/C-terminus or replacement of a domain by another. A discovery platform system, called RaPID (Random non-standard Peptides Integrated Discovery) system, has enabled rapid discovery of small de novo macrocyclic peptides that bind a target protein with high binding specificity and affinity. Capitalizing on the optimized binding properties of the RaPID-derived peptides, here we show that RaPID-derived pharmacophore sequences can be readily implanted into surface-exposed loops on recombinant proteins and maintain both the parental peptide binding function(s) and the host protein function. We refer to this protein engineering method as lasso-grafting and demonstrate that it can endow specific binding capacity toward various receptors into a diverse set of scaffolds that includes IgG, serum albumin, and even capsid proteins of adeno-associated virus, enabling us to rapidly formulate and produce bi-, tri-, and even tetra-specific binder molecules.

Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation.

Osteoporosis is caused by a disequilibrium between bone resorption and bone formation. Therapeutics for osteoporosis can be divided into antiresorptives that suppress bone resorption and anabolics which increase bone formation. Currently, the only anabolic treatment options are parathyroid hormone mimetics or an anti-sclerostin monoclonal antibody. With the current global increases in demographics at risk for osteoporosis, development of therapeutics that elicit anabolic activity through alternative mechanisms is imperative. Blockade of the PlexinB1 and Semaphorin4D interaction on osteoblasts has been shown to be a promising mechanism to increase bone formation. Here we report the discovery of cyclic peptides by a novel RaPID (Random nonstandard Peptides Integrated Discovery) system-based affinity maturation methodology that generated the peptide PB1m6A9 which binds with high affinity to both human and mouse PlexinB1. The chemically dimerized peptide, PB1d6A9, showed potent inhibition of PlexinB1 signaling in mouse primary osteoblast cultures, resulting in significant enhancement of bone formation even compared to non-Semaphorin4D-treated controls. This high anabolic activity was also observed in vivo when the lipidated PB1d6A9 (PB1d6A9-Pal) was intravenously administered once weekly to ovariectomized mice, leading to complete rescue of bone loss. The potent osteogenic properties of this peptide shows great promise as an addition to the current anabolic treatment options for bone diseases such as osteoporosis.

Non-clinical combination toxicology studies: strategy, examples and future perspective.

Over the last decade, combination of drugs in all stages of pharmaceutical development has accelerated availability of promising new therapies for difficult to treat diseases. Safety assessment of combined drugs to be tested in humans can occur at a critical path prior to proceeding in clinical testing. A recent survey by The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ DruSafe) summarized member companies' approaches to combination safety strategies. In addition, feedback from Health Authorities (HAs) support a case-by-case scientific approach in assessing combination products' safety in accordance with the International Council on Harmonization (ICH) guidelines. Here, we present Pfizer's drug combination safety approach for various therapeutic areas (TA) including inflammation and immunology, metabolic, and anti-cancer products. There is no one-size-fits-all approach; rather, our main considerations include: strength of the existing clinical safety data for the individual compounds, common target organs, the potential for a synergistic effect, potential drug-drug interaction, routes of administration of each product and disease indications. No formal toxicity studies are considered necessary for anti-cancer drugs, while safety endpoints may be collected in preclinical pharmacology studies especially when the combined drugs present a novel mechanism. Combination safety studies when conducted for non-cancer indications can range from 2 to 13-weeks in duration, conducted usually in rodents, with dosages of individual molecules within clinical pharmacologic ranges. A case-by-case strategy guided by scientific rationale and in close collaboration with HAs remains the best approach to decide on the design and conduct of combination safety studies.

Enzalutamide and Apalutamide: In Vitro Chemical Reactivity Studies and Activity in a Mouse Drug Allergy Model.

Enzalutamide and apalutamide are two androgen receptor inhibitors approved for the treatment of castration-resistant prostate cancer (CRPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC), respectively. Apalutamide is associated with an increased incidence of skin rash above the placebo groups in the SPARTAN trial in nmCRPC and in the TITAN trial in metastatic castration-sensitive prostate cancer patients. On the contrary, the rate of skin rash across all clinical trials (including PROSPER [nmCRPC]) for enzalutamide is similar to the placebo. We hypothesized that the apalutamide-associated increased skin rash in patients could be linked to a structural difference. The 2-cyanophenyl and dimethyl moieties in enzalutamide are substituted in apalutamide with 2-cyanopyridine and cyclobutyl, respectively. In our evaluations, the 2-cyanopyridine moiety of apalutamide was chemically reactive with the thiol nucleophile glutathione, resulting in rearranged thiazoline products. Radiolabeled apalutamide, but not radiolabeled enzalutamide, was shown to react with mouse and human plasma proteins. Thiol nucleophiles decreased the extent of covalent binding to the model protein bovine serum albumin, whereas amine and alcohol nucleophiles had no effect, suggesting reactivity with cysteine of proteins. Subcutaneous administration of apalutamide dose dependently increased lymphocyte cellularity in draining lymph nodes in a mouse drug allergy model (MDAM). Enzalutamide, and its known analogue RD162 in which the cyanophenyl was retained but the dimethyl was replaced by cyclobutyl, demonstrated substantially less covalent binding activity and negative results in the MDAM assay. Collectively, these data support the hypothesis that the 2-cyanopyridine moiety in apalutamide may react with cysteine in proteins forming haptens, which may trigger an immune response, as indicated by the activity of apalutamide in the MDAM assay, which in turn may be leading to increased potential for skin rash versus placebo in patients in the SPARTAN and TITAN clinical trials.

Changes in optical characteristics induced by polymer blending in printed colloidal quantum dots microlasers.

On-chip microlasers are desirable to meet the different control requirements and unique demands in different application scenarios. In this work, we obtained the on-chip microlaser by printing pixelated CdSe/ZnS colloidal quantum dots (CQDs), incorporating the quantum dot self-assembly mechanism and the external cavity-free configuration. The spectral purity of the microlaser can be significantly improved by slightly blending polymer into the CQD matrix. The quasitoroid profile was gradually changed to microdisks as the polystyrene (PS) concentration increased from 0 wt.% to 10 wt.%. Specially, when the PS solution varied from 0 wt.% to 1 wt.%, the lasing threshold of 1.4 µJ/mm2 was increased up to 14 µJ/mm2, meanwhile the emission wavelength range showed a 25 nm blue-shift approximately. The easy printing technologies and the low-cost polymer blending method employed in the obtained microlasers will further facilitate the development of printing photonics and electronics, especially in the high-performance microlaser displays and high-precision sensors.

Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICI) targeting PD1, PDL1, or CTLA4 are associated with immune-related adverse events (irAE) in multiple organ systems including myocarditis. The pathogenesis and early diagnostic markers for ICI-induced myocarditis are poorly understood, and there is currently a lack of laboratory animal model to enhance our understanding. We aimed to develop such a model using cynomolgus monkeys. EXPERIMENTAL DESIGN: Chinese-origin cynomolgus monkeys were dosed intravenously with vehicle or nivolumab 20 mg/kg plus ipilimumab 15 mg/kg once weekly and euthanized on day 29. RESULTS: Multiple organ toxicities were observed in cynomolgus monkeys, and were characterized by loose feces, lymphadenopathy, and mononuclear cell infiltrations of varying severity in heart, colon, kidneys, liver, salivary glands, and endocrine organs. Increased proliferation of CD4+ and CD8+ T lymphocytes as well as an increase in activated T cells and central memory T cells in the blood, spleen, and lymph nodes, were observed. Transcriptomic analysis suggested increased migration and activation of T cells and increased phagocytosis and antigen presentation in the heart. Mononuclear cell infiltration in myocardium was comprised primarily of T cells, with lower numbers of macrophages and occasional B cells, and was associated with minimal cardiomyocyte degeneration as well as increases in cardiac troponin-I and NT-pro-BNP. Morphologically, cardiac lesions in our monkey model are similar to the reported ICI myocarditis in humans. CONCLUSIONS: We have developed a monkey model characterized by multiple organ toxicities including myocarditis. This model may provide insight into the immune mechanisms and facilitate biomarker identification for ICI-associated irAEs.

Facile Synthesis of Dimeric Thioether-Macrocyclic Peptides with Antibody-like Affinity against Plexin-B1.

Macrocyclic peptides have gained increasing attention due to their ease of discovery through various in vitro display platforms as well as their potential in possessing favorable properties of both small molecule and antibody drug classes. It is well-known that the avidity achieved through the bivalent binding mode of antibodies gives rise to their slow dissociation rates and thus high potency as drug molecules. Here, we report the synthesis of dimeric thioether-macrocyclic peptides through a branched synthesis approach allowing for synthesis of dimeric peptides in a comparable number of steps as monomers and tunability of linker lengths from 30 to 200 Å. Applying this method to synthesize dimers of a model PlexinB1-binding macrocyclic peptide showed close to 300-fold increases in their apparent binding affinity, bringing the KD down from 8 nM to 30 pM as well as affording improved biological activities when compared to their monomeric counterparts. These enhancements demonstrate that this is a simple synthetic strategy to harness the benefits of bivalence that antibodies naturally possess.

In vivo programming of endogenous antibodies via oral administration of adaptor ligands.

Vaccination is a reliable method of prophylaxis and a crucial measure for public health. However, the majority of vaccines cannot be administered orally due to their degradation in the harsh gut environment or inability to cross the GI tract. In this study, we report the first proof-of-concept study of orally producible chemically programmed antibodies via specific conjugation of adaptor ligands to endogenous antibodies, in vivo. Pre-immuniztion with 2,4-dinitrophenyl (DNP), or the reactive hapten, 1,3-diketone (DK), or a novel reactive hapten, vinyl sulfone (VS) in mice, followed by oral administration of adaptor ligands composed of the hapten and biotin to the pre-immunized mice resulted in successful in vivo formation of the biotin-hapten-antibody complexes within 2h. Pharmacokinetic evaluations revealed that apparent serum concentrations of programmed antibodies were up to 144nM and that the serum half-lives reached up to 34.4h. These findings show promise for the future development of orally bioavailable drug-hapten-antibody complexes asa strategy to quickly and easily modulate immune targets for aggressive pathogens as well as cancer.

Recurrence of cutaneous coccidioidomycosis 6 years after valley fever: A case presentation and literature review.

Coccidioidomycosis is usually acquired by inhalation of spores of Coccidioides immitis and C. posadasii. The disease ranges from a self-limited acute pneumonia (Valley Fever) to a disseminated disease. We present a 44-year-old healthy male who had patchy hair loss of several months duration resembling discoid lupus. He developed a firm non-scaly red plaque on the right forehead. Initial biopsy showed spongiotic dermatitis, and he was treated with systemic steroids. He then developed forehead and periorbital cellulitis and was treated with systemic antibiotics. A second biopsy showed fungal hyphae, and he was treated with itraconazole 200mg bid for 4months beyond clinical resolution. A year later, he presented with intermittent swelling of the right forehead lesion and worsening of the scalp lesions. A forehead biopsy showed interface dermatitis and negative PAS stain for fungi. Scalp biopsy was highly suggestive of discoid lupus and he was started on plaquenil. Many months later, a third biopsy showed fungal infection, and the culture grew C. immitis. He was treated with itraconazole. Retrospectively, the patient gave a history of Valley fever 6 years back when he was in Arizona, USA.

HIV/HCV coinfection and the risk of cardiovascular disease: A meta-analysis.

The emergence of improved antiretroviral therapy has increased the life expectancy of human immunodeficiency virus (HIV)-infected individuals, although there is an increased susceptibility to developing cardiovascular diseases (CVD). The risk for CVD is purported to be even higher among people with HIV and hepatitis C virus (HCV) coinfection because of the increased inflammatory response, which may synergistically impact CVD risk. However, studies comparing CVD outcomes between HIV alone and HIV/HCV individuals have been discordant. Accordingly, we conducted a meta-analysis to clarify and quantify the association between HIV/HCV coinfection and the risk for CVD. We searched EMBASE, CINAHL, Google Scholar, PubMed, and Web of Science from inception to December 2016 to identify studies that provided information on HIV/HCV coinfection and CVD, defined as coronary artery disease, congestive heart failure and stroke. We used a random-effects model to abstract and pool data on the hazard ratios (HRs) for CVD. HRs were adjusted for traditional CVD risk factors including age, sex, smoking, hypertension, diabetes and LDL cholesterol. Among the 283 articles reviewed, four cohort studies met inclusion criteria with a total of 33 723 participants. The pooled adjusted HRs for the association between HIV/HCV coinfection and CVD were 1.24 (95% CI: 1.07-1.40) compared to HIV monoinfection. The test for heterogeneity was not statistically significant (I2 =0.0%, P=.397). In conclusion, individuals with HIV/HCV coinfection had an increased CVD risk compared to those with HIV monoinfection. More research is needed to further examine the nature of this association, and response to traditional risk-reduction therapies.

Subclinical cardiovascular disease in patients with chronic obstructive pulmonary disease: a systematic review.

BACKGROUND: Cardiovascular disease (CVD) accounts for a significant portion of deaths in patients with COPD; however, evidence for early detection strategies for CVD in this population remain limited. Our paper aims to summarize existing data regarding subclinical CVD in patients with COPD with a view to identifying screening strategies in these patients. METHODS: A systematic review of published literature was conducted for studies examining the relationship of COPD and markers of subclinical disease such as coronary artery calcification (CAC), carotid intima media thickness (cIMT), endothelial dysfunction, arterial stiffness as measured by pulse wave velocity (PWV) and augmentation indices (AIx). Both MEDLINE and EMBASE databases were searched till October 2015. RESULTS: A total of 22 studies were included in the review. Compared with control subjects, patients with COPD had significantly higher cIMT (SMD 0.53, 95% CI 0.16-0.90), PWV (SMD 0.91, 95% CI 0.67-1.16) and AIx (SMD 0.86, 95% CI 0.52-1.19). Additionally, an overall higher prevalence of subclinical CVD as assessed by CAC, ABI and FMD was noted in our review. CONCLUSION: Although our findings need further evaluation in prospective studies, our review presents significant evidence in support of increased subclinical CVD burden in COPD patients independent of smoking status. Further large-scale case-control studies are required to highlight the significance of subclinical CVD screening in COPD patients.

Allosteric Inhibition of a Semaphorin 4D Receptor Plexin B1 by a High-Affinity Macrocyclic Peptide.

Semaphorin axonal guidance factors are multifunctional proteins that play important roles in immune response, cancer cell proliferation, and organogenesis, making semaphorins and their signaling receptor plexins important drug targets for various diseases. However, the large and flat binding surface of the semaphorin-plexin interaction interface is difficult to target by traditional small-molecule drugs. Here, we report the discovery of a high-affinity plexin B1 (PlxnB1)-binding macrocyclic peptide, PB1m6 (KD = 3.5 nM). PB1m6 specifically inhibited the binding of physiological ligand semaphorin 4D (Sema4D) in vitro and completely suppressed Sema4D-induced cell collapse. Structural studies revealed that PB1m6 binds at a groove between the fifth and sixth blades of the sema domain in PlxnB1 distant from the Sema4D-binding site, indicating the non-competitive and allosteric nature of the inhibitory activity. The discovery of this novel allosteric site can potentially be used to target plexin family proteins for the development of drugs that modulate semaphorin and plexin signaling.

Transmission electron microscopy of carbon-coated and iron-doped titania nanoparticles.

We present a study on the properties of iron (Fe)-doped and carbon (C)-coated titania (TiO2) nanoparticles (NPs) which has been compiled by using x-ray diffraction (XRD), transmission electron microscopy (TEM), and x-ray photoelectron spectroscopy (XPS). These TiO2 NPs were prepared by using the flame synthesis method. This method allows the simultaneous C coating and Fe doping of TiO2 NPs. XRD investigations revealed that the phase of the prepared NPs was anatase TiO2. Conventional TEM analysis showed that the average size of the TiO2 NPs was about 65 nm and that the NPs were uniformly coated with the element C. Furthermore, from the x-ray energy dispersive spectrometry analysis, it was found that about 8 at.% Fe was present in the synthesized samples. High-resolution TEM (HRTEM) revealed the graphitized carbon structure of the layer surrounding the prepared TiO2 NPs. HRTEM analysis further revealed that the NPs possessed the crystalline structure of anatase titania. Energy-filtered TEM (EFTEM) analysis showed the C coating and Fe doping of the NPs. The ratio of L3 and L2 peaks for the Ti-L23 and Fe-L23 edges present in the core loss electron energy loss spectroscopy (EELS) revealed a +4 oxidation state for the Ti and a +3 oxidation state for the Fe. These EELS results were further confirmed with XPS analysis. The electronic properties of the samples were investigated by applying Kramers-Kronig analysis to the low-loss EELS spectra acquired from the prepared NPs. The presented results showed that the band gap energy of the TiO2 NPs decreased from an original value of 3.2 eV to about 2.2 eV, which is quite close to the ideal band gap energy of 1.65 eV for photocatalysis semiconductors. The observed decrease in band gap energy of the TiO2 NPs was attributed to the presence of Fe atoms at the lattice sites of the anatase TiO2 lattice. In short, C-coated and Fe-doped TiO2 NPs were synthesized with a rather cost-effective and comparatively easily scalable method. The presented analysis enables us to predict the excellent efficiency of these NPs for solar-cell and photo-catalysis applications.

Frequency of kidney diseases and clinical indications of pediatric renal biopsy: A single center experience.

Kidney biopsy occupies a fundamental position in the management of kidney diseases. There are very few renal pathology studies available in the literature from developing world. This study scrutinized the frequency and clinicopathological relationship of kidney biopsies done at the kidney center from 1997 to 2013 amongst pediatric patients. Kidney allograft biopsy were excluded. The specimen was examined under light microscopy and immunofluorescence while electron microscopy was not done. The study includes 423 patients, mean age was 10.48 ± 4.58 years, males 245 (57.9%) were more than females 178 (42.1%). Nephrotic syndrome 314 (74.2%) was the most common clinical presentation followed by acute nephritic syndrome 35 (8.3%) and acute renal failure 24 (5.7%). Primary glomerulonephritis (PGN) was the most common group of diseases, seen in 360 (85.1%) followed by secondary glomerulonephritis (SGN) in 27 (6.4%) and tubulointerstitial nephritis in 21 (5.0%). Among PGN, minimal change disease (MCD) was the most dominant disease, with 128 (30.3%) cases followed by focal segmental glomerulosclerosis FSGS in 109 (25.8%) and membranous glomerulonephropathy in 27 (6.4%). Lupus nephritis (LN) was the leading cause of glomerular disease in SGN followed by hemolytic uremic syndrome. In conclusion, MCD is the most common histological finding, especially in younger children and FSGS is second to it. SGN is rare, and the most common disease in this category is LN while tubulointerstitial and vascular diseases are infrequent.

Ciliated foregut cyst in the triangle of Calot: the first report.

Ciliated foregut cysts are rare anomalies arising from remnants of aberrant embryological development. Around 100 reports on the presence of these congenital masses in the tracheobronchial tree, mediastinum, liver, pancreas and, rarely, the gallbladder have been described. In this article, the case of a 33-year-old woman, who was operated for a laparoscopic cholecystectomy, is presented. During the dissection of the triangle of Calot, a cystic mass, attached to the common hepatic duct, was discovered incidentally. This cyst was dissected off the hepatic duct, and no communication between both structures was found. The histopathological diagnosis was consistent with a ciliated foregut cyst. The postoperative course was uneventful. After reviewing the literature on this pathological entity, we found that this is the first report of a ciliated foregut cyst that is located in the triangle of Calot and found separate from the biliary structures, the gallbladder and the liver. We present a review of the literature on this entity, discussing diagnostic measures and therapeutic options.

Association between non-alcoholic hepatic steatosis and hyper reactive blood pressure response on the exercise treadmill test.

AIMS: Non-alcoholic hepatic steatosis (HS) is associated with hypertension and increased cardiovascular risk. While Blood pressure hyper-reactive response (HRR) during peak exercise indicates an increased risk of incident hypertension and increased cardiovascular risk, no data on the association of non-alcoholic HS and HRR exists. In this study, we have evaluated the association of HS with HRR. METHODS: We included 13 410 consecutive individuals with a mean age: 42.4 ± 8.9 years, 3561 (26.6%) female with normal resting blood pressure and without a previous diagnosis of hypertension, who underwent symptom limited exercise treadmill test, abdominal ultrasonography and clinical and laboratory evaluation. HS was detected by abdominal ultrasonography. HRR was defined by a peak exercise systolic blood pressure >220 mmHg and/or elevation of 15 mmHg or more in diastolic blood pressure from rest to peak exercise. RESULTS: The prevalence of HS was 29.5% (n = 3956). Overall, 4.6% (n = 619) of the study population presented a HRR. Subjects with HS had a higher prevalence of HRR (8.1 vs. 3.1%, odds ratio 2.8, 95% CI 2.4-3.3, P < 0.001). After adjustment for body mass index, waist circumference, fasting plasma glucose and low density lipoprotein cholesterol, HS (odds ratio 1.4, 95% CI 1.1-1.6, P = 0.002) remained independently associated with HRR. HS was additive to obesity markers in predicting exercise HRR. CONCLUSIONS: Non-alcoholic HS is independently associated with hyper-reactive exercise blood pressure response.