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.

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.

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.

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.

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.

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.

Secondary prevention through comprehensive cardiovascular rehabilitation: From knowledge to implementation. 2020 update. A position paper from the Secondary Prevention and Rehabilitation Section of the European Association of Preventive Cardiology.

Secondary prevention through comprehensive cardiac rehabilitation has been recognized as the most cost-effective intervention to ensure favourable outcomes across a wide spectrum of cardiovascular disease, reducing cardiovascular mortality, morbidity and disability, and to increase quality of life. The delivery of a comprehensive and 'modern' cardiac rehabilitation programme is mandatory both in the residential and the out-patient setting to ensure expected outcomes. The present position paper aims to update the practical recommendations on the core components and goals of cardiac rehabilitation intervention in different cardiovascular conditions, in order to assist the whole cardiac rehabilitation staff in the design and development of the programmes, and to support healthcare providers, insurers, policy makers and patients in the recognition of the positive nature of cardiac rehabilitation. Starting from the previous position paper published in 2010, this updated document maintains a disease-oriented approach, presenting both well-established and more controversial aspects. Particularly for implementation of the exercise programme, advances in different training modalities were added and new challenging populations were considered. A general table applicable to all cardiovascular conditions and specific tables for each clinical condition have been created for routine practice.

Evolving determinants of carotid atherosclerosis vulnerability in asymptomatic patients from the MAGNETIC observational study.

MRI can assess plaque composition and has demonstrated an association between some atherosclerotic risk factors (RF) and markers of plaque vulnerability in naive patients. We aimed at investigating this association in medically treated asymptomatic patients. This is a cross-sectional interim analysis (August 2013-September 2016) of a single center prospective study on carotid plaque vulnerability (MAGNETIC study). We recruited patients with asymptomatic carotid atherosclerosis (US stenosis > 30%, ECST criteria), receiving medical treatments at a tertiary cardiac rehabilitation. Atherosclerotic burden and plaque composition were quantified with 3.0 T MRI. The association between baseline characteristics and extent of lipid-rich necrotic core (LRNC), fibrous cap (CAP) and intraplaque hemorrhage (IPH) was studied with multiple regression analysis. We enrolled 260 patients (198 male, 76%) with median age of 71-y (interquartile range: 65-76). Patients were on antiplatelet therapy, ACE-inhibitors/angiotensin receptor blockers and statins (196-229, 75-88%). Median LDL-cholesterol was 78 mg/dl (59-106), blood pressure 130/70 mmHg (111-140/65-80), glycosylated hemoglobin 46 mmol/mol (39-51) and BMI 25 kg/m2 (23-28); moreover, 125 out of 187 (67%) patients were ex-smokers. Multivariate analysis of a data-set of 487 (94%) carotid arteries showed that a history of hypercholesterolemia, diabetes, hypertension or smoking did not correlate with LRNC, CAP or IPH. Conversely, maximum stenosis was the strongest independent predictor of LRNC, CAP and IPH (p < 0.001). MRI assessment of plaque composition in patients on treatment for asymptomatic carotid atherosclerosis shows no correlation between plaque vulnerability and the most well-controlled modifiable RF. Conversely, maximum stenosis exhibits a strong correlation with vulnerable features despite treatment.

Better adherence with out-of-hospital healthcare improved long-term prognosis of acute coronary syndromes: Evidence from an Italian real-world investigation.

BACKGROUND: Patients who experience a hospital admission for acute coronary syndromes (ACS) exhibit poor prognosis over the years. The purposes of this study were to evaluate the real-world patterns of out-of-hospital practice in the management of ACS patients and to assess their impact on the risk of selected outcomes. METHODS: The cohort of 87,530 residents in the Lombardy Region (Italy) who were newly hospitalised for ACS during 2011-2015 was followed until 2018. Exposure to medical treatment including use of selected drugs, diagnostic procedures and laboratory tests was recorded. The main outcome of interest was re-hospitalisation for cardiovascular (CV) outcomes. Proportional hazards models were fitted to estimate hazard ratio, and 95% confidence intervals (CI), for the exposure-outcome association. Analyses were stratified according to the ACS type. RESULTS: The cumulative incidence of re-hospitalisation for CV disease was 33%, 42% and 38% at 5 years after index discharge among STEMI, NSTEMI and unstable angina patients. Within one year from index discharge, between 70% and 80% of patients had at least a prescription of statins, beta-blockers and renin-angiotensin-system blocking agents, underwent ECG and lipid profile examination, and had a cardiologic examination. One patient in five underwent cardiac rehabilitation. Compared with patients who did not adhere to healthcare recommendations, the risk of CV hospital readmission was reduced from 10% (95% CI: 4%-10%) to 23% (12%-32%) among patients who underwent lipid profile examinations and who experienced cardiac rehabilitation. CONCLUSION: Close out-of-hospital healthcare must be considered the cornerstone for improving the long-term prognosis of ACS 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.

[The rehabilitation phase]. / La fase della riabilitazione.

Preventive Cardiology and Cardiac Rehabilitation (CR) is the specialty of clinical cardiology dedicated to the care of post-acute and chronic heart disease patients. The goals are to improve quality of life and prognosis, clinical stability, optimization of pharmacological and non-pharmacologic therapy, management of comorbidities, treatment of disabilities, reinforcement of secondary prevention interventions and adherence to therapy. The global mandate of CR has changed over time. From the acute intervention, we moved on to the care in the medium and long-term period.Despite its clear benefits and guideline recommendations, CR is still not fully considered within the cardiovascular landscape. Furthermore, the importance of CR at the clinical level and of the "health" gain of CR is little known by the beneficiaries themselves, i.e. patients on one side and the health system on the other. The main criticism is the low referral rate of cardiac patients to CR programs. In Italy, in Europe and in the USA it appears to be <30%. The challenge for CR is to work on the changes induced by epidemiology and the healthcare system needs. CR inpatient wards must be increasingly available and organized to acquire complex patients, often elderly and frail, up to the development of sub-intensive rehabilitation therapy units; in Italy, it is also necessary to develop outpatient pathways for patients of moderate-low complexity, in order to increase the referral rate to CR. Finally, integrating CR programs with long-term follow-up pathways of cardiac patients is a very important task, fully entering in the areas of e-Health and m-Health.

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.

[Cardiac rehabilitation "3.0": from the acute to the chronic stage. A position paper from the Italian Association for Cardiovascular Prevention and Rehabilitation (GICR-IACPR)]. / La Cardiologia Preventiva e Riabilitativa "3.0": dalle acuzie alla cronicità. Position paper del Gruppo Italiano di Cardiologia Riabilitativa e Preventiva (GICR-IACPR).

Cardiac rehabilitation (CR) represents a cardiology subspecialty that is devoted to the care of cardiac patients, early and long term after an acute event. CR aims at improving both quality of life and prognosis through risk and prognostic stratification, clinical stabilization and optimization of therapy, management of comorbidities, treatment of disability, and the provision of sustained long-term preventive and rehabilitative services.The mission of CR has changed over time. From being centred on the acute phase, health care of cardiac patients is increasingly involving the long-term chronic phase. The aim of the present position paper is to provide the state of the art of CR in Italy, discussing strengths and weaknesses as well as future perspectives.

[Treatment adherence in cardiovascular prevention]. / L'aderenza globale al trattamento nel continuum della prevenzione cardiovascolare.

Treatment adherence is a key element for (i) improving prognosis in cardiovascular and/or high-risk patients, (ii) reducing the burden of morbidity and mortality associated with cardiovascular disease at a population level, and (iii) decreasing costs due to rehospitalizations.Promotion of adherence should embrace all pharmacological and non-pharmacological interventions in cardiovascular prevention, including lifestyle and behavioral changes. In this perspective, cardiac prevention and rehabilitation programs are the most appropriate and cost-effective setting for delivering structured and multi-component interventions on patient's adherence. In this expert opinion document authored by the Italian Association for Cardiovascular Prevention and Rehabilitation, a modern reappraisal of the adherence issue is provided, together with simple, practical, and feasible suggestions to achieve this goal in the real life as well.