Assessing cytokines' talking patterns following experimental myocardial damage by applying Shannon's information theory.

BACKGROUND: The simultaneous measurement of multiple cytokines in parallel by using multiplex proteome arrays (MPA) is of great interest to understanding the inflammatory response following myocardial infarction; however, since cytokines are pleiotropic and redundant, increase of information throughput (IT) attained by measuring multiple cytokines remain to be determined. We aimed this study to assess the IT of an MPA system designed to assess 8 cytokines - commercially available at the time of the study - serum levels, before (control state) and after experimental myocardial cryoinjury (activated state) in rats. METHODS: By assuming that redundant information do not generally increase the IT, we derived Entropy (H) and Redundancy (R) of information by using formulas of Shannon modified accordingly, where a high IT (high H and low R) corresponds to a low level of correlation between cytokines and vice versa for a low IT. The maximum theoretical level of IT and the contribution of each cytokine were also estimated. RESULTS: In control state, no significant correlations were found between cytokines showing high IT; on the contrary, in activated state, several significant correlations were found supporting a complex cross-talk pattern between cytokines with low IT. Using as reference the maximum theoretical level of IT, in activated state, H was reduced of 67.0% and R was increased of 77.4% supporting a reduction of IT. Furthermore, the contribution of individual cytokines to H value of MPA was variable: in control state, IL-2 gave the most contribution to H value, conversely during activated state IL-10 gave most contribution. Finally during activated state, IL-1ß was the only cytokine strongly correlated with values of all other cytokines, suggesting a crucial role in the inflammatory cascade. CONCLUSIONS: Paradoxically, by analyzing an MPA system designed for redundant analytes such as cytokines, translating the Shannon's information theory from the field of communication to biology, the IT system in our model deteriorates during the activation state by increasing its redundancy, showing maximum value of entropy in the control conditions. Finally, the study of the mutual interdependence between cytokines by the contribution to the IT may allow formulating alternative models to describe the inflammatory cascade after myocardial infarction.

Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis.

OBJECTIVES: Mavrilimumab, a human monoclonal antibody targeting the alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor, was evaluated in a phase 2 randomised, double-blind, placebo-controlled study to investigate efficacy and safety in subjects with rheumatoid arthritis (RA). METHODS: Subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a ≥1.2 decrease from baseline in Disease Activity Score (DAS28-CRP) at week 12. RESULTS: 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo (p=0.003) at week 12; for the 10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% (p=0.543), 61.0% (p=0.011), 53.8% (p=0.071), and 66.7% (p=0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-CRP<2.6 (23.1% vs 6.7%, p=0.016), all categories of the American College of Rheumatology (ACR) criteria (ACR20: 69.2% vs 40.0%, p=0.005; ACR50: 30.8% vs 12.0%, p=0.021; ACR70: 17.9% vs 4.0%, p=0.030), and the Health Assessment Questionnaire Disability Index (-0.48 vs -0.25, p=0.005). A biomarker-based disease activity score showed a dose-dependent decrease at week 12, indicating suppression of disease-related biological pathways. Adverse events were generally mild or moderate in intensity. No significant hypersensitivity reactions, serious or opportunistic infections, or changes in pulmonary parameters were observed. CONCLUSIONS: Mavrilimumab induced rapid clinically significant responses in RA subjects, suggesting that inhibiting the mononuclear phagocyte pathway may provide a novel therapeutic approach for RA.

Demographics and baseline disease characteristics of Black and Hispanic patients with multiple sclerosis in the open-label, single-arm, multicenter, phase IV CHIMES trial.

BACKGROUND: Black/African American patients with multiple sclerosis (BpwMS) and Hispanic/Latino patients with multiple sclerosis (HpwMS), who historically have been underrepresented in multiple sclerosis (MS) clinical trials, exhibit greater disease severity and more rapid disease progression than White patients with MS (WpwMS). The lack of diversity and inclusion in clinical trials, which may be due to barriers at the system, patient and study levels, impacts the ability to effectively assess risks, benefits and treatment responses in a generalized patient population. METHODS: CHIMES (Characterization of Ocrelizumab in Minorities With Multiple Sclerosis), an open-label, single-arm, multicenter, phase IV study of self-identified BpwMS and HpwMS aged 18-65 years with relapsing MS and an Expanded Disability Status Score (EDSS) of ≤5.5, was developed in collaboration with patients with MS, national advocacy groups and clinical researchers. Patients were enrolled at study centers across the US, including Puerto Rico, and 1 site in Kenya. RESULTS: A total of 182 patients enrolled in CHIMES: 113 (62.1%) were BpwMS, and 69 (37.9%) were HpwMS; the mean (SD) baseline EDSS score was 2.4 (1.4), and 62.6% of patients were treatment naive. Using the pooled non-BpwMS/HpwMS group in the OPERA ocrelizumab trials as a reference population, patients enrolled in CHIMES were younger, had a higher mean body mass and had a greater T2 lesion volume but similar T2 lesion number on MRI. CONCLUSION: BpwMS and HpwMS have been consistently underrepresented in clinical trials, limiting the understanding of disease biology and response to treatment in this population. Data from the CHIMES study revealed differences in demographics and some baseline disease characteristics and disease burden between BpwMS and HpwMS vs WpwMS. These differences could have an impact when assessing clinical outcomes in BpwMS and HpwMS. GOV IDENTIFIER: NCT04377555.

The prognostic value of heart rate variability in the elderly, changing the perspective: from sympathovagal balance to chaos theory.

Heart rate variability (HRV) is the temporal beat-to-beat variation in successive RR intervals on an electrocardiographic (ECG) recording and it reflects the regulation of the heart rate (HR) by the autonomic nervous system (ANS). HRV analysis is a noninvasive tool for the assessment of autonomic function that gained momentum in the late 1980s when its clinical relevance as a predictor of mortality was established by a milestone study by Kleiger et al. in patients with postacute myocardial infarction. In the last few decades, the increasing availability of commercial ECG devices offering HRV analysis has made HRV a favorite marker for risk stratification in the setting of cardiovascular disease. The rapid aging of the world population and the growing popularity of HRV have also fueled interest for the prognostic value of HRV in the elderly, outside a specific cardiological context. However, the discussion of HRV measures in the elderly is still very much centered on the rather reductionistic model of sympathovagal balance, with the orthosympathetic and parasympathetic limbs of the ANS exercising opposing effects on the heart via autonomic tone. The expanding application of nonlinear dynamics to medicine has brought to the forefront the notion of system complexity, embedded in the mathematical concepts of chaos theory and fractals, and provides an opportunity to suggest a broader interpretation for the prognostic significance of HRV, especially in the elderly. Although the use of novel indices of HRV may be hampered by practical issues, a more holistic approach to HRV may still be safeguarded if traditional time- and frequency-domain measures are viewed in terms of autonomic modulation. This review focuses on HRV in geriatric populations. It considers studies on the prognostic value of HRV in elderly subjects, discussing the potential confounding effect of erratic rhythm, and concentrates on the conceptual distinction between autonomic tone and autonomic modulation. It also briefly addresses the question of the practicality of ECG recordings and identifies a promising area for future research in the effects of common noncardioactive drugs on HRV.

[A data base of a thoracic and cardiovascular department: information on 1001 patients]. / Data base di un Dipartimento toracopolmonare e cardio-circolatorio: informazioni su 1001 pazienti.

The Authors illustrate the results derived from a data base of a thoracic and cardiovascular Department, comprehensive of 1001 patients (464 M and 537 F, average age 71, minimum age 18 and maximum age 101). The conducted analysis results in several considerations: the cause of patient's hospitalization was not relevant to the direct expertise of the Department in the 27,5% of the cases and the profile of the typical-patient is of an elderly person (73% of the cases over 65 years old), basically overweight or obese (35% of the cases with BMI > 25) and with medium-low cultural level (70% of the cases not over middle school); moreover our patients, although under poly-therapy before hospitalization, were discharged with a number of prescribed medicines even more plentiful. The data base of the Department proved to be a useful tool both to instantaneously monitor the departmental activity and also to rationalize the pharmacological therapies.

Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, in subjects with rheumatoid arthritis (RA). METHODS: A randomised, double-blind, placebo-controlled, dose-escalating phase I study in subjects with RA who received stable methotrexate treatment for ≥3 months before enrolment. SUBJECTS: received single intravenous escalating doses of mavrilimumab (0.01-10.0 mg/kg) or placebo. RESULTS: 32 subjects were enrolled in this study (1 unblinded subject at 0.01 mg/kg and another at 0.03 mg/kg were followed by five sequential double-blinded cohorts, n=6 each, treated with 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg, respectively). Adverse events were mild or moderate and were reported with similar frequency across all treatment cohorts. One subject (10.0 mg/kg) experienced moderate face and neck urticaria during infusion that resolved with symptomatic treatment. Systemic clearance of mavrilimumab approached that of endogenous IgG at doses >1.0 mg/kg; pharmacodynamic activity was confirmed in the 1.0 and 3.0 mg/kg cohorts by suppression of suppressor of cytokine signalling 3 mRNA transcripts. In exploratory analyses, reductions of acute phase reactants were observed in subjects with elevated C-reactive protein (>5 mg/l) and erythrocyte sedimentation rate (≥20.0 mm/h) at baseline. No significant change in Disease Activity Score 28-joint assessment (DAS28) was seen in any of the cohorts. In mavrilimumab-treated subjects (n=15) with baseline DAS28 >3.2, mean disease activity (DAS28) was significantly reduced at 4 weeks. CONCLUSION: In this first-in-human study, mavrilimumab showed preliminary evidence of pharmacodynamic activity. Importantly, the safety and pharmacokinetic profiles of mavrilimumab support further clinical studies in RA. TRIAL REGISTRATION NUMBER: NCT00771420.

[Echocardiographic indices related with acute coronary anatomy in acute phase of myocardial infarction: our experience]. / Indici ecocardiografici correlati con l'anatomia coronarica in fase acuta di infarto miocardico: la nostra esperienza.

UNLABELLED: Inferior acute myocardial infarction (IAMI) is often associated with right ventricle involvement (RVAMI). Echocardiogram (Echo) shows the ischemic involvement of the right ventricle with an initial dilatation (RVD) and segmental cinetic abnormalities (RVSCS). During RVAMI the normal convexity of the interatrial septum (IAS) toward right atrium is inverted (IASI). 53 patients with IAMI were studied with ECG, echo and hemodinamic monitoring by a Swan-Ganz catheter. Echo was early performed and patients were subdivided into three groups: 1. IAMI with RVSCS and/or RVD with IASI (12 patients); 2. IAMI with RVSCS and/or RVD without IASI (8 patients); 3. IAMI without VSCS, RVD IASI (33 patients). ECG showed RV involvement only in A and B groups (ST-T segment elevation more than 2 mm in V3 r - V5 r). Echo-Doppler showed no statistically differences between the two groups on RV protodiastolic pression; no hemodinamic differences between the two groups (p = n.s.); no statistically differences in central venous pressure, right ventricular pressure, cardiac output, wedge pressure. Complications (arrhytmias, heart failure, ipotension, pericarditis, 3rd A-V block) were so subdivided: group A: 6 patients (50%); group B: 2 patients (24%); group C: 4 patients (12%) with statistical significance (p<0.03) between all three groups. Coronarography showed that in group A significative lesions were localized in the proximal tract of the right coronary and/or in the proximal tract of the circumflex coronary; on the contrary in B and C groups the lesions were localized in medium and distal tract of the two vessels. Mortality at six months was 41 % in group A (5 patients); 20 % in group B (2 patients); 6 % in group C (2 patients), with p<0.01 between all three groups. Echo after six months showed IASI only in two patients of group A. Patients with IASI revealed complications (residual angina, ventricular ipercinetic arrytmias). IN CONCLUSION: IASI in patients with IAMI and RVAMI seems to identify a group with higher risk in developing complications and with a more adverse prognosis.

Burden and cost of comorbidities in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with various comorbidities, including non-autoimmune and autoimmune conditions. The burden and cost of illness for NMOSD are unclear, particularly in the context of comorbidities. METHODS: Claims data from IBM MarketScan Commercial and Medicare Supplemental Databases between 2014 and 2018 were analyzed. Patients with NMOSD were specified as having inpatient or outpatient claims for NMOSD diagnosis or specific NMOSD symptoms claims and no subsequent claims for multiple sclerosis (MS) or use of MS disease-modifying therapy (DMT). Continuous enrollment ≥ 6 months before and ≥ 1 year after the first claim (index date) was required for study inclusion. Total costs stratified by comorbidities within 12 months post-index date were calculated per patient and compared 1:5 with matched non-NMOSD controls. RESULTS: A total of 162 patients with NMOSD and 810 non-NMOSD controls were evaluated. A significantly higher proportion of NMOSD patients had comorbidities than non-NMOSD controls (66.7% vs 41.5%; P < 0.001). Concomitant autoimmune disease occurred in 19.1% vs 4.9% (P < 0.001) of patients with NMOSD vs non-NMOSD controls. NMOSD patients incurred significantly higher total median (interquartile range) healthcare costs per patient ($68,386.48 [$23,373.54-$160,862.70]) than matched non-NMOSD controls with autoimmune disease ($17,215.13 [$6715.48-$31,441.93]; P < 0.001) or patients with NMOSD without autoimmune comorbidity ($23,905.42 [$8632.82-$67,251.54]; P = 0.022). Similarly, patients with NMOSD and non-autoimmune comorbidities incurred higher median healthcare costs than matched controls. CONCLUSIONS: Patients with NMOSD experience significant disease burden and cost that are amplified by comorbidities. Effective therapies are needed, particularly for patients with concomitant autoimmune disease.

The costs of care from a US claims database in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the central nervous system that often leads to severe disability. Patients with highly active NMOSD have approximately a 10-times higher hospital inpatient admission rate compared with patients without NMOSD. Accurate assessments of the impact of NMOSD treatments on the burdens of illness require quantitative metrics of these burdens, including costs of care. METHODS: This study evaluated claims data from the IBM MarketScan Commercial and Medicare Supplemental Databases between 2014 and 2018. Patients were included based on inpatient or outpatient claims meeting criteria defined for NMOSD. Non-NMOSD controls were matched 5:1 to patients with NMOSD. Total costs of healthcare services in consumer price index-adjusted 2019 US dollars during the 1-year postindex follow-up period were calculated for patients and controls. RESULTS: Patients with NMOSD required more healthcare services and incurred significantly greater costs for inpatient hospitalizations (annual mean [SD] cost: $29,054 [$144,872] vs controls $1521 [$10,759]), outpatient services ($24,881 [$35,463] vs $4761 [$26,447]), and emergency department (ED) visits ($2400 [$7771] vs $408 [$2579]). Almost 12% of patients with NMOSD were further burdened with plasma exchange or intravenous immunoglobulin G treatments, costing an annual median (interquartile range) of $1684 ($566-$3817) and $24,353 ($5425-$42,975), respectively. CONCLUSIONS: Compared with controls, patients with NMOSD had significantly higher costs associated with hospitalizations, ED visits, and prescriptions. These results highlight the considerable economic burden of NMOSD, which may be favorably impacted by disease-modifying therapies that are regulatory-approved to be safe and effective.

Potential advantages of cell administration on the inflammatory response compared to standard ACE inhibitor treatment in experimental myocardial infarction.

BACKGROUND: Bone Marrow (BM) progenitor cells can target the site of myocardial injury, contributing to tissue repair by neovascolarization and/or by a possible direct paracrine effect on the inflammatory cascade. Angiotensin Converting Enzyme inhibitors (ACE-I) are effective in reducing mortality and preventing left ventricular (LV) function deterioration after myocardial infarction. METHODS: We investigated the short term effects of BM mononuclear cells (BMMNCs) therapy on the pro-inflammatory cytokines (pro-CKs) and on LV remodelling and compared these effects over a standard ACE-I therapy in a rat model of myocardial cryodamage. Forty two adult inbread Fisher-F344 rats were randomized into three groups: untreated (UT; n = 12), pharmacological therapy (ACE-I; n = 14, receiving quinapril), and cellular therapy (BMMNCs; n = 16, receiving BMMNCs infusion). Rats underwent to a standard echocardiogram in the acute setting and 14 days after the damage, before the sacrifice. Pro-CKs analysis (interleukin (IL)1beta, IL-6, tumor necrosis factor (TNF)alpha was performed (multiplex proteome arrays) on blood samples obtained by direct aorta puncture before the sacrifice; a control group of 6 rats was considered as reference. RESULTS: Concerning the extension of the infarcted area as well as the LV dimensions, no differences were observed among the animal groups; treated rats had lower left atrial diameters and higher indexes of LV function. Pro-Cks were increased in infarcted-UT rats if compared with controls, and significantly reduced by BMMNCs and ACE-I ; TNFalpha inversely correlated with LV fractional shortening. CONCLUSION: After myocardial infarction, both BMMNCs and ACE-I reduce the pattern of pro-Ck response, probably contributing to prevent the deterioration of LV function observed in UT rats.

Antihypertensive effect of barnidipine 10 mg or amlodipine 5 to 10 mg once daily in treatment-naive patients with essential hypertension: A 24-week, randomized, open-label, pilot study.

BACKGROUND: Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure. OBJECTIVE: The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine. METHODS: This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140-179 mm Hg and diastolic BP of 90-109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets. RESULTS: Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, -10.3/-9.4 vs -16.6/-9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13%]; P < 0.05). CONCLUSION: In this small sample of treatment-naive hypertensive patients, the antihypertensive effect of barnidipine 10 mg once daily was not significantly different from that of amlodipine 5 to 10 mg once daily.

Effects of simulated altitude (normobaric hypoxia) on cardiorespiratory parameters and circulating endothelial precursors in healthy subjects.

BACKGROUND: Circulating Endothelial Precursors (PB-EPCs) are involved in the maintenance of the endothelial compartment being promptly mobilized after injuries of the vascular endothelium, but the effects of a brief normobaric hypoxia on PB-EPCs in healthy subjects are scarcely studied. METHODS: Clinical and molecular parameters were investigated in healthy subjects (n = 8) in basal conditions (T0) and after 1 h of normobaric hypoxia (T1), with Inspiratory Fraction of Oxygen set at 11.2% simulating 4850 mt of altitude. Blood samples were obtained at T0 and T1, as well as 7 days after hypoxia (T2). RESULTS: In all studied subjects we observed a prompt and significant increase in PB-EPCs, with a return to basal value at T2. The induction of hypoxia was confirmed by Alveolar Oxygen Partial Pressure (PAO2) and Spot Oxygen Saturation decreases. Heart rate increased, but arterial pressure and respiratory response were unaffected. The change in PB-EPCs percent from T0 to T1 was inversely related to PAO2 at T1. Rapid (T1) increases in serum levels of hepatocyte growth factor and erythropoietin, as well as in cellular PB-EPCs-expression of Hypoxia Inducible Factor-1alpha were observed. CONCLUSION: In conclusion, the endothelial compartment seems quite responsive to standardized brief hypoxia, possibly important for PB-EPCs activation and recruitment.

How long shall the patient rest before clinic blood pressure measurement?

BACKGROUND: The optimal time at rest before clinic blood pressure (BP) measurement is still undefined. In this study in patients with essential hypertension, the time course of the hemodynamic changes during a 16-min rest in the chair-seated position was evaluated and compared with that observed in a stabilized postural condition, such as after a prolonged supine rest. METHODS: In 55 untreated essential hypertensive patients, BP, heart rate, stroke volume (impedance cardiography), and systemic vascular resistances were measured every other minute during a 16-min rest in the chair-seated position and, in random sequence, in the last 16 min of a 60-min supine rest. RESULTS: Overall, systolic BP (SBP) and diastolic BP (DBP) decreased by 11.6 and 4.3 mm Hg, respectively, during the chair-seated rest; only a 1.8-mm Hg decrease in SBP was observed in the control supine study. The chair-seated fall in BP was associated with a decrease in systemic vascular resistances, in the absence of significant changes in cardiac index. From the logarithmic curve of SBP and DBP decrements, a half-time of 5.8 and 5.5 min respectively, was calculated. Decrements in SBP, but not DBP, were inversely related to the corresponding baseline values. CONCLUSIONS: In untreated essential hypertensive patients a significant decrease in SBP and DBP associated with a systemic vasodilation was observed during a 16-min rest in the chair-seated position. Because approximately 75% of the spontaneous fall in BP occurred within 10 min, it appears that this time at rest before clinic BP evaluation could improve the precision and accuracy of the measurement.

Endothelial colony forming capacity is related to C-reactive protein levels in healthy subjects.

The majority of clinical studies on endothelial progenitor cells (EPCs) focuses on the role of these cells in cardiovascular diseases and no systematic studies exist regarding their variations in healthy subjects. In order to define the burden of angiogenesis in physiological conditions we assessed the frequency of peripheral blood endothelial colonies (PB-ECs) and their relation with other factors possibly involved in their function such as high-sensitivity C-reactive protein (hs-CRP), endothelial cell-specific mitogen factor (VEGF) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in a highly selected healthy population. A PB sample was obtained from 37/47 healthy subjects (age 40.2+/-15.0yrs; M/F 15/22) without known cardiovascular risk factors. The serum level of hs-CRP, VEGF, TIMP-1, the frequency of PB-ECs by clonogenic assay, and the number of early EPCs and late EPCs by flow cytometry analysis were evaluated. PB-ECs were formed by 40.5% of studied subjects with a mean of 0.40+/-0.82 colonies/10(6) cells. The differences in the frequency of colony formation between genders were not statistically significant. The subjects with PB-ECs were characterized by higher values of hs-CRP, when compared with those not forming colonies, 0.276+/-0.230 vs 0.095+/-0.077 mg/l (p=0.003) respectively, and of VEGF, 328.3+/-162.9 vs 202.68+/-118.53 pg/ml (p=0.02). No significant differences were found in TIMP-1 values. The EPC clonogenic potential seems to be related to hs-CRP and VEGF levels even in healthy population supporting the concept that these mediators are involved in physiological ECs function.

Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: results of a randomized trial.

BACKGROUND: In hypertensive left ventricular hypertrophy (LVH), myocardial texture is altered by a disproportionate increase in fibrosis, but there is insufficient clinical evidence whether antihypertensive therapy or individual agents can induce regression of myocardial fibrosis. METHODS AND RESULTS: We compared the effects of an angiotensin II receptor antagonist with a beta-blocker on myocardial collagen volume (assessed by echoreflectivity and serum collagen markers) in 219 hypertensive patients with echocardiographically documented LVH. Patients were allocated randomly to receive losartan 50 to 100 mg/d (n=111) or atenolol 50 to 100 mg/d (n=99) with or without hydrochlorothiazide 12.5 to 25 mg/d for 36 weeks. Echoreflectivity analysis was conducted on ultrasound tracings of the midapex septum with specifically designed and validated software. A color histogram of reflecting echoes was obtained, and its spread (broadband [BB], previously shown to correlate directly with collagen volume fraction on endomyocardial biopsies) was used as the primary outcome measure. Mean color scale and serum markers of collagen synthesis (PIP, PIIIP) or degradation (CITP) were secondary outcome variables. Echoreflectivity analysis proved feasible in 106 patients (losartan 52, atenolol 54). Losartan reduced BB over 36 weeks (from 114.5 to 104.3 color levels, P<0.02), whereas atenolol treatment was associated with an increase in BB (from 109.0 to 113.6 color levels, P=NS), the difference between treatments being -12.8 color levels (95% CI -23.6 to -2.0, P=0.02). Secondary end points (mean color scale and collagen markers) also changed in the direction of decreased collagen in patients receiving losartan, but differences between groups were not statistically significant. CONCLUSIONS: In hypertensive patients with LVH, losartan decreases myocardial collagen content, whereas atenolol does not. The difference between the 2 treatments is statistically significant.

Prevalence and correlates of left atrial enlargement in essential hypertension: role of ventricular geometry and the metabolic syndrome: the Evaluation of Target Organ Damage in Hypertension study.

BACKGROUND: The cardiac effects of hypertension include a variety of structural changes such as increases in left ventricular mass (LVM) and left atrium (LA) size. Although data on hypertension-induced left ventricular changes are extensive, relatively little information is available on LA size from large-scale studies. OBJECTIVE: We sought to assess the prevalence of LA enlargement in a large selected hypertensive population and to determine the relations of LA size to several biologic variables including left ventricular hypertrophy (LVH) and metabolic disturbances. METHODS: A total of 2500 untreated and treated uncomplicated essential hypertensives consecutively attending, for the first time, our hospital out-patient hypertension clinic and included in the Evaluation of Target Organ Damage in Hypertension, an observational ongoing registry of hypertension-related target organ damage (TOD), were considered for this analysis. All patients underwent extensive clinical, laboratory and ultrasonographic investigations searching for cardiac (and extracardiac) TOD. The LA was considered enlarged when its anteroposterior diameter exceeded 3.7 cm in women and 4.1 cm in men. LVH was defined according to two different criteria: >/= 125 g/m in men and >/= 110 g/m in women; or >/= 51 g/m in men and >/=47 g/m in women. RESULTS: Enlarged LA diameter was present in 24.5% of women and in 21.5% of men. Compared with 1925 patients with normal LA size, the 575 patients with enlarged LA were older, more frequently overweight, had higher systolic blood pressure and included a greater proportion of subjects under antihypertensive treatment, with diabetes and metabolic syndrome. Both LA size and prevalence of LA enlargement differed significantly in relation to left ventricular geometry and LVM, being greater in patients with concentric or eccentric LVH than in those with left ventricular concentric remodeling or normal geometry. The prevalence of LA enlargement was similar in patients with concentric and eccentric LVH. According to a logistic regression analysis, overweight, LVH, fasting blood glucose > 7.0 mmol/l and metabolic syndrome were the main independent predictors of LA enlargement in the overall population as well as in both untreated and treated hypertensive subgroups. CONCLUSIONS: Our study suggests that: LA enlargement is a common echocardiographic finding in selected essential hypertensive patients with different left ventricular geometric patterns; LA size and LA enlargement is related to LVM rather than the type of LVH; and, in addition to LVH, overweight, high fasting glucose and metabolic syndrome are associated with LA dimensions.

Carotid wall composition in hypertensive patients after 4-year treatment with lacidipine or atenolol: an echoreflectivity study.

OBJECTIVE: In the European Lacidipine Study on Atherosclerosis (ELSA), against a similar antihypertensive effect, a significantly greater effect of lacidipine was found on carotid intima-media thickness (IMT) progression, indicating a specific anti-atherosclerotic effect of lacidipine. However, not only the extent but also the composition of an atherosclerotic plaque is a determinant of subsequent events. DESIGN AND METHODS: Among the 2334 patients enrolled in ELSA, 420 with 4-year treatment were chosen, videodensitometric analysis of their ultrasound carotid scan was performed and the maximum wall lesion (Tmax) was classified as lipidic, fibrolipidic and fibrotic by means of software previously validated against histology. Of the 420 patients, 244 had scans suitable for videodensitometry. RESULTS: Excellent reproducibility of videodensitometry analysis was found using the Bland-Altman and other methods. At baseline, ELSA hypertensive patients had predominantly fibrolipidic walls (70%), with an echoreflectivity indicating a mean collagen content of 25%. After 4 years of antihypertensive treatment, little change in the frequency distribution of carotid lesions (fibrolipidic 73%) was found, with no significant differences between patients randomized to lacidipine or atenolol. CONCLUSIONS: Our study provides previously unavailable information that carotid wall composition changes to an extremely small extent during 4-year effective blood pressure lowering. With lacidipine, stable composition is associated with a lower IMT progression than with atenolol.

What is the accuracy of clinic blood pressure measurement?

BACKGROUND: In clinical practice, blood pressure (BP) is frequently measured at the end of the visit in patients sitting on one side of the bed and not on a chair according to guidelines. METHODS: In 540 consecutive subjects with essential hypertension (EH) attending a hospital outpatient clinic, BP was measured in the following sequence: 1) patient seated on chair for at least 5 min, 2) patient supine, 3) patient seated on bed, and 4) patient standing for a few minutes. RESULTS: We found that mean (+/-SEM) BP was 143.5/87.2 +/- 0.9/0.5, 153.4/89.7 +/- 1.0/0.5, 148.9/90.9 +/- 1.0/0.5, and 144.8/91.7 +/- 1.0/0.6 mm Hg, respectively (P < .05 v position 1 for all). In 14% of patients, either systolic BP (SBP) or diastolic BP (DBP) was above the conventional upper limits of normality in the seated-on-bed but not in the recommended seated-on-chair position ("false" high clinic BP), whereas SBP and DBP were "false" normal (below limit for bed-seated and above limit for chair-seated position) in only 6% and 2% of patients, respectively. Overall, SBP and DBP increments from the chair- to the bed-seated position were inversely related to the baseline chair-seated values; systolic increments were directly related to age, in particular in the subgroup of untreated EH (n = 70), and to body mass index. A gender-related difference was apparent, as female subjects had more pronounced increments in SBP (+7.4 +/- 0.8 v +3.5 +/- 0.7 mm Hg) and DBP (+4.4 +/- 0.5 v 2.9 +/- 0.4 mm Hg) than did male subjects (P < .05 for both). CONCLUSIONS: Clinic SBP and DBP are overestimated in the bed-seated position at the end of the visit compared with the recommended chair-seated position in treated and untreated patients with EH, in particular in elderly obese women with mild hypertension.

Aortic coarctation suspected by Doppler echocardiography of renal arteries in hypertensive patients referred to a hospital outpatient hypertension clinic.

Coarctation of the aorta is the fourth most frequent form of congenital cardiovascular disease, which is diagnosed by the presence of higher blood pressures in the arms than in the legs. In this report we describe 3 cases of aortic coarctation, in which the correct diagnosis was suspected only months or years after the detection of hypertension, when a renal ultrasound examination was requested, despite the fact that the hallmarks of the disease were present at the physical examination in all patients. A marked reduction in renal flow velocities was suggestive of proximal aortic stenosis in all 3 cases. We conclude that the diagnosis of aortic coarctation, an uncommon but not so rare form of secondary hypertension, by renal ultrasonography rather than by a complete physical examination, reflects a commitment failure of physicians in everyday management of hypertension.

Assessment of carotid plaque composition in hypertensive patients by ultrasonic tissue characterization: a validation study.

OBJECTIVE: Ultrasonic tissue characterization of epi-aortic vessels may be useful to define the composition of atherosclerotic plaques. Videodensitometry provides a histogram representing the frequency distribution of gray levels corresponding to different compositions of the carotid wall. However, lack of standardization limits the clinical application of this technique. In the present study, the echoreflectivity (ER) pattern of atherosclerotic plaques in vivo was compared with their histological pattern after surgical removal, and the reproducibility of measurement was tested. DESIGN AND METHODS: We studied 19 hypertensive patients with a carotid artery stenosis >or= 70%, eligible for carotid thromboendarterectomy (TEA). Before TEA, all patients underwent standard high-resolution B-mode carotid ultrasound. ER parameters (mean gray level, broad band, skewness, and kurtosis) were obtained in a region of interest selected along the whole plaque, between the intima-blood and the media-adventitia interfaces. The plaques removed during TEA were examined by a histologist and classified into three groups on the basis of fibrous tissue (FT) content: lipidic (FT < 20%), fibrolipidic (20 50%). Discriminant function analysis was used to evaluate classification efficacy of different histological groups based on ER parameters. RESULTS: Histologically, five lesions were classified as lipidic, six as fibrolipidic and eight as fibrous. Analysis of variance showed significant between group differences in all ER parameters. The combined use of all ER parameters provided correct classification of plaques in 94.73% of cases (P < 0.0001), improving the classification made using single parameters. Intra-observer and inter-observer variabilities (Bland-Altman method) of mean gray level measurements were small. CONCLUSIONS: Videodensitometry can discriminate between tissue composition of carotid lesions and complement the quantitative assessment of intima-media thickness by additionally providing a well-reproducible semiquantitative evaluation of vascular wall constituents.