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Giuseppe MC Rosano,1,2 Cristiana Vitale,1,2 Ilaria Spoletini,1 Maurizio Volterrani11Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; 2Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK Abstract: Ivabradine is a selective antagonist of the funny channels with anti-anginal and anti-ischemic properties, approved for the treatment of coronary artery disease (CAD) and heart failure (HF). It provides pure heart rate reduction, reducing the diastolic depolarization slope, without altering hemodynamic parameters. This review summarizes the current knowledge on the efficacy of ivabradine in patients with cardiovascular diseases, with a particular focus on its role in the clinical management of patients with CAD and HF. There is consistent evidence that ivabradine is effective in reducing angina pectoris symptoms and myocardial ischemia. At approved doses ivabradine is safe, improves exercise tolerance, and reduces heart rate. Available data from clinical trials support its use in the management of patients with stable CAD and chronic HF. Recent studies have cast doubt on the safety of non-approved high doses of ivabradine for the treatment of patients with CAD and without clinical HF, but have shown no concerns on the doses approved for clinical use. Keywords: ivabradine, coronary artery disease, heart failure, angina pectoris, exercise performance

Oxidative stress,which contributes to neuronal damage, is thought to be a pathophysiologicalmechanism of Alzheimer's disease (AD). Markers of oxidative stress may appear early in the preclinical, mild cognitive impairment (MCI) phase of AD.We investigated the interaction among enzymatic-derived oxysterols (24S-hydroxycholesterol and 27-hydroxycholesterol), markers of oxidative stress, including free radical-related oxysterols (7 hydroxycholesterol and 7-ketocholesterol), and vitamin E in AD patients and two amnestic MCI subtypes, amnestic single-domain MCI (a-MCI) subjects, and multidomain MCI (md-MCI) subjects, compared to healthy control subjects (HC). The study included 37 patients with AD, 24 with a-MCI, 29 with md-MCI, and 24 HC. Plasma assessments were made using isotope dilution-mass spectrometry. Although we found no significant change in free radical- or enzymatic-derived oxysterol concentrations in AD or MCI patients, vitamin E levels corrected for cholesterol were reduced in AD patients compared to HC. Results suggest that AD patients have upregulated cerebral oxidative stress or a nutritional deficit of vitamin E. The oxysterols investigated here are not useful markers for diagnosing AD or MCI. [ABSTRACT FROM AUTHOR]

OBJECTIVES: A deficit in facial emotion recognition was described in patients with Alzheimer disease (AD). However, this issue has been underexplored in subjects with amnestic mild cognitive impairment (a-MCI). Thus, the authors aimed to determine whether a deficit in facial emotion recognition is present in a-MCI phase and whether this is intensity dependent. A secondary aim was to investigate relationships between facial emotion recognition and cognitive performances. DESIGN: Case-control study. SETTING: Memory clinic. PARTICIPANTS: Fifty a-MCI patients, 50 mild AD patients, and 50 comparison subjects (COM) were enrolled. MEASUREMENTS: Information about facial emotion recognition was obtained from Penn Emotion Recognition Test. The Mental Deterioration Battery was used to measure cognitive impairment. RESULTS: Mild AD patients were more impaired in the recognition of almost all emotional stimuli of all intensities than a-MCI and COM subjects. However, there was an increased progression only in low-intensity facial emotion recognition deficit from COM to a-MCI to mild AD patients. In particular, a-MCI subjects differed significantly from COM in low-intensity fearful face recognition performance. This deficit in a-MCI patients was explained by the short-term verbal memory impairment, whereas the same deficit in mild AD patients was explained by the long-term verbal memory impairment. CONCLUSIONS: Emotion recognition progresses from a deficit in low-intensity fearful facial recognition in a-MCI phase to a deficit in all intensities and emotions in mild AD. This could be an effect of the progressive degeneration of brain structures modulating emotional processing. An early detection of emotional impairment in MCI phases of dementia may have clinical implications. [ABSTRACT FROM AUTHOR]

Physicians' adherence to guideline-recommended heart failure (HF) treatment remains suboptimal, especially regarding the target doses. In particular, there is evidence that non-cardiologists are less compliant with HF guideline recommendations. This is likely to have a detrimental impact on patients' survival, readmissions and quality of life. Thus, the present document aims to address the reasons underlying low implementation and under-dosing of guideline-directed medical therapy in HF and to update a guidance for the initiation and rapid titration of HF drugs. In particular, aim of this document is to provide practical indications for drug implementation, to be applied not only by cardiologists but also by GPs and internal medicine doctors., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Frailty is highly prevalent among patients with heart failure (HF) and independently predicts adverse outcomes. However, optimal frailty definitions, assessments, and management in HF remain unclear. Frailty is common in HF, affecting up to 80% of patients depending on population characteristics. Even pre-frailty doubles mortality risk versus robust patients. Frailty worsens HF prognosis through systemic inflammation, neurohormonal changes, sarcopenia, and micronutrient deficiency. Simple screening tools like gait speed and grip strength predict outcomes but lack HF-specificity. Comprehensive geriatric assessment is ideal but not always feasible. Exercise, nutrition, poly-pharmacy management, and multidisciplinary care models can help stablize frailty components and improve patient-centred outcomes. Frailty frequently coexists with and exacerbates HF. Routine frailty screening should guide supportive interventions to optimize physical, cognitive, and psychosocial health. Further research on HF-specific frailty assessment tools and interventions is warranted to reduce this dual burden., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2024. Korean Society of Heart Failure.)

Heart failure with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) represent over half of heart failure cases but lack proven effective therapies beyond sodium-glucose cotransporter 2 inhibitor and diuretics. HFmrEF and HFpEF are heterogeneous conditions requiring precision phenotyping to enable tailored therapies. This review covers concepts on precision medicine approaches for HFmrEF and HFpEF. Areas discussed include HFmrEF mechanisms, anti-inflammatory and antifibrotic treatments for obesity-related HFpEF, If inhibition for HFpEF with atrial fibrillation, and mineralocorticoid receptor antagonism for chronic kidney disease-HFpEF. Incorporating precision phenotyping and matched interventions in HFmrEF and HFpEF trials will further advance therapy compared to blanket approaches., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (© 2024. Korean Society of Heart Failure.)

Psychopathology is a process: it unfolds over time and involves several different factors. To extend our knowledge of such process, it is vital to understand the trajectories that lead to developing and maintaining a specific disorder. The construct of continuity appears very useful to this aim. It refers to the consistency, similarity, and predictability of behaviors or internal states across different developmental phases. This paper aims to present a narrative review of the literature on homotypic and heterotypic continuity of psychopathology across the lifespan. A detailed search of the published literature was conducted using the PsycINFO Record and Medline (PubMed) databases. Articles were included in the review based on the following criteria: (1) publication dates ranging from January 1970 to October 2022; and (2) articles being written in the English language. To ensure a thorough investigation, multiple combinations of keywords such as "continuity," "psychopathology," "infancy," "childhood," "adolescence," "adulthood," "homotypic," and "heterotypic" were used. Articles were excluded if exclusively focused on epidemiologic data and if not specifically addressing the topic of psychopathology continuity. The literature yielded a total of 36 longitudinal studies and an additional 190 articles, spanning the research published between 1970 and 2022. Studies on continuity focus on the etiology of different forms of mental disorders and may represent a fundamental resource from both a theoretical and clinical perspective. Enhancing our understanding of the different trajectories beneath psychopathology may allow clinicians to implement more effective strategies, focusing both on prevention and intervention. Since literature highlights the importance of early detection of clinical signs of psychopathology, future research should focus more on infancy and pre-scholar age., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Speranza, Liotti, Spoletini and Fortunato.)

Obesity and oestrogen containing contraceptive products are well-known independent cardiovascular risk factors. However, a significant number of obese women continue to receive prescriptions of hormonal products that contain oestrogens for their contraception. We have conducted a narrative review to discuss the latest evidence, ongoing research, and controversial issues on the synergistic effect of obesity and contraceptive use, in terms of cardiovascular risk. There is compelling evidence of an interplay between obesity and contraception in increasing cardiovascular risk. Women who present both obesity and use of combined oral contraceptives (COCs) have a greater risk (between 12 and 24 times) to develop venous thromboembolism than non-obese non-COC users. Data here discussed offer new insights to increase clinicians' awareness on the cardiovascular risk in the clinical management of obese women. The synergistic effect of obesity and COCs on deep venous thrombosis risk must be considered when prescribing hormonal contraception. Progestin-only products are a safer alternative to COCs in patients with overweight or obesity. Obese women taking contraceptives should be viewed as an 'at risk' population, and as such, they should receive advice to change their lifestyle, avoiding other cardiovascular risk factors, as a form of primary prevention. This indication should be extended to young women, as data show that COCs should be avoided in obese women of any age., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Heart failure (HF) is a long-term clinical syndrome, with increasing prevalence and considerable healthcare costs that are further expected to increase dramatically. Despite significant advances in therapy and prevention, mortality and morbidity remain high and quality of life poor. Epidemiological data, that is, prevalence, incidence, mortality, and morbidity, show geographical variations across the European countries, depending on differences in aetiology, clinical characteristics, and treatment. However, data on the prevalence of the disease are scarce, as are those on quality of life. For these reasons, the ESC-HFA has developed a position paper to comprehensively assess our understanding of the burden of HF in Europe, in order to guide future policies for this syndrome. This manuscript will discuss the available epidemiological data on HF prevalence, outcomes, and human costs-in terms of quality of life-in European countries., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Chronic ischemic heart disease (IHD) is a multifactorial disease with different underlying pathogenetic mechanisms. Percutaneous coronary intervention (PCI) is widely used in patients with IHD in order to reduce angina recurrence. However, after complete or incomplete revascularization procedures, patients may still present anginal symptoms, with a detrimental impact on quality of life and prognosis. This review summarizes the pathogenic mechanisms and the main challenges encountered in the diagnosis and management of post-PCI angina.

Aims: There is evidence that stable angina patients may suffer from emotional disorders that further impair their quality of life. However, the emotional experience of living with stable angina from the patient's perspective still has to be explored. Thus, the main aim of this study was to explore patients' emotional experience of having stable angina and their reported needs during the pathway from the first symptoms, through the process of diagnosis, to management and related lifestyle changes., Methods: A survey was conducted in 75 chronic ischemic heart disease patients with angina (Brazil, China, Romania, Russia, and Turkey) using a 75-min, face-to-face in-depth interview., Results and Conclusion: Patients' responses highlighted the need to increase individuals' awareness on the first signs and symptoms of the disease. The survey also showed that chronic stable angina patients need constant emotional support to overcome stress, anxiety, and depression. Finally, this study suggests the need to offer greater space for dialogue with healthcare professionals to get more comprehensive and 'patient-friendly' information.

Benefits and safety on statins have been well-established over 20 years of research. Despite this, the vast majority of patients are not adequately treated and do not achieve the low-density lipoprotein cholesterol target levels. This is mainly due to poor adherence, which is associated with dangerous and sometimes fatal outcomes. To increase adherence and prevent worse outcomes, a combination therapy with lower dosage of statins and new lipid-lowering drugs may be used. However, the implementation of new lipid-lowering drugs in European countries is still at the beginning. For these reasons, the aim of this position paper is to give an up-to-date indication from the ESC Working Group on Cardiovascular Pharmacotherapy in order to discuss the barriers towards statins adherence and new lipid-lowering drugs implementation in Europe., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Comorbidities are increasingly recognized as crucial components of the heart failure syndrome. Main specific challenges are polypharmacy, poor adherence to treatments, psychological aspects, and the need of monitoring after discharge. The chronic multimorbid patient therefore represents a specific heart failure phenotype that needs an appropriate and continuous management over time. This supplement issue covers the key points of a series of meeting coordinated by the Heart Failure Association of the European Society of Cardiology (ESC), that have discussed the issues surrounding the effective monitoring of our ever more complex and multimorbid heart failure patients. Here, we present an overview of the complex issues from a healthcare delivery perspective., (Published on behalf of the European Society of Cardiology. © The Author(s) 2019.)

This document reflects the key points of a consensus meeting of the Heart Failure Association of European Society of Cardiology (ESC) held to provide an overview the role of physiological monitoring in the complex multimorbid heart failure (HF) patient. This article reviews assessments of the functional ability of patients with HF. The gold standard measurement of cardiovascular functional capacity is peak oxygen consumption obtained from a cardiopulmonary exercise test. The 6-min walk test provides an indirect measure of cardiovascular functional capacity. Muscular functional capacity is assessed using either a 1-repetition maximum test of the upper and lower body or other methods, such as handgrip measurement. The short physical performance battery may provide a helpful, indirect indication of muscular functional capacity., (Published on behalf of the European Society of Cardiology. © The Author(s) 2019.)

Congestion, renal function, and electrolyte imbalance (particularly potassium) are common problems in the management of the complex multi-morbid patient with heart failure (HF). Poor control of these fundamental clinical features is associated with adverse outcomes. Close monitoring of serum potassium and renal function is recommended by most current guidelines during the management of an episode of acute decompensated HF, yet the recommendations remain poorly implemented. Physicians are advised to treat a state of euvolaemia after an admission with decompensated HF and residual congestion is a marker of worse outcome, yet control of congestion is poorly assessed and managed in real-world practice. This document reflects the key points discussed by a panel of experts during a Heart Failure Association meeting on physiological monitoring of the complex multi-morbid HF patient, and here, we present to aspects related to renal function, electrolyte, and congestion monitoring., (Published on behalf of the European Society of Cardiology. © The Author(s) 2019.)

The role of biomarkers is increasingly recognized in heart failure (HF) management, for diagnosis, prognostication, and screening of high-risk patients. Beyond natriuretic peptides and troponins, the utility of novel, emerging biomarkers is less established. This document reflects the key points of a Heart Failure Association of the European Society of Cardiology (ESC) consensus meeting on biomarker monitoring in HF., (Published on behalf of the European Society of Cardiology. © The Author(s) 2019.)

Several devices have been developed for heart failure (HF) treatment and monitoring. Among device-based monitoring tools, CardioMEMS™ has received growing research attention. This document reflects the key points of an ESC consensus meeting on implantable devices for monitoring in HF, with a particular focus on CardioMEMS™., (Published on behalf of the European Society of Cardiology. © The Author(s) 2019.)

Imaging modalities are used for screening, risk stratification and monitoring of heart failure (HF). In particular, echocardiography represents the cornerstone in the assessment of left ventricular (LV) dysfunction. Despite the well-known limitations of LV ejection fraction, this parameter, repeated assessment of LV function is recommended for the diagnosis and care of patients with HF and provides prognostic information. Left ventricular ejection fraction (LVEF) has an essential role in phenotyping and appropriate guiding of the therapy of patients with chronic HF. This document reflects the key points concerning monitoring LV function discussed at a consensus meeting on physiological monitoring in the complex multi-morbid HF patient under the auspices of the Heart Failure Association of the ESC., (Published on behalf of the European Society of Cardiology. © The Author(s) 2019.)

It has been long known that incessant tachycardia and severe hypertension can cause heart failure (HF). In recent years, it has also been recognized that more modest elevations in either heart rate (HR) or blood pressure (BP), if sustained, can be a risk factor both for the development of HF and for mortality in patients with established HF. Heart rate and BP are thus both modifiable risk factors in the setting of HF. What is less clear is the question whether routine systematic monitoring of these simple physiological parameters to a target value can offer clinical benefits. Measuring these parameters clinically during patient review is recommended in HF management in most HF guidelines, both in the acute and chronic phases of the disease. More sophisticated systems now allow long-term automatic or remote monitoring of HR and BP and whether this more detailed patient information can improve clinical outcomes will require prospective RCTs to evaluate. In addition, analysis of patterns of both HR and BP variability can give insights into autonomic function, which is also frequently abnormal in HF. This window into autonomic dysfunction in our HF patients can also provide further independent prognostic information and may in itself be target for future interventional therapies. This article, developed during a consensus meeting of the Heart Failure Association of the ESC concerning the role of physiological monitoring in the complex multi-morbid HF patient, highlights the importance of repeated assessment of HR and BP in HF, and reviews gaps in our knowledge and potential future directions., (Published on behalf of the European Society of Cardiology. © The Author(s) 2019.)

Major considerations in the provision of healthcare are availability, affordability, accessibility, and appropriateness, especially in the setting of heart failure where disease burden is growing, developments have been rapid and newer biomarkers, diagnostic and imaging techniques, monitoring systems, devices, procedures, and drugs have all been developed in a relatively short period of time. Many monitoring and diagnostic systems have been developed but the disproportionate cost of conducting trials of their effectiveness has limited their uptake. There are added complexities, in that the utilization of doctors for the supervision of the monitoring results may be optimal in one setting and not in another because of differences in the characteristics of organization of healthcare provision, making even interpretation of the trials we have had, still difficult to interpret. New technologies are continuously changing the approach to healthcare and will reshape the structure of the healthcare systems in the future. Mobile technologies can empower patients and carers by giving them more control over their health and social care needs and reducing their dependence on healthcare professionals for monitoring their health, but a significant problem is the integration of the multitude of monitored parameters with clinical data and the recognition of intervention thresholds. Digital technology can help, but we need to prove its cost/efficacy and how it will be paid for. Governments in many European countries and worldwide are trying to establish frameworks that promote the convergence of standards and regulations for telemedicine solutions and yet simultaneously health authorities are closely scrutinizing healthcare spending, with the objective of reducing and optimizing expenditure in the provision of health services. There are multiple factors to be considered for the reimbursement models associated with the implementation of physiological monitoring yet it remains a challenge in cash-strapped health systems., (Published on behalf of the European Society of Cardiology. © The Author(s) 2019.)

Renin-angiotensin-aldosterone system inhibitors (RAASi) are known to improve outcomes in patients who have heart failure with reduced ejection fraction (HFrEF). To reduce mortality in these patients, RAASi should be uptitrated to the maximally tolerated dose. However, RAASi may also cause hyperkalemia. As a result of this side-effect, doses of RAASi are reduced, discontinued and seldom reinstated. Thus, the therapeutic target needed in these patients is often not reached because of hyperkalemia. Also, submaximal dosing of RAASi may be a result of symptomatic hypotension, syncope, hypoperfusion, reduced kidney function and other factors. The reduction of RAASi dose leads to adverse outcomes, such as an increased risk of mortality. Management of these side-effects is pivotal to maximise the use of RAASi in HFrEF, particularly in high-risk patients., Competing Interests: Disclosure: The authors have no conflicts of interest to declare., (Copyright © 2019, Radcliffe Cardiology.)

Hyperkalaemia is a life-threatening condition, resulting from decreased renal function or dysfunctional homoeostatic mechanisms, often affecting patients with cardiovascular (CV) disease. Drugs such as renin-angiotensin-aldosterone system inhibitors (RAASi) are known to improve outcomes in CV patients but can also cause drug-induced hyperkalaemia. New therapeutic options exist to enhance potassium excretion in these patients. To this aim, we reviewed pharmacological properties and available data on patiromer and sodium zirconium cyclosilicate for the treatment of hyperkalaemia. These agents have been shown in randomized trials to significantly reduce serum potassium in patients with hyperkalaemia on renin-angiotensin-aldosterone system inhibitors. Additional research should focus on their long-term effects/safety profiles and drug-drug interactions.

Frailty is a complex clinical syndrome associated with ageing and chronic illness, resulting from multiple organ impairment; physiological reserves decrease and vulnerability to stressors increase. The role of frailty in cardiovascular disease has become increasingly recognised. Up to 79% of patients with heart failure are frail. Moreover, frailty is associated with a worse quality of life and poor prognosis. This review summarises the available literature on frailty in HF and highlights indications for its management., Competing Interests: Disclosure: The authors have no conflicts of interest to declare.

Background: Prevention of stroke is a pivotal intervention in the management of patients with atrial fibrillation (AF). Because of the difficulties of safely implementing Vitamin K Antagonists in all patients, there has been a growing interest in improving the pharmacological management of AF with newer antithrombotic agents. The new oral anticoagulants (NOACs) have been developed to overcome the limitations and improve the efficacy of the conventional oral anticoagulant drugs. Among the NOACs, apixaban - a very specific antagonist of activated factor Xa - has pharmacokinetic and pharmacodynamic properties that allow significant efficacy in AF management., Objective: The aim of this review is to summarise the available data on the efficacy of apixaban in patients with AF, with a particular focus on the implications for its clinical management., Results and Conclusion: Clinical application of apixaban in subgroups of patients with AF is still under investigation and some contraindications should be taken into account. Despite these limitations, apixaban is an effective alternative to warfarin and aspirin for stroke prevention in AF, with encouraging evidence also in terms of adherence to treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Elderly and women have been often under-represented in randomised clinical trials (RCTs) testing the effect of treatments on cardiovascular diseases (CVDs) even though these diseases highly affect both of them., Aims: Taking into account these issues, the aim of this review is to critically analyse the topic of under-representation of elderly and women in cardiovascular RCTs., Conclusions: Compared to their younger counterparts, elderly have a higher incidence of disease-related morbidities, take more medicines and account for more adverse drug related events. Similarly, women present several differences in CVD pathophysiology, clinical manifestations and outcomes in comparison to their male counterparts. For these reasons, the results of RCTs obtained in younger men cannot be simply translated in elderly and women. Unfortunately, although international guidelines have been published to increase the enrolment of elderly and women, their recruitment is still insufficient. Thus, the inclusion of these subgroups in cardiovascular RCTs is a key aspect to acquire evidence-based knowledge in the understanding and management of CVDs in elderly and women., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Drospirenone (DRSP) is an antialdosterone agent with progestogenic and antiandrogenic effects. This compound, has been recently used in combination with 17β-estradiol (E2) as hormonal therapy in postmenopausal women and has been shown to exert a significant antihypertensive effect in hypertensive post-menopausal women. Aim of the present study was to compare the effect of DRSP/E2 with those of Tibolone (T) on endothelial function, arterial stiffness, and lipid profile of early postmenopausal women naïve on post-menopausal hormonal therapy. Twenty-four women met the inclusion criteria and entered the study. Women were randomized to receive either DRSP/E2 or T for 6months. Blood pressure and heart rate were similar in both groups at baseline and at the end of the study. Compared to baseline, endothelial function assessed by Reactive Hyperemia (RH) significantly improved in women receiving E2/DRSP, whereas no significant differences between baseline and follow up were detected in women receiving Tibolone. Women receiving E2/DRSP showed a significant decrease in pulse wave velocity and Augmentation Index compared to baseline while no changes were observed in women receiving Tibolone. The capacity of sera to trigger endothelial cells apoptosis in vitro measured by cell death assay was significantly reduced by E/DRSP but not by T (HFA-E 70±5,6% vs HFD-E 41±4,5%, p<0,001). In conclusion, the present study shows that the association of Estradiol and Drospirenone as hormonal replacement therapy significantly improves vascular parameters and the composition of sera relevant for vascular protection in early post-menopausal normotensive women. These effects are not shared by Tibolone., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Pharmacotherapy in chronic heart failure (HF) is challenging, due to the diverse neuroendocrine, inflammatory, metabolic and immunological mechanisms involved in its pathogenesis, the presence of co-morbidities and use of multiple therapies. Further, physiological parameters influencing drug pharmacokinetics (PKs) and pharmacodynamics (PDs) may be altered in patients with HF. There is growing evidence that the disease-induced physiological changes may influence the PKs and PDs of all drugs used in patients with HF. Therapeutic approaches should consider all factors that might influence the response to treatment and dosage should be tailored to individual patients. Hence, further studies are required to understand the PK and PD differences between chronic HF patients and healthy subjects. Because PK is difficult to be assessed in the individual patient with HF, PD effects should be used to tailor therapy in patients with HF., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Significance: Skeletal muscle is a highly plastic tissue. Exercise evokes signaling pathways that strongly modify myofiber metabolism and physiological and contractile properties of skeletal muscle. Regular physical activity is beneficial for health and is highly recommended for the prevention of several chronic conditions. In this review, we have focused our attention on the pathways that are known to mediate physical training-induced plasticity., Recent Advances: An important role for redox signaling has recently been proposed in exercise-mediated muscle remodeling and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) activation. Still more currently, autophagy has also been found to be involved in metabolic adaptation to exercise., Critical Issues: Both redox signaling and autophagy are processes with ambivalent effects; they can be detrimental and beneficial, depending on their delicate balance. As such, understanding their role in the chain of events induced by exercise and leading to skeletal muscle remodeling is a very complicated matter. Moreover, the study of the signaling induced by exercise is made even more difficult by the fact that exercise can be performed with several different modalities, with this having different repercussions on adaptation., Future Directions: Unraveling the complexity of the molecular signaling triggered by exercise on skeletal muscle is crucial in order to define the therapeutic potentiality of physical training and to identify new pharmacological compounds that are able to reproduce some beneficial effects of exercise. In evaluating the effect of new "exercise mimetics," it will also be necessary to take into account the involvement of reactive oxygen species, reactive nitrogen species, and autophagy and their controversial effects.

High platelet reactivity during co-administration of clopidogrel and a CYP3A4-metabolized statin (i.e. atorvastatin) can be lowered by switching to a non-CYP3A4-metabolized statin (i.e rosuvastatin). Aim of this study was to verify if atorvastatin and rosuvastatin have different pharmacodynamic effects also when platelet reactivity while on dual antiplatelet therapy (DAPT) is normal at baseline. A total of 122 stable coronary artery disease patients receiving DAPT (clopidogrel 75 mg plus aspirin 100mg) who had evidence of normal platelet reactivity after a 1-week statin wash-out entered the trial. Patients were randomly assigned to atorvastatin (40 mg day, n=61) or rosuvastatin (20mg day, n=61) for 30 days. After another 1-week wash-out to avoid any carryover effect, cross-over was performed, and patients were switched to the other drug which was continued for 30 days. Platelet reactivity (expressed as P2Y(12) reaction units (PRU) by the VerifyNow assay [Accumetrics, San Diego, California]) was measured after 1-week statin wash-out and at the end of each treatment period. High platelet reactivity was defined as a PRU value >235. After 30-day atorvastatin, platelet reactivity did not significantly change as compared with pre-treatment evaluation (119 ± 66 vs. 136 ± 59 PRU, NS), with 2 patients only showing a PRU>235. Similarly, after 30-day rosuvastatin, platelet reactivity was unchanged vs. baseline (135 ± 46 vs. 128 ± 62 PRU, NS), with PRU>235 occurring in 3 patients. Atorvastatin does not negatively affect DAPT as compared with rosuvastatin when is given to stable coronary artery disease patients with normal platelet reactivity while in statin wash-out (ClinicalTrials.gov Identifier: NCT01567774)., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background:  Levels of platelet reactivity in patients on dual antiplatelet therapy (DAPT) can be influenced by concomitant treatment with statins. We verified if the pharmacodynamic effects of CYP3A4-metabolized statins (atorvastatin) and non-CYP3A4-metabolized statins (pitavastatin) differ in patients with coronary artery disease (CAD) treated with DAPT., Methods and Results:  A total of 155 CAD patients receiving DAPT (clopidogrel 75mg plus aspirin 100mg) entered the PORTO trial. Patients were randomly assigned to atorvastatin (20mg day) or pitavastatin (4mg day) for 30 days, and then switched to the other drug for 30 days. Platelet reactivity was expressed as VerifyNow P2Y12 platelet response units (PRU) before and after each 30-day treatment period. High platelet reactivity was defined as PRU >208. As compared with pretreatment (192±49), PRU was significantly higher after 30-day atorvastatin (210±56; P=0.003), but was unchanged after 30-day pitavastatin (199±47 PRU, NS). In the 48 patients with PRU >208 at baseline (232±44), PRU increased significantly after 30-day atorvastatin (258±41, P=0.004), but not after 30-day pitavastatin (237±43, NS). In the 107 patients with PRU <208 at baseline (174±52), PRU did not change significantly with respect to baseline either after 30-day atorvastatin (188±61, NS) or after 30-day pitavastatin (181±59, NS)., Conclusions:  Pitavastatin, a non-CYP3A4-metabolized statin, does not affect clopidogrel's response as compared with atorvastatin in patients who are borderline or poor responders to DAPT.

Background/objectives: Trimetazidine (TMZ) is a metabolic agent of proven efficacy in improving myocardial ischemia and angina. VASCO, a randomised double-blinded, placebo-controlled trial, assessed anti-anginal efficacy and safety of standard and high dose of modified-release TMZ (70 mg/d and 140 mg/d) in symptomatic and asymptomatic patients with chronic ischemic heart disease receiving background atenolol 50mg/d on exercise test parameters. The VASCO-angina study assessed the efficacy of the two doses of TMZ on total exercise duration (TED) and time to 1-mm ST segment depression (T1), in symptomatic patients with chronic stable angina receiving background atenolol treatment., Methods and Results: In the all cohort of chronic stable angina patients TMZ significantly improved TED compared to baseline and to placebo. Both doses of TMZ significantly increased TED (p=0.0044 and p=0.0338 for TMZ 140 mg/d and TMZ 70 mg/d, respectively). A greater TED improvement was observed in TMZ 140 mg/d than in TMZ 70 mg/d, although the difference was not significant. Amongst patients with limiting angina during exercise test, both doses of TMZ significantly improved both T1 and TED. No difference in serious adverse events was noted between TMZ and placebo., Conclusions: The VASCO-angina gives evidence for the efficacy and tolerability of standard and high dose of TMZ in improving effort-induced myocardial ischemia and functional capacity in patients with chronic stable angina receiving background beta-blockers., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Androgens are known to play a pivotal role in cardiovascular function. However, a definitive explanation as to how their impact differs between genders is yet to be provided. In this review, the existing studies on the link between androgens and cardiovascular disease have been analysed, with a particular focus on the gender-specific differences. Several studies agree that both direct and indirect effects of testosterone on cardiovascular function show a gender-related dimorphism. Consistently, men and women display different responses to androgen supplementation treatment. Post-menopausal women may particularly benefit from testosterone supplementation therapy. Future studies should further clarify the optimal dose and route of administration of testosterone, and more women should be included in clinical trials, in order to identify novel gender-specific targets, and finally to develop therapeutic strategies.

Background: Arterial hypertension affects endothelial function and arterial stiffness. The angiotensin (AT1) receptor antagonist irbesartan improves endothelial function and arterial stiffness in hypertensive patients. Nebivolol, a beta(1)-selective beta blocker, reduces systemic vascular resistance and stimulates nitric oxide release thus exerting positive effects on vascular function. However, comparative studies on the vascular effects of third generation beta-blockers and AT1 receptor blockers are lacking. Aim of this randomized, double-blind study was to test the hypothesis of non-inferiority of nebivolol to irbesartan, both in association with hydrochlorothiazide, on endothelial function, arterial stiffness and central hemodynamic parameters in patients with arterial hypertension naïve on therapy., Methods: Sixty-five patients were randomized to receive irbesartan/hydrochlorothiazide (150 mg/12.5 mg day) or nebivolol/hydrochlorothiazide (5mg/12.5 mg day) for 8-weeks. Endothelial function, pulse wave velocity, augmentation index, central and brachial blood pressures were measured at baseline and at the end of the study., Results: Systolic and diastolic central blood pressure, as well as brachial arterial pressure, decreased to a similar extent after both treatments. Similar changes in endothelial function between groups were detected at the end of the study. A significant reduction in pulse wave velocity, central blood pressure, and augmentation index adjusted for heart rate, was found in both the treatment groups at the end of the study, without significant differences between groups., Conclusions: The results of this study confirm the hypothesis of non-inferiority of short-term treatment with nebivolol compared to irbesartan, both in association with hydrochlorothiazide, on endothelial function, arterial stiffness and central hemodynamic parameters in hypertensive patients naïve on therapy., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In recent years, it has become clear that women and men may differ for drug response. Also, there is an increasing recognition on the role of sex hormones on pharmacokinetics and pharmacodynamics as mechanism accounting for sex differences in drug effects.In women, the phases of menstrual cycle, of reproductive life and fluctuations in the concentrations of sexual steroids on pharmacokinetics and pharmacodynamics must be considered. Furthermore, the use of oral contraceptives or hormonal replacement therapy, the sex hormone-related changes in total body water or in the amount of fat influence the overall effect of drugs.On the contrary, the influence of androgens on drug effects is minimal because of the even plasma levels of these hormones in adult males.Nevertheless, since women have been scarcely included in the early phases of clinical trials, the results obtained in men have been often translated to women and their exact response to drugs is still not well known.The available evidence suggests that sex hormones influence drug absorption, distribution, metabolism, pharmacodynamics, and adverse effects. For instance, many cardiovascular drugs are metabolized by enzymes of the cytochrome P450 mono-oxygenases system, which is more expressed in females than in males, showing sex differences in drug response.Upcoming pharmacological research should aim to further clarify the influence of sex hormones on drug effects and, for this purpose, to increase the number of women enrolled in all phases of clinical trials. An evidence-based pharmacotherapy in women is therefore auspicable for women's health.

Pharmacological outcomes depend on many factors, with many of them being sexually dimorphic. Thus, physiological gender/sex (GENS) differences can influence pharmacokinetics, pharmacodynamics and, thus, bioavailability and resulting in efficacy of treatment, meaning GENS differences should be an important consideration in therapeutics. In particular, drug response can change according to different hormonal environments. Therefore, GENS-specific differences have a particular clinical relevance in terms of drug delivery, especially for those substances with a narrow therapeutic margin. Since adverse effects are more frequent among women, safety is a key issue. Overall, the status of women, from a pharmacological point of view, is often different and less studied than that of men and deserves particular attention. Further studies focused on women's responses to drugs are necessary in order to make optimal pharmacotherapeutic decisions.

Background: Several drugs, including β-blockers (β-adrenoceptor antagonists), are largely under-utilized in older patients with cardiovascular disease., Objectives: The aims of this study were to evaluate whether older patients (aged ≥65 years) with coronary artery disease (CAD) have a different pattern of use of β-blockers than younger adult patients (aged <65 years) and whether gender differences or other clinical variables may influence the use of these drugs., Methods: Over 6 months, 2226 outpatients with stable CAD were enrolled in an observational, cross-sectional, multicentre survey. Of these, 1416 patients aged ≥65 years were grouped into four subgroups according to age. Predictors of β-blocker use were determined using logistic regression analyses. Comparisons between younger adults and older patients were conducted using Student's t-tests and chi-squared (χ2) tests., Results: Up to 47% of older patients were not receiving β-blockers, and this percentage progressively increased with age, with the oldest patients showing the lowest rate of utilization. No gender difference in the pattern of use of β-blockers was noted. The prescription of β-blockers was higher in patients with heart failure (HF) than in patients without HF. The presence of HF abolished the decrease in β-blocker use with age. Logistic regression analysis confirmed that lower age and severe HF were independent predictors of β-blocker use in older people., Conclusions: Age appears to be a key factor in the under-prescription of β-blockers in CAD outpatients. Despite the recommendations, and the efforts of cardiologists, the use of β-blockers in the elderly is still limited, possibly because of practical constraints such as adverse effects and co-morbidity. In patients with HF, age is less important in determining the use of β-blockers.