Multimodality Imaging in Advanced Heart Failure for Diagnosis, Management and Follow-Up: A Comprehensive Review.

Advanced heart failure (AHF) presents a complex landscape with challenges spanning diagnosis, management, and patient outcomes. In response, the integration of multimodality imaging techniques has emerged as a pivotal approach. This comprehensive review delves into the profound significance of these imaging strategies within AHF scenarios. Multimodality imaging, encompassing echocardiography, cardiac magnetic resonance imaging (CMR), nuclear imaging and cardiac computed tomography (CCT), stands as a cornerstone in the care of patients with both short- and long-term mechanical support devices. These techniques facilitate precise device selection, placement, and vigilant monitoring, ensuring patient safety and optimal device functionality. In the context of orthotopic cardiac transplant (OTC), the role of multimodality imaging remains indispensable. Echocardiography offers invaluable insights into allograft function and potential complications. Advanced methods, like speckle tracking echocardiography (STE), empower the detection of acute cell rejection. Nuclear imaging, CMR and CCT further enhance diagnostic precision, especially concerning allograft rejection and cardiac allograft vasculopathy. This comprehensive imaging approach goes beyond diagnosis, shaping treatment strategies and risk assessment. By harmonizing diverse imaging modalities, clinicians gain a panoramic understanding of each patient's unique condition, facilitating well-informed decisions. The aim is to highlight the novelty and unique aspects of recently published papers in the field. Thus, this review underscores the irreplaceable role of multimodality imaging in elevating patient outcomes, refining treatment precision, and propelling advancements in the evolving landscape of advanced heart failure management.

Cardiovascular prevention in childhood: a consensus document of the Italian Society of Cardiology Working Group on Congenital Heart Disease and Cardiovascular Prevention in Paediatric Age.

Cardiovascular diseases (CVD) may be manifested from a very early age. Genetic and environmental (epigenetic) factors interact to affect development and give rise to an abnormal phenotypical expression of genetic information, although not eliciting changes in the nucleotide sequence of DNA. It has been scientifically proven that increased oxidative stress (OS) caused by disease (overweight, obesity, diabetes), nutritional imbalances, unhealthy lifestyles (smoking, alcohol, substance abuse) in the mother during pregnancy may induce placental dysfunction, intrauterine growth restriction, prematurity, low birth weight, postnatal adiposity rebound, metabolic alterations and consequent onset of traditional cardiovascular risk factors. OS represents the cornerstone in the onset of atherosclerosis and manifestation of CVD following an extended asymptomatic period. OS activates platelets and monocytes eliciting the release of pro-inflammatory, pro-atherogenic and pro-oxidising substances resulting in endothelial dysfunction, decrease in flow-mediated arterial dilatation and increase in carotid intima-media thickness. The prevention of CVD is defined as primordial (aimed at preventing risk factors development), primary (aimed at early identification and treatment of risk factors), secondary (aimed at reducing risk of future events in patients who have already manifested a cardiovascular event), and tertiary (aimed at limiting the complex outcome of disease). Atherosclerosis prevention should be implemented as early as possible. Appropriate screening should be carried out to identify children at high risk who are apparently healthy and implement measures including dietary and lifestyle changes, addition of nutritional supplements and, lastly, pharmacological treatment if risk profiles fail to normalise. Reinstating endothelial function during the reversible stage of atherosclerosis is crucial.

The gray areas of oral anticoagulation for prevention of thromboembolic events in atrial fibrillation patients.

Thromboembolic events (TEE) associated with atrial fibrillation (AF) are highly recurrent and usually severe, causing permanent disability or, even, death. Previous data consistently showed significantly lower TEE in anticoagulated patients. While warfarin, a vitamin K antagonist, is still used worldwide, direct-acting oral anticoagulants (DOACs) have shown noninferiority to warfarin in the prevention of TEE, and represent, to date, the preferred treatment. DOACs present favorable pharmacokinetic, safety and efficacy profiles, especially among vulnerable patients including the elderly, those with renal dysfunction or previous TEE. Yet, regarding specific settings of AF patients it is unclear whether oral anticoagulation therapy is beneficial, or otherwise it is the maintenance of sinus rhythm, mostly achieved through a catheter ablation-based rhythm control strategy, that prevents the causal complications linked to AF. While it is known that low-risk patients [CHA2DS2-VASc 0 (males), or score of 1 (females)] present low ischemic stroke or mortality rates (<1%/year), it remains unclear whether they need any prophylaxis. Furthermore, the appropriate anticoagulation regimen for those individuals requiring cardioversion, either pharmacologic or electric, as well as peri-procedural anticoagulation in patients undergoing trans-catheter ablation that nowadays encompasses different energies, are still a matter of debate. In addition, AF concomitant with other clinical conditions is discussed and, lastly, the choice of prescribing anticoagulation to asymptomatic patients diagnosed with subclinical AF at either wearable or implanted devices. The aim of this review will be to provide an update on current strategies in the above-mentioned settings, and to suggest possible therapeutic options, finally focusing on AF-related cognitive decline.

Cardiovascular prevention in women: an update by the Italian Society of Cardiology working group on 'Prevention, hypertension and peripheral disease'.

The recent pandemic has substantially changed the approach to the prevention of cardiovascular diseases in women. Women have been significantly impacted by the changes that occurred during the pandemic and the quarantine adopted to prevent the spread of the disease. Changes involved prevention both through the reduction of visits and preventive screening and through social and economic changes. It is necessary to adopt new cardiovascular prevention approaches focused on returning to healthy lifestyles, reducing stress and depression also using modern tools such as telemedicine, mobile phone applications and the web. These tools convey messages in a persuasive way especially in young and adult women. There is less impact of these new tools on older women towards whom it is important to adopt a more traditional approach. This review focuses on the new approach to cardiovascular prevention in women in light of the lifestyle changes recorded during the pandemic and which led to an increase in obesity examines the effects on the cardiovascular system induced by stress and depression and analyses the new high blood pressure guidelines and indications that are specific to women.

Evolving concepts in the pathophysiology of atherosclerosis: from endothelial dysfunction to thrombus formation through multiple shades of inflammation.

Atherosclerosis is the anatomo-pathological substrate of most cardio, cerebro and vascular diseases such as acute and chronic coronary syndromes, stroke and peripheral artery diseases. The pathophysiology of atherosclerotic plaque and its complications are under continuous investigation. In the last 2 decades our understanding on the formation, progression and complication of the atherosclerotic lesion has greatly improved and the role of immunity and inflammation is now well documented and accepted. The conventional risk factors modulate endothelial function determining the switch to a proatherosclerotic phenotype. From this point, lipid accumulation with an imbalance from cholesterol influx and efflux, foam cells formation, T-cell activation, cytokines release and matrix-degrading enzymes production occur. Lesions with high inflammatory rate become vulnerable and prone to rupture. Once complicated, the intraplaque thrombogenic material, such as the tissue factor, is exposed to the flowing blood, thus inducing coagulation cascade activation, platelets aggregation and finally intravascular thrombus formation that leads to clinical manifestations of this disease. Nonconventional risk factors, such as gut microbiome, are emerging novel markers of atherosclerosis. Several data indicate that gut microbiota may play a causative role in formation, progression and complication of atherosclerotic lesions. The gut dysbiosis-related inflammation and gut microbiota-derived metabolites have been proposed as the main working hypothesis in contributing to disease formation and progression. The current evidence suggest that the conventional and nonconventional risk factors may modulate the degree of inflammation of the atherosclerotic lesion, thus influencing its final fate. Based on this hypothesis, targeting inflammation seems to be a promising approach to further improve our management of atherosclerotic-related diseases.

Speckle tracking echocardiography in early disease stages: a therapy modifier?

Echocardiography has been included as a first-line tool in several international guidelines for the management of patients with various cardiac diseases. Beyond diagnosis, echocardiographic examination helps in characterizing the severity of the condition since the very first stages. In particular, the application of second-level techniques, speckle tracking echocardiography in particular, can also reveal a subclinical dysfunction, while the standard parameters are in the normality range. The present review describes the potentialities of advanced echocardiography in different settings, including arterial hypertension, atrial fibrillation, diastolic dysfunction, and oncological patients, thus opening up potential starting points for its application as a clinical routine changer.

Computed tomography and nuclear medicine for the assessment of coronary inflammation: clinical applications and perspectives.

There is increasing evidence that in patients with atherosclerotic cardiovascular disease (ASCVD) under optimal medical therapy, a persisting dysregulation of the lipid and glucose metabolism, associated with adipose tissue dysfunction and inflammation, predicts a substantial residual risk of disease progression and cardiovascular events. Despite the inflammatory nature of ASCVD, circulating biomarkers such as high-sensitivity C-reactive protein and interleukins may lack specificity for vascular inflammation. As known, dysfunctional epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) produce pro-inflammatory mediators and promote cellular tissue infiltration triggering further pro-inflammatory mechanisms. The consequent tissue modifications determine the attenuation of PCAT as assessed and measured by coronary computed tomography angiography (CCTA). Recently, relevant studies have demonstrated a correlation between EAT and PCAT and obstructive coronary artery disease, inflammatory plaque status and coronary flow reserve (CFR). In parallel, CFR is well recognized as a marker of coronary vasomotor function that incorporates the haemodynamic effects of epicardial, diffuse and small-vessel disease on myocardial tissue perfusion. An inverse relationship between EAT volume and coronary vascular function and the association of PCAT attenuation and impaired CFR have already been reported. Moreover, many studies demonstrated that 18F-FDG PET is able to detect PCAT inflammation in patients with coronary atherosclerosis. Importantly, the perivascular FAI (fat attenuation index) showed incremental value for the prediction of adverse clinical events beyond traditional risk factors and CCTA indices by providing a quantitative measure of coronary inflammation. As an indicator of increased cardiac mortality, it could guide early targeted primary prevention in a wide spectrum of patients. In this review, we summarize the current evidence regarding the clinical applications and perspectives of EAT and PCAT assessment performed by CCTA and the prognostic information derived by nuclear medicine.

Innovations in medical therapy of heart failure with reduced ejection fraction.

Heart failure with reduced ejection fraction (HFrEF) is a pathological condition still characterized by high rates of mortality and disease exacerbation frequently leading to hospitalization, thus there is a continuous need for pharmacological treatments impacting on disease stability and long-term prognosis. Moreover, the phenotype of heart failure patients is continuously changing over time, and the development of new heart failure drugs is crucial to promote a personalized and targeted approach. In recent years, several therapeutic innovations have emerged in the landscape of acute and chronic HFrEF, largely changing and improving our approach to the disease. Various studies on new drugs and experimental therapeutic approaches are ongoing. The present review discusses the latest data on both recently approved drugs and developing therapeutic targets, in order to provide a critical overview for an informed and optimal approach to such a complex disease.

Impact of COVID-19 on the cardiovascular health of women: a review by the Italian Society of Cardiology Working Group on 'gender cardiovascular diseases'.

The coronavirus disease 19 (COVID-19), due to coronavirus 2 (SARS-CoV-2) infection, presents with an extremely heterogeneous spectrum of symptoms and signs. COVID-19 susceptibility and mortality show a significant sex imbalance, with men being more prone to infection and showing a higher rate of hospitalization and mortality than women. In particular, cardiovascular diseases (preexistent or arising upon infection) play a central role in COVID-19 outcomes, differently in men and women. This review will discuss the potential mechanisms accounting for sex/gender influence in vulnerability to COVID-19. Such variability can be ascribed to both sex-related biological factors and sex-related behavioural traits. Sex differences in cardiovascular disease and COVID-19 involve the endothelial dysfunction, the innate immune system and the renin-angiotensin system (RAS). Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19 and it shows hormone-dependent actions. The incidence of myocardial injury during COVID-19 is sex-dependent, predominantly in association with a greater degree of inflammation and coagulation disorders among men. Its pathogenesis is not fully elucidated, but the main theories foresee a direct role for the ACE2 receptor, the hyperimmune response and the RAS imbalance, which may also lead to isolated presentation of COVID-19-mediated myopericarditis. Moreover, the latest evidence on cardiovascular diseases and their relationship with COVID-19 during pregnancy will be discussed. Finally, authors will analyse the prevalence of the long-covid syndrome between the two sexes and its impact on the quality of life and cardiovascular health.

Combining echo-derived haemodynamic phenotypes and myocardial strain for risk stratification of chronic heart failure with reduced ejection fraction.

AIMS: Echocardiography has shown to categorize heart failure (HF) patients according to haemodynamic profiles. Whether left ventricular (LV) global longitudinal strain (LV-GLS) could integrate echo-derived haemodynamic profiles to risk stratify chronic HF patients is still unknown. METHODS AND RESULTS: Chronic HF outpatients with LV ejection fraction (LV-EF) <50% (n = 351) and LV-GLS assessment were evaluated and divided according to four haemodynamic phenotypes based on LV stroke volume index (SVI), LV filling pressure (LVFP), and right ventricular (RV) function: normal output-normal LVFP (NO-NP), normal output-high LVFP (NO-HP), low output-no RV dysfunction (LO-NRVD), and low output-RV dysfunction (LO-RVD). RV function was defined using the tricuspid annular plane systolic excursion and RV free-wall longitudinal strain. The median follow-up duration was 3.3 years. The combination of all-cause mortality and HF hospitalization was the primary endpoint. Secondary endpoints were all-cause mortality and cardiovascular mortality. The prevalence of NO-NP, NO-HP, LO-NRVD, and LO-RVD were 38%, 22%, 30%, and 10%, respectively. The haemodynamic model independently predicted primary and secondary outcomes, with incremental prognostic information over LV-EF (all P-values <0.001 for C-statistics). When univariate Cox regression analysis was performed to assess the prognostic stratification capability of LV-GLS in different haemodynamic subgroups, we observed a reduction in LV-GLS hazard ratios from the NO-NP to the LO-RVD for every endpoint. CONCLUSION: There was a continuum in LV-GLS impairment across the spectrum of haemodynamic phenotypes and its prognostic value resulted variable depending on the types of chronic HF patients. The highest prognostic information added by LV-GLS was in patients with normal SVI.

Binding of Gamma-Glutamyl Transferase to TLR4 Signalling Allows Tissue Factor Activation in Monocytes.

Gamma-glutamyl transferase (GGT) is involved in the progression of atherosclerosis, since its enzymatic activity promotes the generation of reactive oxygen species (ROS). Besides, GGT may act as a prothrombotic factor by inducing tissue factor (TF) expression, independently of its enzymatic activity. The aim of this study was to assess whether GGT-induced TF stimulation was a consequence of binding to toll-like receptor 4 (TLR4) expressed on monocytes, the precursors of macrophages and foam cells which colocalize with GGT activity within atherosclerotic plaques. Experiments were performed in human peripheral blood mononuclear cells (PBMCs), THP-1 cells (a monocytic cellular model), and HEK293 cells, which were genetically modified to study the activation of TLR4. TF procoagulant activity was assessed by a one-stage clotting time test, and TF protein expression was estimated by western blot. Human recombinant (hr) GGT protein increased TF procoagulant activity and protein expression in both PBMCs and THP-1 cells. The GGT-induced TF stimulation was prevented by cellular pretreatment with TLR4/NF-κB inhibitors (LPS-Rs, CLI-095, and BAY-11-7082), and HEK293 cells lacking TLR4 confirmed that TLR4 is essential for GGT-induced activation of NF-κB. In conclusion, hrGGT induced TF expression in monocytes through a cytokine-like mechanism that involved the activation of TLR4/NF-κB signaling.

[Italian Society of Cardiology-Italian Society of Nephrology Consensus document: The cardio-renal interaction in the prevention and treatment of cardiovascular diseases - Part II: From preventive strategies to treatment of patients with cardio-renal damage]. / Documento di consenso Società Italiana di Cardiologia- Società Italiana di Nefrologia: Ruolo dell'asse cardio-renale nella prevenzione e trattamento delle patologie cardiovascolari ­ Parte II: Dalle strategie di prevenzione al trattamento del paziente con coinvolgimento cardio-renale.

Chronic kidney disease and cardiovascular disease are strictly connected each other with a bidirectional interaction. Thus, the prevention of cardio-renal damage, as its appropriate treatment, are essential steps for a correct management of long-term patients' prognosis. Several preventive and therapeutic strategies, pharmacological and not, are now available for cardio-renal damage prevention and treatment, and for the management of its complications. The second part of this consensus document focuses on the management and treatment of cardio-renal damage, directing the attention on the correct use of drugs that may slow renal disease progression, on the application of preventive strategies in case of invasive cardiac procedures with the use of contrast agents, and on the accurate use of cardiological drugs in patients with chronic kidney disease.

[Italian Society of Cardiology-Italian Society of Nephrology Consensus document: The cardio-renal interaction in the prevention and treatment of cardiovascular diseases - Part I: From cardiovascular risk factors to the mechanisms of cardio-renal syndrome]. / Documento di consenso Società Italiana di Cardiologia- Società Italiana di Nefrologia: Ruolo dell'asse cardio-renale nella prevenzione e trattamento delle patologie cardiovascolari ­ Parte I: Dai fattori di rischio cardiovascolare ai meccanismi di danno cardio-renale.

Chronic kidney disease (CKD) and cardiovascular (CV) disease are highly prevalent conditions in the general population and are strictly connected to each other with a bidirectional interaction. In patients affected by CKD, the leading cause of morbidity and mortality is represented by CV disease, since CKD promotes the atherosclerotic process increasing inflammation, and modifying lipid and bone mineral metabolism. On the other side, a strict relationship exists between CKD and CV risk factors, which are prevalent in nephropathic patients and impose a stringent assessment of the risk of CV events in this population together with an optimized pharmacological approach, complicated by the coexistence of the two pathological conditions. The first part of this consensus document focuses on the mechanisms of cardio-renal damage and on the impact, as well as the management, of the main CV risk factors in the context of CKD.

Perspectives in noninvasive imaging for chronic coronary syndromes.

Both the latest European guidelines on chronic coronary syndromes and the American guidelines on chest pain have underlined the importance of noninvasive imaging to select patients to be referred to invasive angiography. Nevertheless, although coronary stenosis has long been considered the main determinant of inducible ischemia and symptoms, growing evidence has demonstrated the importance of other underlying mechanisms (e.g., vasospasm, microvascular disease, energetic inefficiency). The search for a pathophysiology-driven treatment of these patients has therefore emerged as an important objective of multimodality imaging, integrating "anatomical" and "functional" information. We here provide an up-to-date guide for the choice and the interpretation of the currently available noninvasive anatomical and/or functional tests, focusing on emerging techniques (e.g., coronary flow velocity reserve, stress-cardiac magnetic resonance, hybrid imaging, functional-coronary computed tomography angiography, etc.), which could provide deeper pathophysiological insights to refine diagnostic and therapeutic pathways in the next future.

[Italian Society of Cardiology (SIC) Expert consensus document: Post-acute cardiovascular sequelae of SARS-CoV-2 infection]. / Expert consensus document della Società Italiana di Cardiologia (SIC): Sequele cardiovascolari post-acute dell'infezione da SARS-CoV-2.

Although the clinical course of COVID-19 in its acute phase is now delineated, less known is its late phase characterized by a heterogeneous series of sequelae affecting various organs and systems, including the cardiovascular system, which continue after the acute episode or arise after their resolution. This syndrome, now referred with the new acronym "PASC" (post-acute sequelae of SARS-CoV-2 infection) has been formally recognized by various scientific societies and international organizations that have proposed various definitions. The World Health Organization defines PASC, distinguishing it from "ongoing symptomatic COVID-19", as a condition that arises few weeks after infection, persists at least 8 weeks, and cannot be explained by alternative diagnoses.There are multiple mechanisms responsible for PASC: inflammation, immune activation, viral persistence, activation of latent viruses, endothelial dysfunction, impaired response to exercise, and profound cardiac deconditioning following viral infection. The key symptoms of PASC are palpitations, effort dyspnea, chest pain, exercise intolerance, and postural orthostatic tachycardia syndrome.For PASC treatment, it may be useful to take salt and fluid loading, to reduce symptoms such as tachycardia, palpitations, and/or orthostatic hypotension, or in some subjects the use of drugs such as beta-blockers, non-dihydropyridine calcium channel blockers, ivabradine, and fludrocortisone.Finally, in PASC a gradual resumption of physical activity is recommended, starting with recumbent or semi-recumbent exercise, such as cycling, swimming, or rowing, and then moving on to exercise in an upright position such as running when the ability to stand improves without dyspnea appearance. Exercise duration should also be short initially (5 to 10 min per day), with gradual increases as functional capacity improves.

[2022 Update on myocarditis and pericarditis following COVID-19 vaccination. Expert Opinion of the Italian Society of Cardiology]. / Update 2022 dell'Expert Opinion della Società Italiana di Cardiologia su miocarditi, pericarditi e vaccini contro il COVID-19.

Vaccine-associated myocarditis and pericarditis usually develop within 14 days of COVID-19 vaccination, are exceptionally rare, manifest with mild clinical pictures and are commonly characterized by a favorable evolution. Young men inoculated with two doses of an mRNA vaccine are the subgroup at higher risk. Recent epidemiological studies evaluated the incidence and risk of vaccine-associated myocarditis and pericarditis among men and women, in different ranges of age and specific types of vaccines. Long-term population analyses demonstrated that the cardiovascular risk conferred by COVID-19 extends beyond the acute phase, representing the rationale for implementing prevention strategies for SARS-CoV-2 infection, monitoring specific populations at higher risk and pursuing the completion of the vaccination campaign. This document provides an update on the most recent scientific evidence and critical interpretation of available data in constant evolution towards personalized strategies of immunization.

Renin-angiotensin-aldosterone system inhibition in patients affected by heart failure: efficacy, mechanistic effects and practical use of sacubitril/valsartan. Position Paper of the Italian Society of Cardiology.

Renin-angiotensin-aldosterone system (RAAS) inhibition is a mainstay of the pharmacological treatment of heart failure with reduced ejection fraction (HFrEF). In the last years RAAS blockade has been improved by the introduction of the Angiotensin Receptor-Neprilysin Inhibitor (ARNI) sacubitril/valsartan, that combines RAAS inhibition with the block of neprilysin, boosting the positive effects of natriuretic peptides. The PARADIGM-HF trial demonstrated a significant advantage of sacubitril/valsartan over enalapril on the reduction of cardiovascular (CV) mortality and heart failure hospitalizations rates. Then, several randomized clinical trials and observational studies investigated its role in different clinical settings and its efficacy has been fully recognized in the most recent HFrEF European and USA guidelines. The effects of sacubitril/valsartan on major CV outcomes are associated with reduction of NT-proBNP levels and reverse cardiac remodeling and mitral regurgitation, recognized as one of the mechanistic effects of the drug explaining the favorable prognostic effects. A careful evaluation of patients' clinical profile is relevant to implement the use of ARNI in the clinical practice and to obtain the maximal treatment efficacy. The present Position Paper reports the opinion of the Italian Society of Cardiology on the optimal blockade of the RAAS system in HF patients with the aim of fostering widespread implementation of scientific evidence and practice guidelines in the medical community.

A novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells.

BACKGROUND: Proprotein convertase subtilisin kexin 9 (PCSK9) is a serin protease synthesized mainly in the liver that binds the receptor of low-density lipoprotein and promotes its degradation in lysosomes. PCSK9 is considered a promising target for the development of new therapies for the treatment of hypercholesterolemia and related cardiovascular diseases. Extracellular vesicles represent a heterogeneous population of vesicles, ranging in size between 0.05 and 1 µm involved in numerous pathophysiological processes, including blood coagulation. We investigated whether PCSK9 stimulation induces the release of procoagulant extracellular vesicles from human mononuclear cells (PBMCs) and THP-1 cells. METHODS AND RESULTS: PBMCs and THP-1 cells were stimulated whit PCSK9, the generation of EV was assessed by the prothrombinase assay and by cytofluorimetric analysis. EV-associated tissue factor activity was assessed by a one-stage clotting assay. PCSK9 induced an increase in extracellular generation by PBMCs and THP-1 cells as well as an increase in extracellular vesicle-associated tissue factor. Pre-treatment with inhibitors of the toll like receptor, TLR4 (C34), and of NF-κB signaling (BAY 11-7082), downregulated PCSK9-induced extracellular vesicle generation and of extracellular- bound tissue factor. Similar effect was obtained by an anti-PCSK9 human-monoclonal antibody. CONCLUSIONS: PCSK9-mediated generation of procoagulant EV could contribute to increase the prothrombotic status in patients with cardiovascular diseases.