Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?

Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.

Comprehensive multicomponent cardiac rehabilitation in cardiac implantable electronic devices recipients: a consensus document from the European Association of Preventive Cardiology (EAPC; Secondary prevention and rehabilitation section) and European Heart Rhythm Association (EHRA).

Cardiac rehabilitation (CR) is a multidisciplinary intervention including patient assessment and medical actions to promote stabilization, management of cardiovascular risk factors, vocational support, psychosocial management, physical activity counselling, and prescription of exercise training. Millions of people with cardiac implantable electronic devices live in Europe and their numbers are progressively increasing, therefore, large subsets of patients admitted in CR facilities have a cardiac implantable electronic device. Patients who are cardiac implantable electronic devices recipients are considered eligible for a CR programme. This is not only related to the underlying heart disease but also to specific issues, such as psychological adaptation to living with an implanted device and, in implantable cardioverter-defibrillator patients, the risk of arrhythmia, syncope, and sudden cardiac death. Therefore, these patients should receive special attention, as their needs may differ from other patients participating in CR. As evidence from studies of CR in patients with cardiac implantable electronic devices is sparse, detailed clinical practice guidelines are lacking. Here, we aim to provide practical recommendations for CR in cardiac implantable electronic devices recipients in order to increase CR implementation, efficacy, and safety in this subset of patients.

Referral from vascular surgery to cardiovascular rehabilitation and related outcomes in patients with peripheral arterial disease: the THINKPAD-RELOADED survey.

The utilization of cardiovascular rehabilitation (CR) programmes in patients with Lower Extremity Peripheral Artery Disease (LEPAD) is generally poor, with limited evidence of current policies for referral. The aim of the study was to evaluate, within a cohesive network of CR and vascular surgery facilities with facilitated referral process, the clinical characteristic of LEPAD patients referred to CR and related outcomes, as compared to patients not referred. The present is an observational prospective study of consecutive patients recruited at vascular surgery facilities. Out of 329 patients observed, the average referral rate to CR was 34% (28% and 39% in patients with and without recent peripheral revascularization, p<0.05). LEPAD patients entering the CR programme were similar to those who did not according to sex, age, the vascular surgery setting of evaluation, and localization of arterial lesions. Patients with moderate intermittent claudication and patients with acute limb ischemia as index event were more represented among those who attended CR (41% vs 21% and 9% vs 2% respectively, p<0.05). Patients referred to CR had five times more episodes of acute coronary syndrome and heart failure as complication of the index event. The cardiovascular risk profile (obesity 29.5% vs 11%, p<0.05; hypercholesterolemia 80% vs 61%, p<0.05) was much worse in LEPAD patients referred to CR, but conversely, they better achieved secondary prevention targets, particularly for blood pressure control (97% vs 57%, p<0.05). All-cause 2-year mortality in the whole patients' population was 6%. Patients entering the CR programme displayed less events (13.5% vs 37.7%, p<0.05), mainly death (3.1% vs 11.3%, p<0.05) and limb-related events (4.2% vs 15.2%, p<0.05). The results of our study suggest that when a cohesive network of vascular surgery and CR facilities becomes available, the referral rate to rehabilitation may increase up to one third of eligible patients. Patients with higher comorbidity and cardiovascular risk seem to have priority in the referral process, nevertheless those with peripheral revascularization are still underestimated. Entering CR may ensure better cardiovascular risk profile and cardiovascular prognosis in LEPAD patients, and consequently the systematic adoption of this care model needs to be strongly recommended and facilitated.

Beta-blockers after myocardial infarction: Are they useful to all patients? And how long should be the beta-blocker therapy?

Some observational studies raised questions about the need for ß-blockers in all patients after a first heart attack. Surprisingly, in some clinical settings, a limited mortality reduction was found in those who received ß-blockade.Some studies suggest that patients without heart failure may not need post-MI ß-blockers. The lack of data from randomized controlled clinical trials has led to clinical uncertainty and conflicting recommendations. Therefore, there are multiple information to revaluate the value of ß-blocker therapy after a heart attack in absence of heart failure or left ventricular dysfunction and the time for new trials of an old group of drugs has arrived.

Best practice in psychological activities in cardiovascular prevention and rehabilitation: Position Paper.

Recent guidelines on cardiovascular disease prevention suggest multimodal behavioral interventions for psychosocial risk factors and referral for psychotherapy in the case of clinically significant symptoms of depression and anxiety overall. Accordingly, psychologists of the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR) have reviewed the key components of psychological activities in cardiovascular prevention and rehabilitation (CPR). The aim of this study was to elaborate a position paper on the best practice in routine psychological activities in CPR based on efficacy, effectiveness and sustainability. The steps followed were: i) a review of the latest international guidelines and position papers; ii) analysis of the evidence-based literature; iii) a qualitative analysis of the psychological services operating in some reference Italian cardiac rehabilitation facilities; iv) classification of the psychological activities in CPR as low or high intensity based on the NICE Guidelines on psychological interventions on anxiety and depression. We confirm the existence of an association between depression, anxiety, social factors, stress, personality and illness onset/outcome and coronary heart disease. Evidence for an association between depression, social factors and disease outcome emerges particularly for chronic heart failure. Some positive psychological variables (e.g., optimism) are associated to illness outcome. Evidence is reported on the impact of psychological activities on 'new' conditions which are now indicated for cardiac rehabilitation: pulmonary hypertension, grown-up congenital heart, end-stage heart failure, implantable cardioverter-defribrillator and mechanical ventricular assist devices, frail and oldest-old patients, and end-of-life care. We also report evidence related to caregivers. The Panel divided evidence-based psychological interventions into: i) low intensity (counseling, psycho-education, self-care, self-management, telemedicine, self-help); or ii) high intensity (individual, couples and/or family and group psychotherapy, such as stress management). The results show that psychotherapy is mainly consisting of cognitive-behavior therapy, interpersonal therapy, and short-term psycho-dynamic therapy. The current data further refine the working tools available for psychological activities in CPR, giving clear directions about the choice of interventions, which should be evidence-based and have at least a minimum standard. This document provides a comprehensive update on new knowledge and new paths for psychologists working in the CPR settings.

Cardiac Prevention and Rehabilitation "3.0": From acute to chronic phase. Position Paper of the ltalian Association for Cardiovascular Prevention and Rehabilitation (GICR-IACPR).

Cardiac rehabilitation (CR) is the subspecialty of clinical cardiology dedicated to the treatment of cardiac patients, early and in the long term after an acute event. The aim of CR is to improve both quality of life and prognosis through prognostic stratification, clinical stabilization and optimization of therapy (pharmacological and non), management of comorbidities, treatment of disability, as well as through the provision and reinforcement of secondary prevention interventions and maintenaince of adherence to treatment. The mission of CR has changed over time. Once centered on the acute phase, aimed primarily at short-term survival, the healthcare of cardiac patients now increasingly involves the chronic phase where the challenge is to guarantee continuity and quality of care in the medium and long-term. The aim of the present position paper is to provide the state-of-the-art of CR in Italy, discussing its trengths and weaknesses as well as future perspectives.

[Chronicity and aging in Cardiology: Geriatric Cardiology, Cardiac Rehabilitation or Care-Related Cardiogeriatric Rehabilitation? delle cure correlate?] / Cronicità ed invecchiamento in Cardiologia: Cardiologia Geriatrica, Riabilitazione Cardiaca o Riabilitazione Cardiogeriatrica.

OBJECTIVES: The population of elderly adults is constantly increasing and age is a strong determinant of the development of chronic diseases, especially cardiovascular diseases; therefore old subjects represent a very high proportion of cardiac patients. Since cardiology is progressively more and more involved in the care of aged patients, a new area of Cardiology has been identified, the Geriatric Cardiology (GC). METHODS: On the other hand, Cardiac Rehabilitation (CR) and GC show a wide overlap, and GC seems to be the application in the aged cardiac patient of the core-components that CR has already tested in younger cardiac patients. RESULTS: Now, CR is probably the cardiological area that seems better equipped, both from a cultural and organizational point of view, to care the aged cardiac patients who are often complex and frail, with multimorbidity, and "frequent users" of the health care services. CONCLUSIONS: The CR is therefore a concrete response, already ready and operative, to the demographic expansion of chronicity and aging. Beyond the definitions, CR and GC operate according to principles and methods which are in large part common; thus, CR and GC could merge themselves into a new area of cardiology, the Cardiogeriatric Rehabilitation (CGR).

How to define the relative contraindications to oral anticoagulant therapy.

There is currently a lack of consensus on which anticoagulant therapy contraindications should be considered "absolute" and which should be considered "relative". Guidelines do not clearly identify absolute and relative contraindications to anticoagulant therapy. Recent guidelines on AF of the European Society of Cardiology underline the relevance of several factors and their use in scores, leaving anyway space to the clinical judgment of the physician. A high bleeding risk score should generally not result per se in a contraindication to anticoagulant therapy. Rather, bleeding risk factors should be identified and treatable factors corrected. A combined use of a more hierarchical classification of the different bleeding risk factors and the risk scores probably represents the best approach to maximize the benefit of anticoagulant therapy in various clinical settings.

Exercise-based cardiac rehabilitation in cardiac resynchronization therapy recipients: A primer for practicing clinicians.

Cardiac resynchronization therapy (CRT) is a therapeutic option of increasing importance for chronic heart failure (CHF) and criteria for implantation now concern a large amount of patient populations. As a consequence, subjects with ongoing CRT (or immediately after CRT implantation) are more often referred to Cardiac Rehabilitation (CR) programmes, and it has been recently estimated that about one third of CHF patients attending CR in Italy currently have this kind of device. The presence of CRT represents a modulating factor for exercise prescription and monitoring, since CRT patients may be considered per se as a target group for CR. Exercise therapy (ET) increases benefits from CRT on functional capacity, and recent evidence suggests an adjuvant role of ET in improving cardiovascular prognosis also. Both aerobic endurance and resistance training activities may involve CHF patients with CRT, while the potential role of aerobic interval training needs more studies and evidence. Prescription of an ET program should be associated with information regarding device programming and possible limiting factors associated with pacing therapy, tailoring of the basic principles of ET (in terms of type of exercise, intensity and program duration) in this patient group is mandatory.

Characteristics of structured physical training currently provided in cardiac patients: insights from the Exercise Training in Cardiac Rehabilitation (ETCR) Italian survey.

BACKGROUND: Uncertainty exists about current delivery levels of exercise training (ET) during Cardiac Rehabilitation (CR) programmes. AIM OF THE STUDY: To evaluate ET modalities in the real world of CR facilities in Italy. METHODS: This was an observational survey of aggregate data, collected from CR facilities on a voluntary basis. Snapshots of a single working day at a local site were made, in terms of characteristics of patients and ET programmes delivered. RESULTS. Overall, 612 patients from 26 CR units were included, with an in-patient vs. out-patient ratio of 3:1. Coronary artery disease (57.6%), heart failure (20.3%), and valve disease/surgery (22.1%) were the most represented target groups. The prevalence of endurance continuous training, interval training, and resistance/strength training was 66.7%, 11.1%, and 9.0%; other non-aerobic endurance and non-resistance training modalities such as respiratory muscle training and calisthenics were reported in 39.9% and 42.9% of cases respectively. Workloads for endurance exercise training were determined by cardiopulmonary test, conventional 12-leads ECG exercise testing, 6min-walking test, theoretical determination of heart rate, and rating of perceived exertion in 9%, 8%, 27%, 9%, and 40% of cases respectively. The average duration of the programmes (on an intention to treat basis) was 25 sessions of 42±11  minutes, with a frequency of >4 sessions/week in 67% of patients. CONCLUSIONS: Despite advances in CR interventions, there is a significant need for improvement of functional evaluation and exercise training prescription, and consideration of a wider range of training modalities in Italy. .

Current activities of Cardiovascular Rehabilitation in the ambulatory setting of the Lombardy Region.

In the present work, the current activities of Cardiovascular Rehabilitation and Prevention (CRP) in the ambulatory setting of the Lombardy Region (Italy) are described. Based on the 2012 Legislation, ambulatory CRP is delivered by means of three programme categories (MAC 6, 7, and 8) with different degrees of intensity. The patient evaluation of global cardiovascular/clinical risk, comorbidity, and disability is the cornerstone for MAC prescription. Following the organization of MAC activities, a survey on 327 patients was carried out by the regional network of the Italian Society of Cardiovascular Rehabilitation (GICR-IACPR). Globally, acute coronary syndromes (with or without coronary revascularization) constituted the main access group to CRP. More than 60% of patients displayed a condition of high risk, comorbidity, and disability. The outcome of ambulatory CRP by means of MAC 6 and 7 was satisfactory, while in the 'less intensive' MAC 8 patients with complete drug up-titration and achievement of secondary prevention targets were no more than 70%.

Prospective Use of Microvolt T-Wave Alternans Testing to Guide Primary Prevention Implantable Cardioverter Defibrillator Therapy.

BACKGROUND: We hypothesized that a negative microvolt T-wave alternans (MTWA) test would identify patients unlikely to benefit from primary prevention implantable cardioverter defibrillator (ICD) therapy in a prospective cohort. METHODS AND RESULTS: Data were pooled from 8 centers where MTWA testing was performed specifically for the purpose of guiding primary prevention ICD implantation. Cohorts were included if the ratio of ICDs implanted in patients who were MTWA "non-negative" to patients who were MTWA negative was >2:1, indicating that MTWA testing had a significant impact on the decision to implant an ICD. The pooled cohort included 651 patients: 371 MTWA non-negative and 280 MTWA negative. Among non-negative patients, 62% underwent ICD implantation whereas only 13% of MTWA-negative patients received an ICD (P<0.01). Despite a substantially lower prevalence of ICDs, long-term survival (6.9 years) was significantly better among MTWA-negative patients (68.2% non-negative vs. 87.1% negative, P=0.026). CONCLUSIONS: MTWA-negative patients had significantly better survival than MTWA non-negative patients, the majority of whom had ICDs. Despite a very low prevalence of ICDs, long-term survival among patients with left ventricular ejection fraction ≤40% and a negative MTWA test was better than in the ICD arm of any study to date that has demonstrated a benefit of ICDs. This provides further evidence that MTWA-negative patients are unlikely to benefit from primary prevention ICD therapy.

[Erectile dysfunction and cardiovascular disease: focus on]. / Disfunzione erettile e malattia cardiovascolare: Focus on.

Erectile dysfunction (ED) is a common clinical problem and its prevalence increases in frequency with age. ED is a risk marker for major cardiovascular events independently of other more common risk factors in men with and without known cardiovascular disease. On the basis of the "artery-size hypothesis" patients with cardiovascular disease often report ED before disease detection, in average 3 years. Thus, by an early identification of ED, the cardiol- ogist is given a unique opportunity to better assess the cardiovascular risk of each patient. Although there is a general impression that ED has an important predictive role, its diagnosis in clinical practice is widely suboptimal owing to misconceptions from the side of the patient and a suboptimal management of the personal relationship from the side of the physician. This paper explores the critical connection between ED and cardiovascular disease and evaluates how this association may influence clinical practice.

OPTImal PHARMacological therapy for patients with heart failure: Rationale and design of the OPTIPHARM-HF registry.

AIMS: Patients with heart failure (HF) remain often undertreated for multiple reasons, including treatment inertia, contraindications, and intolerance. The OPTIimal PHARMacological therapy for patients with Heart Failure (OPTIPHARM-HF) registry is designed to evaluate the prevalence of evidence-based medical treatment prescription and titration, as well as the causes of its underuse, in a broad real-world population of consecutive patients with HF across the whole ejection fraction spectrum and among different clinical phenotypes. METHODS: The OPTIPHARM-HF registry (NCT06192524) is a prospective, multicenter, observational, national study of adult patients with symptomatic HF, as defined by current international guidelines, regardless of ejection fraction. Both outpatients and inpatients with chronic and acute decompensated HF will be recruited. The study will enroll up to 2500 patients with chronic HF at approximately 35 Italian HF centres. Patients will be followed for a maximum duration of 24 months. The primary objective of the OPTIPHARM-HF registry is to assess prescription and adherence to evidence-based guideline-directed medical therapy (GDMT) in patients with HF. The primary outcome is to describe the prevalence of GDMT use according to target guideline recommendation. Secondary objectives include implementation of comorbidity treatment, evaluation of sequence of treatment introduction and up-titration, description of GDMT implementation in the specific HF population, main causes of GDMT underuse, and assessment of cumulative rate of cardiovascular events. CONCLUSION: The OPTIPHARM-HF registry will provide important implications for improving patient care and adoption of recommended medical therapy into clinical practice among HF patients.

A combined anatomic and electrophysiologic substrate based approach for sudden cardiac death risk stratification.

BACKGROUND: Although left ventricular ejection fraction (LVEF) is the primary determinant for sudden cardiac death (SCD) risk stratification, in isolation, LVEF is a sub-optimal risk stratifier. We assessed whether a multi-marker strategy would provide more robust SCD risk stratification than LVEF alone. METHODS: We collected patient-level data (n = 3355) from 6 studies assessing the prognostic utility of microvolt T-wave alternans (MTWA) testing. Two thirds of the group was used for derivation (n = 2242) and one-third for validation (n = 1113). The discriminative capacity of the multivariable model was assessed using the area under the receiver-operating characteristic curve (c-index). The primary endpoint was SCD at 24 months. RESULTS: In the derivation cohort, 59 patients experienced SCD by 24 months. Stepwise selection suggested that a model based on 3 parameters (LVEF, coronary artery disease and MTWA status) provided optimal SCD risk prediction. In the derivation cohort, the c-index of the model was 0.817, which was significantly better than LVEF used as a single variable (0.637, P < .001). In the validation cohort, 36 patients experienced SCD by 24 months. The c-index of the model for predicting the primary endpoint was again significantly better than LVEF alone (0.774 vs 0.671, P = .020). CONCLUSIONS: A multivariable model based on presence of coronary artery disease, LVEF and MTWA status provides significantly more robust SCD risk prediction than LVEF as a single risk marker. These findings suggest that multi-marker strategies based on different aspects of the electro-anatomic substrate may be capable of improving primary prevention implantable cardioverter-defibrillator treatment algorithms.

How to optimize the adherence to a guideline-directed medical therapy in the secondary prevention of cardiovascular diseases: a clinical consensus statement from the European Association of Preventive Cardiology.

A key factor to successful secondary prevention of cardiovascular disease (CVD) is optimal patient adherence to treatment. However, unsatisfactory rates of adherence to treatment for CVD risk factors and CVD have been observed consistently over the last few decades. Hence, achieving optimal adherence to lifestyle measures and guideline-directed medical therapy in secondary prevention and rehabilitation is a great challenge to many healthcare professionals. Therefore, in this European Association of Preventive Cardiology clinical consensus document, a modern reappraisal of the adherence to optimal treatment is provided, together with simple, practical, and feasible suggestions to achieve this goal in the clinical setting, focusing on evidence-based concepts.

[Measuring change in rehabilitative cardiology: reliability of a short questionnaire to assess an outcome]. / Valutazione psicologica del cambiamento in cardiologia riabilitativa: validazione di un questionario a forma breve per la valutazione di esito.

UNLABELLED: The present Italian health planning demands the use of tools, care and treatments useful for the National Health Service, but with empirical effectiveness scientifically sustained. Aim of the present paper is to verify the validity, the reliability and the responsiveness of the factor "Perception of positive change" (named Schedule C) in cardiovascular rehabilitation. METHOD: The reliability of the Schedule C of the CBA VE has been examined comparing the mean scores obtained from each item at the entry and just before the discharge through the t-Student for paired sample. To assess the concurrent validity we used the AD Short Scale to measure anxiety and depression. 100 patients who underwent cardiac surgery were enrolled during hospitalization for a Cardiac Rehabilitation Programme. Cronbach's alpha was used to assess internal consistency of each item. RESULTS: Each item of the Schedule C demonstrated good internal consistency (Cronbach Alpha > .88) and elevated correlations item-total for each item. The strong correlation of anxiety and depression scores with the Schedule C points out appropriate concurrent validation. CONCLUSIONS: We believe that the Schedule C of the CBA VE is endowed with suitable metric validity and then useful as outcome evaluation in cardiovascular rehabilitation settings.

Worldwide differences of hospitalization for ST-segment elevation myocardial infarction during COVID-19: A systematic review and meta-analysis.

BACKGROUND: Discrepant data were reported about hospital admissions for ST-segment elevation myocardial infarction (STEMI) during COVID-19 pandemic. We reviewed studies reporting STEMI hospitalizations during COVID-19 pandemic, investigating whether differences in COVID-19 epidemiology or public health-related factors could explain discrepant findings in different countries. METHODS: Search through MedLine, Embase, Scopus, Web-of-Science, Cochrane Register of Controlled Trials, of studies comparing STEMI admissions during COVID-19 pandemic with a reference period, without language restrictions, as registered in PROSPERO International Prospective Register of Systematic Reviews. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed. Data independently extracted by multiple investigators were pooled using a random-effects model. Health-related metrics were from publicly-available sources. RESULTS: We included 79 articles (111,557 STEMI cases, from 57 countries). During peak COVID-19 pandemic, overall incidence rate-ratio (IRR) of STEMI hospitalizations over reference period decreased (0.80; 95% CI 0.76-0.84; p < 0.05). Although wide variations and significant heterogeneity were detected among studies (I2 = 89%; p < 0.0001), no significant differences were observed by report methodology (survey vs registry), or observation/reference period. However, large differences emerged at country level not explained by COVID-related epidemiological data, nor by public health strategies. Instead, IRRs for STEMI admissions were inversely related to hospital bed availability in each country (p < 0.05). CONCLUSIONS: During COVID-19 pandemic hospitalization for STEMI significantly decreased, although to a smaller extent than initially reported. Large variability emerged across countries, unrelated to COVID-related epidemiology or social containment measures. Disparities in healthcare organization likely contributed, indicating that proper organization of emergency medicine should be preserved during pandemics.

Epigenetics in the primary and secondary prevention of cardiovascular disease: influence of exercise and nutrition.

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification, and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli and can be transferred to next generations, providing a potential mechanism for inheritance of behavioural intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programmes with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention.