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An improved understanding of the P450 structure is relevant to the development of biomimetic catalysts and inhibitors for controlled CH-bond activation, an outstanding challenge of synthetic chemistry. Motivated by the experimental findings of an unusually short Fe-S bond of 2.18 Å for the wild-type (WT) OleT P450 decarboxylase relative to a cysteine pocket mutant form (A369P), a computational model that captures the effect of the thiolate axial ligand on the iron-sulfur distance is presented. With the computational efficiency and streamlined analysis in mind, this model combines a cluster representation of the enzyme─40-110 atoms, depending on the heme and ligand truncation level─with a density functional theory (DFT) description of the electronic structure (ES) and is calibrated against the experimental data. The optimized Fe-S distances show a difference of 0.25 Å between the low and high spin states, in agreement with the crystallographic structures of the OleT WT and mutant forms. We speculate that this difference is attributable to the packing of the ligand; the mutant is bulkier due to an alanine-to-proline replacement, meaning that it is excluded from the energetically favored low-spin minimum because of steric constraints. The presence of pure spin-state pairs and the intersection of the low/high spin states for the enzyme model is indicative of the limitations of single-reference ES methods in such systems and emphasizes the significance of using the proper state when modeling the hydrogen atom transfer (HAT) reaction catalyzed by OleT. At the same time, the correct characterization of both the short and long Fe-S bonds within a small DFT-based model of 42 atoms paves the way for quantum dynamics modeling of the HAT step, which initiates the OleT decarboxylation reaction.

BesC catalyzes the iron- and O(2)-dependent cleavage of 4-chloro-l-lysine to form 4-chloro-l-allylglycine, formaldehyde, and ammonia. This process is a critical step for a biosynthetic pathway that generates a terminal alkyne amino acid which can be leveraged as a useful bio-orthogonal handle for protein labeling. As a member of an emerging family of diiron enzymes that are typified by their heme oxygenase-like fold and a very similar set of coordinating ligands, recently termed HDOs, BesC performs an unusual type of carbon–carbon cleavage reaction that is a significant departure from reactions catalyzed by canonical dinuclear-iron enzymes. Here, we show that BesC activates O(2) in a substrate-gated manner to generate a diferric-peroxo intermediate. Examination of the reactivity of the peroxo intermediate with a series of lysine derivatives demonstrates that BesC initiates this unique reaction trajectory via cleavage of the C4–H bond; this process represents the rate-limiting step in a single turnover reaction. The observed reactivity of BesC represents the first example of a dinuclear-iron enzyme that utilizes a diferric-peroxo intermediate to capably cleave a C–H bond as part of its native function, thus circumventing the formation of a high-valent intermediate more commonly associated with substrate monooxygenations.

Objective The efficacy of renal sympathetic denervation (RDN) has been affirmed by a number of recent clinical studies, despite controversies in this field over the last five years. Therefore, it is of paramount importance that hypertension experts debate the merits of RDN by revealing and expressing their personal beliefs and perspectives regarding this procedure. Methods A cross-sectional survey was conducted among Greek leaders of the Hypertension Excellence Centers with the use of a closed-type questionnaire specifically designed to elicit information and evaluate the respondent's views and perspectives about RDN efficacy, safety and ideal target patient population. Results A total of 36 participants completed the survey. Based on the results, RDN was considered efficient (91.7%) and safe (94.5%), while the overwhelming majority of the participants felt confident in the long-term efficacy (88.9%) of the intervention and that it lacks reliable predictors of blood pressure response (94.5%). Patients with resistant (91.7%), ultra-resistant (94.4%), and uncontrolled hypertension (80.6%) were suggested as ideal candidates for RDN. Establishing a close co-operation between interventionalists and hypertension experts was considered essential to ensure the efficacy (97.2%) as well as the safety (97.3%) of the procedure. Conclusion The vast majority of Greek hypertension experts surveyed were convinced of the efficacy and safety of RDN based on the preponderance of available scientific and clinical data. Identification of the ideal patient group remains controversial. Respondents generally agreed on the necessity of building close collaborative relationships between interventionalists and hypertension experts in order to improve RDN clinical outcome.

Hypertension remains a major public health issue with inadequate control worldwide. The May Measurement Month (MMM) initiative by the International Society of Hypertension was implemented in Greece in 2019 aiming to raise hypertension awareness and control. Adult volunteers (≥18 years) were recruited through opportunistic screening in five urban areas. Information on medical history and triplicate sitting blood pressure (BP) measurements were obtained using validated automated upper-arm devices. Hypertension was defined as systolic BP ≥140 mmHg and/or diastolic ≥90 mmHg, and/or self-reported use of drugs for hypertension. A total of 5727 were analysed [mean age 52.7 (SD 16.6) years, men 46.5%, 88.3% had BP measurement in the last 18 months]. The prevalence of hypertension was (41.6%) and was higher in men and in older individuals. Among individuals with hypertension, 78.7% were diagnosed, 73.1% treated, and 48.3% controlled. Awareness, treatment, and control of hypertension were higher in women and in older individuals. Hypertensives had a higher body mass index (BMI) and were more likely to have diabetes, myocardial infarction and stroke, and less likely to smoke than normotensives (all P

Introduction The unequivocal association between exposure to smoke and numerous complications of pregnancy, demonstrated in the last decades, has led to a significant decrease of smoking rates in pregnancy. The aim of the present study was to determine the prevalence of maternal smoking and to elucidate factors predisposing to it among pregnant women in Athens, Greece. Methods A population of 1700 pregnant women (mean age: 31.2 ± 5.5 years) who visited consecutively the Cardiology Department of Helena Venizelou Maternity Hospital in Athens, Greece, between September 2016 and August 2017, was prospectively analyzed. Data regarding changes in the future mother’s smoking habit as well as different sociodemographic factors potentially related to these changes were recorded. Results Of the 1700 participants, 704 (41.4%) were smokers, and of those 52.4% quit smoking after knowledge of their pregnancy status. The overall prevalence of smoking in pregnancy was 19.7%. Prevalence was higher in women who were aged

Η συμφορητική καρδιακή ανεπάρκεια (ΣΚΑ) είναι συνήθης οντότητα, η οποία οφείλεται σε διαφορετικά αίτια, τα πλέον σημαντικά των οποίων είναι η ισχαιμική, υπερτασική και διατατική μυοκαρδιοπάθεια.Παρά τις πρόσφατες βελτιώσεις στη θεραπεία της ΣΚΑ, η ετήσια θνησιμότητα των ασθενών του τελικού σταδίου είναι εξαιρετικά υψηλή και κυμαίνεται μεταξύ 20-50%. Έτσι συνεχίζονται οι έρευνες με στόχο την ανακάλυψη θεραπευτικών παρεμβάσεων που θα μπορούσαν να βελτιώσουν τη φυσική, συναισθηματική, αιμοδυναμική και μακροπρόθεσμη επιβίωση των ασθενών αυτών.Σκοπός της μελέτης μας ήταν να διερευνήσει την επίδραση ενός α- ΜΕΑ, συγκεκριμένα της καπτοπρίλης, στην κλινική πορεία και τη θνησιμότητα ασθενών με ΣΚΑ. Επιπλέον, στόχος ήταν η προσπάθεια μελέτης της επίδρασης της καπτοπρίλης στα επίπεδα των ηλεκτρολυτών του ορού (Να, Κ, Mg), καθώς και στα επίπεδα του VIP (vasoacitive intestinal peptide) - του αγγειοδραστικού εντερικού πεπτιδίου του πλάσματος, παραμέτρων δηλαδή οι οποίες ενέχονται όχι μόνον στην παθοφυσιολογία του συνδρόμου, αλλά και στη μακροχρόνια πρόγνωση (θανατηφόρες αρρυθμίες).Τα ευρήματά μας υποδεικνύουν ότι η προσθήκη της καπτοπρίλης στη συμβατική αγωγή της ΣΚΑ, ακολουθήθηκε από ευνοϊκό αποτέλεσμα, όχι μόνον αναφορικά με την επίδραση στις ανωτέρω παραμέτρους, αλλά επίσης και αναφορικά με την κλινική πορεία και τη μακροχρόνια επιβίωση των ασθενών αυτών, εύρημα το οποίο έχει πλέον επιβεβαιωθεί από μεγάλες τυχαιοποιημένες μελέτες.

Approximately half a century has passed since the discovery of beta-blockers. Then, their prime therapeutic purpose was to treat angina and cardiac arrhythmias; nowadays, beta-blockers’ usage and effectiveness are extended to treat other cardiovascular diseases, such as hypertension, congestive heart failure, and coronary artery disease. Safety concerns were raised about beta- blockers and their use for chronic obstructive pulmonary disease (COPD) patients with concurrent cardiovascular disease. After thorough research of the literature, this review summarizes the evidence proving that beta-blockers not only might be well tolerated in COPD patients, but they might also have a beneficial effect in this group of patients.

Preeclampsia (PE) continues to represent a worldwide problem and challenge for both clinicians and laboratory-based doctors. Despite many efforts, the knowledge acquired regarding its pathogenesis and pathophysiology does not allow us to treat it efficiently. It is not possible to arrest its progressive nature, and the available therapies are limited to symptomatic treatment. Furthermore, both the diagnosis and prognosis are frequently uncertain, whilst the ability to predict its occurrence is very limited. MicroRNAs are small non-coding RNAs discovered two decades ago, and present great interest given their ability to regulate almost every aspect of the cell function. A lot of evidence regarding the role of miRNAs in pre-eclampsia has been accumulated in the last 10 years. Differentially expressed miRNAs are characteristic of both mild and severe PE. In many cases they target signaling pathway-related genes that result in altered processes which are directly involved in PE. Immune system, angiogenesis and trophoblast proliferation and invasion, all fundamental aspects of placentation, are controlled in various degrees by miRNAs which are up- or downregulated. Finally, miRNAs represent a potential therapeutic target and a diagnostic tool.

Atrial fibrillation (AF) constitutes a relatively infrequent pregnancy complication, which may be a therapeutic Gordian knot. Indeed, sparse data exist regarding the prevalence, prognosis, and management of AF during pregnancy. In general, AF occurs as a benign, self-limited arrhythmia, but occasionally may have severe hemodynamic consequences in pregnant patients suffering from heart failure, congenital heart disease, or other comorbidities. Extra-cardiac causes of AF should always be meticulously excluded.Treatment decisions are difficult, since medications may cross the placental barrier and potentially affect fetal growth and organogenesis, or even result in fetal bradyarrhythmias. Treatment goals are not differentiated in comparison to those regarding AF occurring in the general population. Still, while maternal treatment is prioritized, issues regarding fetal health must deliberately be considered. Consequently, hemodynamic instability is to be promptly treated with synchronized electrical cardioversion. In contrast, in stable patients, pharmacologic cardioversion, under appropriate antithrombotic regimen, should be attempted. Selection of appropriate antithrombotic therapy, including novel oral anticoagulants, imposes further difficulties on therapeutic decision-making. Further clinical trials are warranted in order to assess the pathophysiology and prognosis of AF in pregnancy and ameliorate the evidence-based therapeutic strategy in this specific group of the population.

Background Randomized controlled trials (RCTs) of antidiabetic agents started in the 1960s. Updated meta-analyses of RCTs investigating glucose-lowering in patients with type 2 diabetes mellitus are lacking. Also, no previous attempt was made to evaluate the role of blood pressure (BP) reduction and LDL cholesterol (LDL-C) change on outcome incidence following glucose-lowering. Objectives Three main clinical questions were investigated: the extent of different outcome reductions by glucose-lowering in patients with diabetes, the proportionality of outcome reductions to glycated hemoglobin (HBA1c) reductions and whether ongoing BP and LDL-C difference in RCTs can change glucose-lowering outcome effects. Methods PubMed between 1960 and January 2019 (any language), Cochrane Collaboration Library and previous overviews were used as data sources to identify and select all RCTs comparing the glucose-lowering drugs with placebo or less intense treatment (intentional glucose-lowering RCTs); comparing glucose-lowering drugs with placebo without glucose-lowering intention, but HBA1c difference (nonintentional glucose-lowering RCTs); enrolling type 2 diabetes mellitus patients; and reporting ongoing SBP and DBP difference. We excluded RCTs of acute care, glucose intolerance, type 1 diabetes, multiple interventions applied and glucose-lowering by lifestyle or other interventions. Risk ratios and 95% confidence intervals, of seven fatal and nonfatal outcomes and of treatment-related discontinuations were calculated (random-effects model) before and after adjustment for the ongoing BP difference, while LDL-C difference was also considered. The relationships of different outcome reductions to HBA1c reductions were investigated by meta-regressions. Results A total of 25 RCTs (174 235 individuals, follow-up 3.5 years) were eligible, and the resulted ongoing SBP/DBP difference was -1.4/-0.4 mmHg. Both before and after adjustment for BP difference, glucose-lowering reduced CHD (coronary heart disease) and both composites of major cardiovascular events were reduced by a mean of 8 and 5%, respectively, while before BP-adjustment the risk of treatment-related discontinuations was increased by 26% and the risk of stroke and all-cause death was reduced by 7 and 6%, respectively. Logarithmic risk ratios were related to HBA1c reductions for the composite of CHD and stroke and for treatment-related discontinuations. Glucose-lowering had no differential outcome effects, before and after estimate adjustment for the ongoing BP difference, at different HBA1c thresholds and targets, as well as when both baseline BP and achieved BP, overall cardiovascular risk and diabetes mellitus duration were considered as dichotomous effect modifiers. Although heart failure incidence was found increased by 15% in the early glucose-lowering RCTs, this effect faded away in contemporary RCTs. LDL-C change was overall trivial and did not change glucose-lowering outcome effects. Conclusion Meta-analyses of all glucose-lowering RCTs involving patients with diabetes provide precise estimates of benefits for CHD and major cardiovascular events after consideration of the resulting ongoing BP difference. No benefit or harm on mortality, heart failure and stroke were noticed, while discontinuations related to adverse events because of treatment were increased following glucose-lowering. The extent of glucose-lowering is proportionally related to changes of CHD and stroke composite, and treatment-related discontinuations.

New era antidiabetic drugs are characterized by cardiovascular safety, including specific outcome benefits observed in randomized clinical trials (RCTs). It has been postulated that the favorable effects of new antidiabetic agents are related both to better control of blood pressure (BP) levels and to activation of multiple anti-atherosclerotic properties. In this review, we aimed to assess whether antidiabetic drugs have a pressor effect in glucose control and outcome-oriented RCTs, and to summarize the activated pathophysiological mechanisms relevant to BP control following the use of different antidiabetic drug classes. We also tried to determine which, if any, are the BP-lowering effects of more intense vs less intense glucose-lowering strategy irrespectively of trial antidiabetic regimen. To provide more robust results and evidence-based argumentation, a meta-analysis of placebo-controlled antidiabetic drug RCTs was undertaken to estimate the ongoing BP reduction for all considered and each separate drug class alone. This quantitative synthesis might be helpful for the clinician 1) to select or avoid the use of some classes of antidiabetic agents with a potential favorable or adverse pressor effect, respectively 2) to organize the overall drug regimen in patients with diabetes mellitus and minimize side effects because of concomitant use of drugs with established pressor effect (i.e. antihypertensive agents). This review was also organized to indicate whether BP change associated with different antidiabetic treatments may explain the specific macrovascular outcome benefits. Between all antidiabetic drugs including exogenous insulin, only sodium-glucose cotransporter 2 inhibitors produce a clinically important BP-lowering effect, but this BP reduction alone cannot explain the observed cardiovascular benefit.

Heart rate is an important factor in coronary artery disease and its manifestations, and as such has been considered as a possible target for therapy. Although in epidemiological, and in less degree, in clinical studies derived indications of a possible pathogenetic role of heart rate in major cardiac diseases, clinical trials did not provided any strong evidence. However, even as a simple risk marker, remains important in the treatment of coronary artery disease and heart failure. Beta-blockers are the drugs most frequently used for heart rate control. However, recent studies constantly find insufficient effectiveness of beta-blockers in heart rate control and go further to question their efficacy on outcomes, making clear the need for an additional therapy. Ivabradine, a pure heart rate inhibitor, added to classic beta-blocker treatment represent the new therapeutic option in stable coronary disease and heart failure.

Morning blood pressure (BP) surge is an important aspect of hypertension research. Morning BP monitoring could be a clinically relevant concept in the therapeutic management of hypertension and in the prevention of cardiovascular complications by defining and treating morning hypertension. Because antihypertensive medication is often taken in the morning, uncontrolled morning BP during the trough effect hours could be a hallmark of inadequate choice of antihypertensive regimen, such as the use of short‐ or intermediate‐acting drugs, underdosing of drugs, or no use or underuse of combination therapy. To improve the management of hypertension in general and morning hypertension in particular, long‐acting antihypertensive drugs should be used in appropriate, often full dosages and in proper combinations. The clinical usefulness of antihypertensive drugs with specific mechanisms for morning BP or split or timed dosing of long‐acting drugs in controlling morning BP remains under investigation.

Objective:Much of the variance in hypertension-related sequelae across ethnic groups is highly related to differences in socioeconomic conditions, attitudes and deficits in accurate health related data. East european countries exhibit higher morbidity and mortality from coronary disease than tha res

Objective:Blunted reduction of blood pressure (BP) fall as well as psychological stress have both been related to adverse cardiovascular prognosis and potentially share the altered sympathetic tone as a common pathophysiological substrate. We hypothesised that dipping status might be correlated with

Sirtuins (SIRTs) are a class of nicotine adenine dinucleotide (NAD+)-dependent proteins which participate in numerous molecular pathways involved in various age-related human diseases, such as type II diabetes, cardiovascular (CV) diseases and cancer. They have a major role in apoptosis, inflammation, oxidative stress and metabolism regulation, traits that have a great impact on CV physiology and pathology. Their unique profile of NAD+ energy dependency makes them an appealing target for human intervention in cellular and metabolic processes. This review focuses on the recent advances of SIRTs research aiming to shed light on the emerging roles of SIRTs in the pathophysiology of CV and metabolic diseases.

This analysis investigated the extent of different outcome reductions from low-density lipoprotein cholesterol (LDL-C) lowering following ezetimibe/simvastatin treatment and the proportionality of outcome to LDL-C reductions. The authors searched PubMed between 1997 and mid-June 2015 (any language) and the Cochrane Library to identify all randomized controlled trials comparing ezetimibe/simvastatin with placebo or less intensive LDL-C lowering. Risk ratios (RR) and 95% confidence intervals (CIs), standardized to 20 mg/dL LDL-C reduction, were calculated for 5 primary outcomes (fatal and nonfatal) and 4 secondary outcomes (non-cardiovascular [CV] death, cancer, myopathy, and hepatopathy). Five ezetimibe/simvastatin RCTs (30 051 individuals) were eligible, 2 comparing ezetimibe/simvastatin vs placebo and 3 vs less intensive treatment. Outcomes reduced almost to the same extent were stroke (RR: -13%, 95% CI: -21% to -3%), coronary heart disease (CHD; RR: -12%, 95% CI: -19% to -5%), and composite of stroke and CHD (RR: -14%, 95% CI: -20% to -8%). Absolute risk reductions: 5 strokes, 10 CHD events, and 16 stroke and CHD events prevented for every 1000 patients treated for 5 years. Residual risk was almost 7× higher than absolute risk reduction for all the above outcomes. All death outcomes were not reduced, and secondary outcomes did not differ between groups. Logarithmic risk ratios were not associated with LDL-C lowering. Our meta-analysis provides evidence that, in patients with different CV disease burden, major CV events are safely reduced by LDL-C lowering with ezetimibe/simvastatin, while raising the hypothesis that the extent of LDL-C lowering might not be accompanied by incremental clinical-event reduction.

Epigenetics refers to functional alterations in gene expression or phenotype without any change of the underlying DNA sequence. It is the study of the potential of a cell or organism to express different traits through functional regulation of its gene transcription. Though it is met as a necessary process in biology, epigenetics may often play a crucial part in the development of specific pathologic conditions, including cardiovascular diseases and hypertension.

Preeclampsia has been linked to high morbidity and mortality during pregnancy. However, no efficient pharmacological options for the prevention of this condition are currently available. Preeclampsia is thought to share several pathophysiologic mechanisms with cardiovascular disease, which has led to investigations for the potential role of statins (HMG CoA reductase inhibitors) in its prevention and early management. Pravastatin seems to have a safer pharmacokinetic profile compared to other statins, however, the existing preclinical evidence for its effectiveness in preeclampsia treatment has been mostly restricted to animal models. This review aims to summarize the current data and delineate the potential future role of statins in the prevention and management of preeclampsia.

[1] Whiting DR, Guariguata L,Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311–21. [2] Kannel WB, Gordon T, Offutt D. Left ventricular hypertrophy by electrocardiogram. Prevalence, incidence, and mortality in the Framingham Study. Ann Intern Med 1969;71:89–105. [3] Levy D, Salomon M, D'Agostino RB, Belanger AJ, Kannel WB. Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy. Circulation 1994;90:1786–93. [4] Hadjadj S, Fumeron F, Roussel R, et al. Prognostic value of the insertion/deletion polymorphism of the ACE gene in type 2 diabetic subjects: results from the Noninsulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies. Diabetes Care 2008;31:1847–52. [5] Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 1949;37:161–86. [6] Gubner RS, Ungerleider HE. Electrocardiographic criteria of left ventricular hypertrophy. Arch Intern Med 1943;72:196–209. [7] Molloy TJ, Okin PM, Devereux RB, Kligfield P. Electrocardiographic detection of left ventricular hypertrophy by the simple QRS voltage–duration product. J Am Coll Cardiol 1992;20:1180–6. [8] Pencina MJ, D'Agostino Sr RB, D'Agostino Jr RB, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157–72. [9] Bruno G, Giunti S, Bargero G, et al. Sex-differences in prevalence of electrocardiographic left ventricular hypertrophy in Type 2 diabetes: the Casale Monferrato Study. Diabet Med 2004;21:823–8. [10] Cea-Calvo L, Conthe P, Gomez-Fernandez P, de Alvaro F, Fernandez-Perez C. Target organ damage and cardiovascular complications in patients with hypertension and type 2 diabetes in Spain: a cross-sectional study. Cardiovasc Diabetol 2006;5:23. [11] Okin PM, Devereux RB, Jern S, et al. Baseline characteristics in relation to electrocardiographic left ventricular hypertrophy in hypertensive patients: the Losartan intervention for endpoint reduction (LIFE) in hypertension study. The Life Study Investigators. Hypertension 2000;36:766–73. [12] Kannel WB, Abbott RD. A prognostic comparison of asymptomatic left ventricular hypertrophy and unrecognized myocardial infarction: the Framingham Study. Am Heart J 1986;111:391–7. [13] Kannel WB. Epidemiology and prevention of cardiac failure: Framingham Study insights. Eur Heart J 1987;8(Suppl F):23–6. [14] Ishikawa J, Ishikawa S, Kabutoya T, et al. Cornell product left ventricular hypertrophy in electrocardiogram and the risk of stroke in a general population. Hypertension 2009;53:28–34.

Canagliflozin-with the patent number WO2011142478A1- belongs to a novel class of antidiabetic drugs known as SGLT2 inhibitors, which has been approved by FDA in March 2013. This medication acts through the inhibition of glucose reabsorption in the kidney resulting in glucosuria and thus lowering of glucose blood levels. There are several phase III clinical ongoing trials involving this new class of medications. So far promising results have been shown. This review article summarizes current knowledge regarding the novel SGLT2 inhibitor canagliflozin and its future perspectives in the treatment of type 2 diabetes mellitus.

Fixed-dose triple drug combinations represent one of the latest innovations of pharmacotherapy for hypertension (HT). They combine a traditional renin-angiotensin system blocker, a diuretic and a calcium channel blocker. The main benefit is the simplification of treatment regimen because 3 different agents are combined at different doses in a single pill. Improving adherence to treatment partly explains why this kind of combination may effectively reduce blood pressure (BP). BP lowering by a single- pill triple-drug combination can be approximately predicted, by using appropriate formulas described in previous meta-analysis of randomized trials. Thus, clinicians may select the appropriate dose for each of the combined drugs. Selection of different types of fixed-dose triple-drug combinations relies upon clinical experience, commercial availability and evidence from clinical trials and metaanalyses for each agent alone. However, triple fixed-dose drug combinations should be reserved only for patients with uncontrolled BP with 2 agents, poor adherence in complex therapeutic regimens or on inappropriate free-drug combinations. Also, triple therapy may help overcome clinical inertia by prescribing more potent antihypertensive formulations in one pill. In contrast, this type of multiple-drug fixed-dose combination might be less safe in very old and frail patients, as well as in those with chronic kidney disease. Although new combinations may help overcome the clinical inertia of achieving individualized BP targets, doctors should also pay attention reinforcement of lifestyle changes.

Objective:Functional capacity assessment is an essential component in the primary and secondary prevention programs, and it is determined objectively by cardiopulmonary exercise (CPX) testing. In an oxygen-dependent biological system, such as the human body, CPX testing summarizes the overall effici

Systemic hypertension and aortic valve stenosis (AVS) are both age-related diseases. The pathophysiology of AVS shares some similarities with essential hypertension, which might be the link between the two diseases. Although AS is usually related with low blood pressure levels, approximately one third of patients with severe AS suffer from arterial hypertension, a percentage that can increase up to 50 % according some studies. This review will summarize various aspects regarding the prevalence the pathophysiology and the natural history of those two diseases that seems to be linked, as well as the effect of blood pressure and antihypertensive treatment on various echocardiographic parameters in patients with AVS.

Recent evidence demonstrates that masked hypertension (MH) is a significant predictor of cardiovascular disease, while apelin and relaxin are two novel factors with a significant role in vascular regulation. Apelin is an adipokine that elicits endothelium-dependent vasorelaxation and reduces arterial blood pressure, while relaxin is a protein hormone that induces the production of nitric oxide and vascular endothelial growth factor and inhibits endothelin and angiotensin II. This study aimed to investigate whether apelin and relaxin plasma levels are affected in patients with MH and compare the findings with those of healthy normotensives. One hundred-thirty (60 men, 70 women) healthy patients with a mean age of 45±12 years who had clinic blood pressure

Preeclampsia is a hypertensive disorder of pregnancy that remains a significant cause of maternal morbidity and mortality worldwide. Preeclampsia can be resolved by delivery, and most of the proposed preventive treatment approaches are based on processes involved in placental development in early pregnancy. Yet, none of these has been established in clinical practice. Low-dose aspirin is the most promising candidate, nevertheless; while some individual randomized controlled trials showed minimal or no statistically significant benefit, recent metanalyses showed that early initiation before 16 weeks of gestation is associated with prevention of early-onset preeclampsia and reduction in prevalence of perinatal death or morbidity of pregnant women. Heparin could be an alternative antithrombotic and anti-inflammatory median to prevent preeclampsia either alone or in combination with aspirin; however, results are conflicting concerning efficacy.

The extent of the increased risk of pregnancy hypertensive disorders following assisted reproductive technology (ART) was investigated. PubMed and the Cochrane Collaboration Library were used as data sources to identify and select longitudinal cohorts comparing pregnancies following ART with spontaneously conceived pregnancies, between 1978 and June 2016. Risk ratios and 95% confidence intervals (CIs) of three outcomes, ie, gestational hypertension (GH), preeclampsia (PE), and their sum (PHD), were calculated. Stratification of results by gestation order (singletons and nonsingletons) was pursued, but a separate “all orders” mixed stratification was considered. Sixty-six longitudinal studies (7 038 029 pregnancies; 203 375 following any ART) were eligible. All outcomes independent of gestation order (“all orders”) were increased following any invasive ART: GH (+79% [95% CI, 24%–157%]) and PE (+75% [95% CI, 50%–103%]) to a greater extent, with smaller increases in PHD (+54% [95% CI, 39%–70%]). The risk of PHD following ART steadily increased independent of gestation order.

Hypertensive complications in pregnancy are the leading cause of maternal morbidity, at least in the developed countries. In recent years, infertility issues are managed with ever growing therapeutic options namely assisted reproductive technologies (ART), which improve the ratio of successful induction of pregnancy. It is still debated whether various ART modalities are associated with adverse pregnancy outcomes, including hypertensive complications, particularly with higher incidence of preeclampsia. The main source of controversy stems from the diversity of effect modifiers modulating the association between ART-oriented pregnancy and hypertensive disorders. Indeed, women undergoing an ART procedure are affected by diverse causes of infertility, are frequently characterized by different genetic patterns with respect to their artificially conceived embryo and experienced multiple gestations. In order to investigate whether ART modalities are associated with increased incidence of hypertensive complications in pregnancy, we reviewed all published studies carried out before the end of 2010 and identified in the PubMed database. Among the 47 studies finally selected and by acknowledging the potential of shortcomings related to the different study design and populations, the overall evidence suggests that ART-oriented pregnancies-especially the in-vitro fertilization techniques-are accompanied by increased risk for gestational hypertension and preeclampsia as compared with non-ART pregnancies, even after adjustment for confounders. Multiple gestations, advanced age and underlying polycystic ovary syndrome resulted in constant confounders of the questioned association. Reducing multiple gestations by implementing single embryo techniques might be the therapeutic limiting step to lower the rate of hypertensive complications in assisted pregnancies.

We investigated whether the resistin (Res) and adiponectin (Adp) levels are associated with different clinical blood pressure (BP) phenotypes. Among 465 consecutive never-treated white subjects, we excluded those with diabetes mellitus; impaired glucose metabolism; history of any cardiovascular disease or other concurrent medical condition; secondary hypertension; ongoing vasoactive treatment. Three separate clinic BP measurements and ambulatory BP monitoring were implemented to divide 328 subjects (aged 48±6 years; 172 males) into hypertensives (n=105), masked hypertensives (n=41), white-coat hypertensives (n=52) and normotensives (n=130). Participants underwent echocardiography and oral glucose tolerance testing, whereas, from fasting venous blood samples metabolic profile, plasma Res and Adp levels were assessed. Hypertensives and masked hypertensives showed higher log(10)(Res) and lower log(10)(Adp) levels compared with normotensives, whereas white-coat hypertensives had similar levels of these adipokines compared with normotensives. Common correlates for both of the adipokines were 24-h systolic BP, standing/sitting difference of both diastolic BP and heart rate, and waist circumference. Hypertensive and masked hypertensive compared with normotensive phenotype were independently associated with log(10)(Res) with odds ratios of 1.24 (1.08-1.44), and 1.16 (1.09-1.34) and log(10)(Adp) with 0.74 (0.65-0.87), and 0.81 (0.67-0.95), respectively. Increased Res and decreased Adp plasma levels are associated with out-of-clinic hypertension, whereas they did not determine white-coat hypertension.

The authors aimed to investigate the association between glucose metabolism measures and the exaggerated blood pressure response (EXBPR) to exercise testing in normotensive nondiabetic patients. One hundred and forty-two consecutive patients underwent office blood pressure (BP) measurements, 24-hour BP monitoring, echocardiography, and treadmill exercise test according to the Bruce protocol. The population was divided into 2 groups according to EXBPR at a submaximal workload level. Furthermore, blood samples were obtained for fasting glucose (FG), fasting insulin (FI), and lipid profile assessment. Measures of insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR], quantitative insulin sensitivity check index [QUICKI], and McAuley index) were also estimated, and a standardized oral glucose tolerance test was performed to evaluate glucose levels at 120 minutes (G120). Patients with EXBPR (n=40; 27 men) compared with those without EXBPR (n=102; 66 men) were older by 4+/-6 years (P

The aim of the study was to investigate whether diverse clinical blood pressure phenotypes are associated with free leptin surrogates, as reflected by plasma leptin, human soluble leptin receptor, and their ratio (ie, free leptin index) in nonobese normoglycemic subjects. Three separate clinic blood pressure measurements and ambulatory blood pressure monitoring were implemented to divide 494 subjects (aged 44±5 years; 272 men; body mass index: 2 ) into hypertensives (n=166), white-coat hypertensives (n=82), masked hypertensives (n=66), and normotensives (n=180). Participants underwent echocardiography, while, from fasting venous blood samples, metabolic profile, plasma leptin, and its receptor levels were assessed. Hypertensives and masked hypertensives demonstrated higher levels of log (10)(leptin) and log (10)(free leptin index), as well as lower levels of log (10)(human soluble leptin receptor) with respect to normotensives. White-coat hypertensives had similar free leptin surrogates compared with normotensives. Younger age, 24-hour systolic and diastolic blood pressures, 24-hour heart rate, and left ventricle mass index were common correlates of free leptin surrogates. After adjustment for confounders, masked hypertensive and hypertensive with respect to normotensive phenotype were associated with log (10)(leptin) with odds ratios (95% CIs) of 1.31 (1.12 to 3.80) and 1.26 (1.09 to 2.24), respectively, log (10)(human soluble leptin receptor) with 0.65 (0.53 to 0.78) and 0.69 (0.57 to 0.84), respectively, and log (10)(free leptin index) with 2.46 (1.32 to 7.23) and 1.84 (1.26 to 3.73), respectively ( P

Recent evidence suggests that masked hypertension (MH) is a predictor of cardiovascular disease and that hypoadiponectinemia and hyperesistinemia may contribute to chronic inflammatory process, insulin resistance, endothelial dysfunction, and accelerated atherogenesis. The aim of this study was to examine the adiponectin and resistin plasma levels in patients with MH and compare the findings with those of healthy normotensive persons matched for age, sex, body mass index, and other risk factors. Overall, 130 (60 men and 70 women) healthy persons (mean age, 45+/-12 years) who had clinic blood pressure values140/90 mm Hg were studied. The study population underwent 24-hour ambulatory blood pressure monitoring (ABPM). According to the ABPM recordings, 24 individuals (8 men and 16 women) had MH (daytime systolic blood pressureor=135 mm Hg or daytime diastolic blood pressureor=85 mm Hg; group A) and the remaining 106 participants (52 men and 54 women) had normal ABPM findings (group B). Adiponectin and resistin plasma levels were determined in both groups by enzyme-linked immunosorbent assay. Significantly higher (P.01) resistin levels (12+/-4 vs 6.8+/-3.6 ng/mL) were found in group A compared with group B, while the adiponectin plasma levels were significantly lower (P.01) in group A compared with group B (6+/-2.3 vs 11+/-2.7 microg/mL). Findings suggest that patients with MH have lower adiponectin levels and higher resistin levels compared with normotensive individuals. This observation may have prognostic significance for future cardiovascular events in patients with MH.

Prehypertension, defined as blood pressure between 120-139/80-89 mmHg, is a major public health concern. The condition is very prevalent (30% of the adult population), is often associated with other cardiovascular risk factors and independently increases the risk of hypertension and subsequent cardiovascular events. The mechanism of elevated risk for cardiovascular events associated with prehypertension is presumed to be the same as that of hypertension. In the general population, prehypertension can be lowered by lifestyle modifications, but often not reliably. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) recommendation for prehypertension management with optimal weight control (largely through diet and exercise) remains the mainstay, except for individuals with diabetes, chronic kidney disease, and perhaps known coronary artery disease, because of the shot-term cost considerations and unproven long-term prognosis. The recently published Trial of Preventing Hypertension (TROPHY) is the first study of pharmacologic intervention among those with prehypertension. Results from this trial demonstrated that angiotensin receptor blockade (ARB) retards age-related blood pressure increases in prehypertensive patients. In this review, we discuss the options for pharmacologic intervention of prehypertension, with a focus on the TROPHY trial results.

The introduction of therapies that inhibit tumor angiogenesis and particularly target to vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) (VEGF inhibitors/VEGFi) have revolutionized the treatment of various cancer types. Although their clinical benefit can be optimal for cancer-affected patients, the safety of these targeted agents is of special concern especially for longer-term adjuvant or maintenance treatment. Importantly, VEGFi therapy has been significantly associated with hypertension (HTN) as an adverse effect and therefore the control of blood pressure (BP) after the administration of these drugs remains a challenging matter to be faced. The aim of this review is to summarize studies which investigate the association of VEGFi agents with HTN manifestation and the possible risks associated with this complication. Additionally, given that the optimal management of HTN caused by VEGFi remains obscure, this review will focus on prevention strategies including BP monitoring plans and propose potential therapeutic approaches.

Preeclampsia (PE) is one of the leading causes of maternal and fetal morbidity and mortality, with incidence rates ranging between 2 and 5 % in the Western World. The exact causes of the disease remain largely unknown, because of the complex pathophysiologic mechanisms involved in the process. Genetic, environmental, and epigenetic parameters have been implicated by various authors as culprits for the pathogenesis of PE. Recent reports in the literature highlight the paternal role. Still, the exact extent and mechanism remain elusive. In this systematic review, we attempt to present data regarding the paternal role in a concise and comprehensive manner.

The need for novel antihypertensive therapies represents a continuous challenge. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that has been shown to enhance endogenous natriuretic peptide (NP) actions on neurohormonal activation. This effect seems to be additive to that of the renin-angiotensin-aldosterone system (RAAS) suppression, as impressively suggested in the PARADIGM HF study. LCZ696 has been shown to be effective in reducing blood pressure in several small studies; however, its effectiveness and safety remain to be proved in larger studies. This review summarizes the role of RAAS and NP system in the pathophysiology of hypertension and reviews the current data on the antihypertensive effects of LCZ696.

This analysis investigated the extent of different outcome reductions from low‐density lipoprotein cholesterol (LDL‐C) lowering following ezetimibe/simvastatin treatment and the proportionality of outcome to LDL‐C reductions. The authors searched PubMed between 1997 and mid‐June 2015 (any language) and the Cochrane Library to identify all randomized controlled trials comparing ezetimibe/simvastatin with placebo or less intensive LDL‐C lowering. Risk ratios (RR) and 95% confidence intervals (CIs), standardized to 20 mg/dL LDL‐C reduction, were calculated for 5 primary outcomes (fatal and nonfatal) and 4 secondary outcomes (non‐cardiovascular [CV] death, cancer, myopathy, and hepatopathy). Five ezetimibe/simvastatin RCTs (30 051 individuals) were eligible, 2 comparing ezetimibe/simvastatin vs placebo and 3 vs less intensive treatment. Outcomes reduced almost to the same extent were stroke (RR: −13%, 95% CI: −21% to −3%), coronary heart disease (CHD; RR: −12%, 95% CI: −19% to −5%), and composite of stroke and CHD (RR: −14%, 95% CI: −20% to −8%). Absolute risk reductions: 5 strokes, 10 CHD events, and 16 stroke and CHD events prevented for every 1000 patients treated for 5 years. Residual risk was almost 7× higher than absolute risk reduction for all the above outcomes. All death outcomes were not reduced, and secondary outcomes did not differ between groups. Logarithmic risk ratios were not associated with LDL‐C lowering. Our meta‐analysis provides evidence that, in patients with different CV disease burden, major CV events are safely reduced by LDL‐C lowering with ezetimibe/simvastatin, while raising the hypothesis that the extent of LDL‐C lowering might not be accompanied by incremental clinical‐event reduction.