Pantelis Zebekakis

Effects of Low-Dose Atorvastatin on Arterial Stiffness and Central Aortic Pressure Augmentation in Patients With Hypertension and Hypercholesterolemia

BACKGROUND Experimental and clinical data suggest that statins exert anti-inflammatory and antiproliferative actions on vasculature beyond their lipid-lowering properties. Whether these pleiotropic effects of statins translate into a beneficial effect on arterial stiffness is not clear. This study aimed to evaluate the potential effects of low-dose atorvastatin treatment on arterial stiffness and central arterial pressure waveforms in patients with mild hypertension and hypercholesterolemia. METHODS In a double-blind, randomized, placebo-controlled fashion, 50 hypertensive and hypercholesterolemic patients were allocated to receive 10 mg of atorvastatin or placebo for 26 weeks. Arterial stiffness was assessed by aortic pulse-wave velocity (PWV) using a Sphygmocor device. Central arterial pressure waveform parameters were estimated by radial artery applanation tonometry. Heart rate-adjusted augmentation index (AIx(75)) was used as measure of wave reflections. RESULTS At study end, aortic PWV (9.0 ± 1.5 vs. 10.9 ± 2.6 m/sec; P < 0.001) and AIx(75) (24.9% ± 9.7% vs 28.8% ± 11.8%; P < 0.001) were significantly lower in the atorvastatin group than that placebo group. Furthermore, decreases in central aortic systolic blood pressure and pulse pressure were evident at study-end with atorvastatin but not with placebo (130 ± 8 vs. 138 ± 6 mm Hg, P < 0.001; 48 ± 7 vs. 53 ± 6 mm Hg, P < 0.05, respectively). Atorvastatin-induced reductions in aortic PWV during follow-up showed significant associations with changes in AIx(75) and central aortic systolic blood pressure and pulse pressure. CONCLUSIONS This study shows that low-dose atorvastatin treatment improves arterial stiffness and exerts a reduction on central aortic pressures. These effects may represent a potential mechanism of cardiovascular risk reduction observed with statin use. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Database Identifier Number: NCT01126684.

Comparative Epidemiology of Resistant Hypertension in Chronic Kidney Disease and the General Hypertensive Population

Until a few years ago, information regarding the epidemiology of resistant hypertension was obtained from indirect sources, such as cross-sectional studies on hypertension control in large cohorts from tertiary hypertension centers and outcome trials in hypertension. During the past 3 years, however, large population-based studies have provided direct epidemiologic data on resistant hypertension and estimated its prevalence at 8% to 12% of adult patients with hypertension. Chronic kidney disease (CKD), in particular, has been long considered a frequent underlying cause of resistant hypertension, however, recently, direct epidemiologic data for this entity in patients with CKD were brought to light again, suggesting an even higher prevalence of resistant hypertension (approximately 20%-35%) among such individuals. Furthermore, recent prospective cohort studies have suggested incident resistant hypertension to be associated with increased cardiovascular and renal risk in both the general hypertensive population and patients with CKD. This article discusses currently available data on epidemiology of resistant hypertension, providing a comparative overview of its prevalence, incidence, and prognosis in these two populations.

Differential Expression of the Insulin-Like Growth Factor Receptor among Early Breast Cancer Subtypes

Introduction We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes. Patients and Methods Archival tumor tissue from 1,021 women with early, node positive breast cancer, who were prospectively evaluated within two randomized clinical trials, was used to construct tissue microarrays that were stained for hormone receptors (HR), Ki67, HER2, epidermal growth factor receptor (EGFR) and cytokeratins 5/6, to classify tumors into five immunophenotypical subgroups. Immunohistochemical (IHC) expression of IGF1R-alpha and beta subunits, IGF2R and IGF-binding protein 2 (IGFBP2) was assessed using the immunoreactive score (IRS). Repeated internal cross-validation was performed to examine the statistical validity of the cut off points for all biomarkers. Results After a median follow-up time of 105.4 months, overall 370 women (36.2%) had relapsed and 270 (26.4%) had died. Tumors expressing IGF1R-alpha above the median IRS were significantly more frequently HR positive (luminal A+B+HER2), as compared to HER2-enriched and triple negative ones (p<0.001 for both comparisons). IGF2R was overexpressed significantly more frequently in HR negative tumors (p = 0.001) and had an inverse correlation with all other biomarkers. Patients with luminal A and B tumors with high IGF1R-alpha and negative EGFR expression (N = 190) had significantly higher 4-year survival rates, as compared to the rest (log-rank p = 0.046), as did patients with luminal A and B tumors with high IGF1R-alpha and low IGF2R expression, as compared to the rest (N = 91), (log-rank p = 0.035). After adjustment for significant variables, patients in the latter group had a relative 45% reduction in the risk of death, as compared to the rest (p = 0.035). Conclusion Aberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer.

Arterial Stiffness and Peripheral and Central Blood Pressure in Patients With Sickle Cell Disease

Blood pressure (BP) in patients with sickle cell disease (SCD) has been reported to be lower than in persons in the general population. Data on arterial stiffness, which is an important risk factor for the progression of BP, are inconclusive for this patient population. Forty‐five adult patients with SCD and 40 controls matched for sex, age, and body mass index were studied. Brachial systolic BP (SBP) and diastolic BP (DBP) were significantly lower in the patient group (SBP 115.1±13.8 mm Hg vs 121.9±11.3 mm Hg and DBP 68.5±8.0 mm Hg vs 80.6±9.1 mm Hg, P<.05, respectively). Augmentation index (AIx), however, was significantly higher in SCD patients compared with healthy controls (24.9±9.6 for patients vs 12.4±10.8 for controls, P<.001), while carotid femoral pulse wave velocity was comparable between the two groups. The study shows that mechanisms other than arterial elasticity are involved in the low BP phenotype of patients with SCD.

The Role of MicroRNAs in Arterial Stiffness and Arterial Calcification. An Update and Review of the Literature

Arterial stiffness is an independent risk factor for fatal and non-fatal cardiovascular events, such as systolic hypertension, coronary artery disease, stroke, and heart failure. Moreover it reflects arterial aging which in many cases does not coincide with chronological aging, a fact that is in large attributed to genetic factors. In addition to genetic factors, microRNAs (miRNAs) seem to largely affect arterial aging either by advancing or by regressing arterial stiffness. MiRNAs are small RNA molecules, ~22 nucleotides long that can negatively control their target gene expression posttranscriptionally. Pathways that affect main components of stiffness such as fibrosis and calcification seem to be influenced by up or downregulation of specific miRNAs. Identification of this aberrant production of miRNAs can help identify epigenetic changes that can be therapeutic targets for prevention and treatment of vascular diseases. The present review summarizes the specific role of the so far discovered miRNAs that are involved in pathways of arterial stiffness.

Prevalence and correlates of persistent intracellular HIV transcription in individuals on efavirenz versus atazanavir-based regimens: A prospective cohort study

Objectives Despite successful virological suppression, HIV transcription frequently persists intracellularly. In this study, we hypothesize that HIV persistent transcription(HIVpt) may affect to a different extent patients on stable efavirenz(EFV) versus atazanavir(ATV)-based regimens. The role of the expression of drug efflux transporters in HIVpt was also investigated. Methods We prospectively enrolled 51 virologically suppressed patients on first-line treatment for one year with EFV or ATV combined with emtricitabine and tenofovir and followed them up for one year. Simultaneous ultrasensitive subpopulation staining/hybridization in situ(SUSHI) was performed to identify HIVpt in CD4+ T-cells and in the CD4+CD45RO+ T-cell subpopulation. The differential mRNA expression of P-glycoprotein(P-gp/ABCB1) and multidrug resistance-associated protein-1(MRP1/ABCC1) was also evaluated. Univariate logistic regression models were used to evaluate predictors of HIVpt. Results In the CD4+ T-cell population, HIVpt affected 13/30 of patients on EFV versus 10/21 on ATV. In the CD4+CD45RO+ T-cell population, HIVpt was present in 14/30 of patients on EFV versus 15/21 on ATV. A trend for association was observed between the risk of HIVpt and ATV treatment in the CD4+CD45RO+ T-cell population (OR 2.86, 95% CI 0.87–9.37, p = 0.083). HIVpt status was not associated with loss of virological suppression or CD4 evolution. We found no evidence of differential expression of the drug efflux transporters P-gp and MRP1. Conclusions Further study is required to evaluate whether the HIVpt profile in specific cell populations may differ across different antiretroviral regimens and to elucidate the potential clinical impact.

Factors associated with poor adherence to vaccination against hepatitis viruses, streptococcus pneumoniae and seasonal influenza in HIV-infected adults

ABSTRACT Introduction: Vaccination against various pathogens is recommended for HIV positive adults. There are not sufficient data either on vaccination coverage of HIV positive adults or the risk factors associated with poor adherence to routine vaccination. Patients-Methods: During the period 2004–2014 vaccination coverage of a group of HIV infected adults against hepatitis A virus (HAV), hepatitis B virus (HBV), seasonal influenza virus and pneumococcal disease was recorded. Vaccination coverage was separated into two chronological periods, before and after 2010, as 2010 marks the start of the economic crisis in Greece. Results: 1210 patients were included in our study. Vaccine coverage throughout the study for hepatitis B, hepatitis A, seasonal influenza and pneumococcal infection was 73.6%, 70.4%, 39% and 79%, respectively. The complete lack of insurance coverage was an independent factor of non-compliance in all proposed vaccines (vaccination against pneumococcal disease: OR: 0.82 95%CI: 0.49–1.35, vaccination against HBV: OR: 0.82, 95% CI: 0.45–1.49, vaccination against HAV OR: 0.54, 95%CI: 0.34–0.87, vaccination against influenza: OR: 1.27, 95% CI: 0.76–2.10). In addition, low educational level was associated with poor compliance to vaccination against pneumococcal disease, hepatitis A, hepatitis B, and influenza. Finally, the recommendation for vaccination after the onset of the economic crisis (2010) led to poor compliance to vaccination against HBV, HAV and pneumococcal disease, but not against influenza. Conclusions: In our study, vaccination coverage for vaccine-preventable diseases was found to be insufficient for HIV positive adults in Northern Greece. Also, low educational level, lack of insurance coverage and economic distress have contributed to poor vaccine compliance, leading to poor protection of the HIV positive population and decreased immune coverage in the community.

Arterial Stiffness in Special Populations.

We greatly appreciate the work by Dr Hidekatsu Yanai that looked for correlations between arterial stiffness parameters and metabolic risk factors. Special subpopulations have different arterial elasticity compared with healthy individuals. Diabetes mellitus has a plethora of risk factors that attribute to arterial stiffness. Identifying which metabolic factors are the strongest players in the association of diabetes mellitus and arterial stiffness is pivotal in understanding those that mostly contribute to atherosclerosis. Age is a nonmodifiable risk factor that is strongly correlated with both augmentation index (AIx) and pulse wave velocity (PWV) in Japanese patients, as described in the study by Yanai. Blood pressure (BP) also correlates with both AIx and PWV. These correlations were also significant in patients with sickle cell disease but also in other special populations such as those with chronic kidney disease. However, patients with sickle cell disease had lower BP than controls but comparable PWV and higher AIx. In this particular subpopulation, AIx and PWV did not determine BP levels. Multivariate analysis in our study showed that PWV was solely influenced by age, but AIx was determined by age, waist circumference, and the presence of sickle cell disease. It would be interesting to see whether such an analysis was conducted in the study by Yanai. In other populations such as patients with rheumatoid arthritis, a more severe inflammatory status impacted arterial stiffness (as measured by PWV, AIx, and AIX standardized to a heart rate of 75 beats per minute). Therefore, arterial stiffness should be assessed in the context of the special features of each individual disease as well as ethnic disparity. PWV and AIx are two different indices of arterial stiffness. PWV is a simple measure of the time taken by the pressure wave to travel over a specific distance. AIx is traditionally obtained from pressure waveforms via arterial applanation tonometry. It is intuitive that these two measurements produce different relative measurements of arterial stiffness in the same patient. Because PWV is highly reproducible and has a strong correlation with cardiovascular events and all-cause mortality, it is widely recognized as the golden standard for measuring arterial stiffness and integral to the diagnosis and treatment of hypertension. Accepted thresholds for defining arterial stiffness exist only for PWV (10 m/s), while several thresholds have been proposed for Aix, with none being endorsed by official guidelines. As PWV is better correlated with cardiovascular outcomes and predicts cardiovascular mortality beyond traditional risk factors, it has a special gravity in describing arterial stiffness. Therefore, it remains the best choice for defining correlations with risk factors. To what extent a second, lesser surrogate of arterial stiffness such as AIx is needed is not yet clear. Perhaps adopting just one measurement may simplify result reporting for arterial stiffness. In conclusion, arterial stiffness is determined by different factors depending on disease and ethnic background. Identifying these risk factors in special populations is pivotal in targeting them and improving cardiovascular outcomes through a more individualized approach. PWV is the best measurement we have to use as an outcome measure of any intervention aimed to improve arterial stiffness.