The Desmoplakin Phenotype Spectrum: Is the Inflammation the "Fil Rouge" Linking Myocarditis, Arrhythmogenic Cardiomyopathy, and Uncommon Autoinflammatory Systemic Disease?

Myocarditis is an inflammatory condition of cardiac tissue presenting significant variability in clinical manifestations and outcomes. Its etiology is diverse, encompassing infectious agents (primarily viruses, but also bacteria, protozoa, and helminths) and non-infectious factors (autoimmune responses, toxins, and drugs), though often the specific cause remains unidentified. Recent research has highlighted the potential role of genetic susceptibility in the development of myocarditis (and in some cases the development of inflammatory dilated cardiomyopathy, i.e., the condition in which there is chronic inflammation (>3 months) and left ventricular dysfunction\dilatation), with several studies indicating a correlation between myocarditis and genetic backgrounds. Notably, pathogenic genetic variants linked to dilated or arrhythmic cardiomyopathy are found in 8-16% of myocarditis patients. Genetic predispositions can lead to recurrent myocarditis and a higher incidence of ventricular arrhythmias and heart failure. Moreover, the presence of DSP mutations has been associated with distinct pathological patterns and clinical outcomes in arrhythmogenic cardiomyopathy (hot phases). The interplay between genetic factors and environmental triggers, such as viral infections and physical stress, is crucial in understanding the pathogenesis of myocarditis. Identifying these genetic markers can improve the diagnosis, risk stratification, and management of patients with myocarditis, potentially guiding tailored therapeutic interventions. This review aims to synthesize current knowledge on the genetic underpinnings of myocarditis, with an emphasis on desmoplakin-related arrhythmogenic cardiomyopathy, to enhance clinical understanding and inform future research directions.

Treating Aortic Valve Stenosis for Vitality Improvement: The TAVI Study.

BACKGROUND: Degenerative aortic valve stenosis (AS) is the most common valvular heart disease among the elderly. Once cardiac symptoms occur, current guidelines recommend aortic valve replacement. Progressive degeneration/calcification reduces leaflet mobility with gradual cardiac output (CO) impairment. Low CO might induce abnormal brain-aging with cognitive impairment and increased risk of dementia, such as Alzheimer's disease or vascular dementia. On the contrary, cognitive improvement has been reported in patients in whom CO was restored. Transcatheter aortic valve implantation (TAVI) has proven to be a safe alternative to conventional surgery, with a similar mid-term survival and stroke risk even in low-risk patients. TAVI is associated with an immediate CO improvement, also effecting the cerebrovascular system, leading to an increased cerebral blood flow. The correlation between TAVI and cognitive improvement is still debated. The present study aims at evaluating this relationship in a cohort of AS patients where cognitive assessment before and after TAVI was available. METHODS: a total of 47 patients were retrospectively selected. A transcranial Doppler ultrasound (TCD) before and after TAVI, a quality of life (QoL) score, as well as a mini-mental state examination (MMSE) at baseline and up to 36 months, were available. RESULTS: TAVI was associated with immediate increase in mean cerebral flow at TCD. MMSE slowly increase at 36-months follow-up with improved QoL mainly for symptoms, emotions and social interactions. CONCLUSIONS: this proof-of-concept study indicates that TAVI might induce cognitive improvement in the long-term as a result of multiple factors, such as cerebral flow restoration and a better QoL.

E-Cigarettes induce expression of procoagulant tissue factor in cultivated human endothelial cells.

BACKGROUND: E-cigarettes (ECIG) are proposed as an alternative for regular tobacco users with less dangerous effects for health. Several studies demonstrated that ECIG exert deleterious cardiovascular effects and promote platelet dependent thrombosis. However, ECIG role on Tissue Factor-dependent thrombosis is still unknown. Dysfunctional endothelial cells (ECs) are known to express Tissue Factor (TF) on their surface. Aim of the present study was to investigate whether ECIG might promote TF expression in ECs, shifting them to a pro thrombotic phenotype. METHODS: Human Umbilical Vein Endothelial Cells (HUVEC) were incubated with increasing doses of ECIG (commercially available and mix of propylene glycol/vegetable glycerine/nicotine 18 mg/mL) up to 1.8 mg/mL. TF gene expression and protein levels were assessed at different time points by Real Time PCR and Western Blot, respectively. TF surface expression and activity were also measured by FACS analysis and coagulation assay. Finally, NF-kB translocation was investigated as possible mechanism of action. Potential protective effects by Rosuvastatin were also investigated. RESULTS: ECIG significantly increased TF expression at both gene and protein levels in a time and dose dependent manner. Surface expression and procoagulant activity were increased as well. These phenomena appeared modulated by the NF-κB pathway. Rosuvastatin reduced ECIG effects on TF-mRNA. CONCLUSIONS: Although in vitro, we indicate that ECIG promote a pro thrombotic phenotype in ECs via expression of functional TF. Data of the present study permit to shed a brighter light on the still partially unresolved issue about the role of ECIG in development of cardiovascular diseases suggesting that they might represent a potential risk factor for thrombotic cardiovascular events.

Renal arterial resistance index before and after vericiguat administration: Should it be considered the fantastic five?

BACKGROUND: Heart failure (HF) is a chronic-progressive disease. Once established, it is almost impossible to obtain a restitutio ad integrum of the cardiac function, but current strategies aim at slowing down the progression towards the terminal stages of the disease, which inevitably lead to the exitus. On the basis of these considerations, it appears clear that pharmacological interventions applied in this clinical condition should prevent first the development of the disease, by controlling the risk factors for HF thus reducing the onset of the disease, second slowing the disease evolution towards the terminal phases thus containing clinical symptoms and reducing the number of hospitalizations. In this scenario, the add-on therapy with vericiguat seems promising as reported in the VICTORIA study without affecting renal function. Several evidence indicates that renal arterial resistance index (RRI) seems to better reflect cardiovascular damage also in HF patients, thus affecting patients prognosis METHODS: In the present study we have analyzed the effect of vericiguat administration in 27 HF patients specifically evaluating RRI. RESULTS: Vericiguat signicantly reduces RRI. CONCLUSIONS: The findings of the present study seems to indicate that vericiguat, beyond its primary mechanism of action, might offer an additional advantage in HF patients.

Evolving Concepts of the SCORE System: Subtracting Cholesterol from Risk Estimation: A Way for a Healthy Longevity?

The role of cholesterol, mainly low-density lipoproteins (LDL-C), as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) is now established and accepted by the international scientific community. Based on this evidence, the European and American guidelines recommend early risk stratification and "rapid" achievement of the suggested target according to the risk estimation to reduce the number of major cardiovascular events. Prolonged exposure over the years to high levels of LDL-C is one of the determining factors in the development and progression of atherosclerotic plaque, on which the action of conventional risk factors (cigarette smoking, excess weight, sedentary lifestyle, arterial hypertension, diabetes mellitus) as well as non-conventional risk factors (gut microbiota, hyperuricemia, inflammation), alone or in combination, favors the destabilization of the atherosclerotic lesion with rupture/fissuration/ulceration and consequent formation of intravascular thrombosis, which leads to the acute clinical manifestations of acute coronary syndromes. In the current clinical practice, there is a growing number of cases that, although extremely common, are emblematic of the concept of long-term exposure to the risk factor (LDL hypercholesterolemia), which, not adequately controlled and in combination with other risk factors, has favored the onset of major cardiovascular events. The triple concept of "go lower, start earlier and keep longer!" should be applied in current clinical practice at any level of prevention. In the present manuscript, we will review the current evidence and documents supporting the causal role of LDL-C in determining ASCVD and whether it is time to remove it from any score.

Semaglutide in Cardiometabolic Diseases: SELECTing the Target Population.

Cardiovascular diseases remain the main cause of death and disability worldwide. Despite the tremendous improvement in pharmacological, minimally invasive and rehabilitative strategies, global deaths due to cardiovascular diseases are still increasing. Additional risk factors have been recently proposed, and thanks to scientific progress, novel drugs for the control of the main risk factors focusing on the cardiometabolic pathways have been identified. Glucagon-like peptide-1 (GLP-1) receptor agonists represent an innovative step in the management of patients affected by type 2 diabetes mellitus. In addition to their significant efficacy on glycemic homeostasis, some members of this class of drugs have indications in the treatment of obesity. Furthermore, accumulated evidence in the literature has finally suggested a protective role in cardiovascular health. The possible role of GLP-1R agonist drugs (GLP-1RAs) on the mechanisms underlying chronic inflammation and the almost ubiquitous distribution of GLP-1 receptors could explain the enormous versatility of these drugs. Semaglutide is a GLP-1RA recently proven to be effective in cardiovascular outcomes. In the present article, we will review the available data on semaglutide in light of the most recent publications to better characterize the target population achieving cardiovascular benefits.

Angiotensin-converting enzyme inhibitors, statins and the polypill in cardiovascular diseases prevention: ignorance is bliss or not?

The polypill strategy, which combines several medicines that simultaneously control different risk factors/diseases in a single pill, is one of the approaches used in cardiovascular therapy. In different guidelines, this one-pill combination therapy is suggested as first-line step in disease management. Because the cardiovascular diseases (CVD) pandemia, prevention is essential. The approaches that could improve adherence are of great importance to achieve health, social and economical benefits. However, direct or indirect experience of adverse drug reaction is often the reason for discontinuation, with serious fatal and non-fatal consequences especially for a polypill. Angiotensin-converting enzyme inhibitors (ACEi) and statins are the most prescribed medications in CVD prevention. It is well known that both drugs may have adverse effects that induce discontinuation. Often, the personal awareness of these effects is a reason for self-discontinuation. In this study an analysis of the ACEi/statin awareness is reported. Is it potentially harmful for polypill?

Engineered heart tissue maturation inhibits cardiomyocyte proliferative response to cryoinjury.

The cellular and molecular mechanisms that are responsible for the poor regenerative capacity of the adult heart after myocardial infarction (MI) are still unclear and their understanding is crucial to develop novel regenerative therapies. Considering the lack of reliable in vitro tissue-like models to evaluate the molecular mechanisms of cardiac regeneration, we used cryoinjury on rat Engineered Heart Tissues (rEHTs) as a new model which recapitulates in part the in vivo response after myocardial injury of neonatal and adult heart. When we subjected to cryoinjury immature and mature rEHTs, we observed a significant increase in cardiomyocyte (CM) DNA synthesis when compared to the controls. As expected, the number of mitotic CMs significantly increases in immature rEHTs when compared to mature rEHTs, suggesting that the extent of CM maturation plays a crucial role in their proliferative response after cryoinjury. Moreover, we show that cryoinjury induces a temporary activation of fibroblast response in mature EHTs, similar to the early response after MI, that is however incomplete in immature EHTs. Our results support the hypothesis that the endogenous maturation program in cardiac myocytes plays a major role in determining the proliferative response to injury. Therefore, we propose rEHTs as a robust, novel tool to in vitro investigate critical aspects of cardiac regeneration in a tissue-like asset free from confounding factors in response to injury, such as the immune system response or circulating inflammatory cytokines.

Non-Conventional Risk Factors: "Fact" or "Fake" in Cardiovascular Disease Prevention?

Cardiovascular diseases (CVDs), such as arterial hypertension, myocardial infarction, stroke, heart failure, atrial fibrillation, etc., still represent the main cause of morbidity and mortality worldwide. They significantly modify the patients' quality of life with a tremendous economic impact. It is well established that cardiovascular risk factors increase the probability of fatal and non-fatal cardiac events. These risk factors are classified into modifiable (smoking, arterial hypertension, hypercholesterolemia, low HDL cholesterol, diabetes, excessive alcohol consumption, high-fat and high-calorie diet, reduced physical activity) and non-modifiable (sex, age, family history, of previous cardiovascular disease). Hence, CVD prevention is based on early identification and management of modifiable risk factors whose impact on the CV outcome is now performed by the use of CV risk assessment models, such as the Framingham Risk Score, Pooled Cohort Equations, or the SCORE2. However, in recent years, emerging, non-traditional factors (metabolic and non-metabolic) seem to significantly affect this assessment. In this article, we aim at defining these emerging factors and describe the potential mechanisms by which they might contribute to the development of CVD.

An Unusual Case of a Double Tricuspid and Mitral Valves Infective Endocarditis Complicated by Multiple Septic Embolisms Secondary to an Atrial Septal Defect: A Case Report and Review of Literature.

Multivalvular endocarditis (MVE) is an uncommon infection that mostly involves mitral and aortic valves, and it is related to a higher risk of congestive heart failure and a higher mortality. We described a case of a bilateral MVE and performed a review of the literature on similar clinical cases. We reported an unusual case of a 68-year-old male patient with a tricuspid and mitral infective endocarditis due to a methicillin-resistant Staphylococcus aureus complicated by multiple right- and left-sided septic embolization (lungs, brain, spleen, L2-L3 vertebral bones) due to an unknown atrial septal defect identified and repaired during cardiac surgery. Despite the severity of the clinical case, the patient experienced a good clinical outcome also thanks to a multidisciplinary approach. We identified 21 case reports describing bilateral MVE. A multidisciplinary approach is essential in the management of valve diseases to improve the prognosis of patients, especially in bilateral MVE.

Uric acid plasma levels are associated with C-reactive protein concentrations and the extent of coronary artery lesions in patients with acute coronary syndromes.

Many studies have pointed out that inflammation plays a pivotal role in pathophysiology of acute coronary syndromes (ACS) because several inflammatory molecules impair the endothelial functions in the coronary circulation and promote atherothrombotic events. Recently, many clinical/experimental evidences indicate that elevated plasma levels of uric acid (UA) might be considered a risk factor for developing ACS. It has been reported that elevated UA doses impair physiologic functions of endothelial cells, shifting them toward a pro atherothrombotic phenotype. In the present manuscript, we investigated the relationship between UA plasma levels, inflammatory burden, and extension of coronary atherosclerotic disease in patients with ACS. Patients with a clinical presentation of ACS (ST-elevated and non-ST-elevated myocardial infarction) admitted to the Vanvitelli Catheterization Laboratory at Monaldi Hospital in 2019, before the COVID-19 pandemia, were retrospectively analyzed. Biochemical profile, type of ACS presentation, as well as extension of coronary atherosclerosis were assessed. A total of 132 ACS patients were included in the analysis, and grouped into 3 tertiles according to the UA values (UA < 4.72 mg/dl, UA between 4.72 and 6.15 mg/dl, and UA > 6.15 mg/dl). Patients with UA plasma levels ≥ 6.15 mg/dL showed higher levels of C-reactive protein (mean of 5.1 mg/dL) as compared to patients with lower UA plasma levels. Moreover, the former group of patients showed higher levels of cardiac troponin and CPK, and presented more often with multivessel disease and complex coronary stenosis (type C of Ellis classification). Even though monocentric and with limited sample size, the present study shows that plasma levels of UA and hs-CRP are elevated in ACS patients and are associated with a more severe coronary disease, suggesting a potential role of UA in the pathophysiology of acute coronary events.

Cardiovascular Effects of Weight Loss in Obese Patients with Diabetes: Is Bariatric Surgery the Additional Arrow in the Quiver?

Obesity is an increasingly widespread disease worldwide because of lifestyle changes. It is associated with an increased risk of cardiovascular disease, primarily type 2 diabetes mellitus, with an increase in major cardiovascular adverse events. Bariatric surgery has been shown to be able to reduce the incidence of obesity-related cardiovascular disease and thus overall mortality. This result has been shown to be the result of hormonal and metabolic effects induced by post-surgical anatomical changes, with important effects on multiple hormonal and molecular axes that make this treatment more effective than conservative therapy in determining a marked improvement in the patient's cardiovascular risk profile. This review, therefore, aimed to examine the surgical techniques currently available and how these might be responsible not only for weight loss but also for metabolic improvement and cardiovascular benefits in patients undergoing such procedures.

New Insights into Antithrombotic Therapy for Cardio- and Cerebrovascular Disease: From Molecular Mechanisms to Clinical Application.

Thrombosis has a pivotal role in the pathophysiology of acute cardiovascular events such as myocardial infarction and stroke [...].

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.

CARdioimaging in Lung Cancer PatiEnts Undergoing Radical RadioTherapy: CARE-RT Trial.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is a common, steady growing lung tumour that is often discovered when a surgical approach is forbidden. For locally advanced inoperable NSCLC, the clinical approach consists of a combination of chemotherapy and radiotherapy, eventually followed by adjuvant immunotherapy, a treatment that is useful but may cause several mild and severe adverse effect. Chest radiotherapy, specifically, may affect the heart and coronary artery, impairing heart function and causing pathologic changes in myocardial tissues. The aim of this study is to evaluate the damage coming from these therapies with the aid of cardiac imaging. METHODS: This is a single-centre, prospective clinical trial. Patients with NSCLC who are enrolled will undergo computed tomography (CT) and magnetic resonance imaging (MRI) before chemotherapy 3 months, 6 months, and 9-12 months after the treatment. We expect to enrol 30 patients in 2 years. CONCLUSIONS: Our clinical trial will be an opportunity not only to highlight the timing and the radiation dose needed for pathological cardiac tissue changes to happen but will also provide useful data to set new follow-up schedules and strategies, keeping in mind that, more often than not, patients affected by NSCLC may present other heart- and lung-related pathological conditions.

The Novel Role of Noncoding RNAs in Modulating Platelet Function: Implications in Activation and Aggregation.

It is currently believed that plaque complication, with the consequent superimposed thrombosis, is a key factor in the clinical occurrence of acute coronary syndromes (ACSs). Platelets are major players in this process. Despite the considerable progress made by the new antithrombotic strategies (P2Y12 receptor inhibitors, new oral anticoagulants, thrombin direct inhibitors, etc.) in terms of a reduction in major cardiovascular events, a significant number of patients with previous ACSs treated with these drugs continue to experience events, indicating that the mechanisms of platelet remain largely unknown. In the last decade, our knowledge of platelet pathophysiology has improved. It has been reported that, in response to physiological and pathological stimuli, platelet activation is accompanied by de novo protein synthesis, through a rapid and particularly well-regulated translation of resident mRNAs of megakaryocytic derivation. Although the platelets are anucleate, they indeed contain an important fraction of mRNAs that can be quickly used for protein synthesis following their activation. A better understanding of the pathophysiology of platelet activation and the interaction with the main cellular components of the vascular wall will open up new perspectives in the treatment of the majority of thrombotic disorders, such as ACSs, stroke, and peripheral artery diseases before and after the acute event. In the present review, we will discuss the novel role of noncoding RNAs in modulating platelet function, highlighting the possible implications in activation and aggregation.

A pitfall in the echographic diagnosis of abdominal aortic aneurysm: when para-aortic lymph nodes are the trick.

The abdominal aortic aneurysm (AAA) is a potentially fatal asymptomatic disease. It progresses silently with clinical complications that, when they occur, constitute a very serious event, frequently resulting in the patient's exitus. As a result, early detection and treatment are critical because the right therapeutic strategy can halt the disease's natural progression. AAA is frequently discovered as an incidental finding during an abdominal ultrasound or a plain X-ray of the abdomen, which is required for other pathologies. The primary diagnostic tool for AAA identification is abdominal B-mode ultrasound. It is cheap, widely available, non-invasive, and has high diagnostic sensitivity. However, this diagnostic tool may fail in rare cases due to misleading anatomical findings. We present an unusual flaw in the echographic AAA evaluation that should be considered during the diagnostic work-up.

Current Views on Infective Endocarditis: Changing Epidemiology, Improving Diagnostic Tools and Centering the Patient for Up-to-Date Management.

Infective endocarditis (IE) is a rare but potentially life-threatening disease, sometimes with longstanding sequels among surviving patients. The population at high risk of IE is represented by patients with underlying structural heart disease and/or intravascular prosthetic material. Taking into account the increasing number of intravascular and intracardiac procedures associated with device implantation, the number of patients at risk is growing too. If bacteremia develops, infected vegetation on the native/prosthetic valve or any intracardiac/intravascular device may occur as the final result of invading microorganisms/host immune system interaction. In the case of IE suspicion, all efforts must be focused on the diagnosis as IE can spread to almost any organ in the body. Unfortunately, the diagnosis of IE might be difficult and require a combination of clinical examination, microbiological assessment and echocardiographic evaluation. There is a need of novel microbiological and imaging techniques, especially in cases of blood culture-negative. In the last few years, the management of IE has changed. A multidisciplinary care team, including experts in infectious diseases, cardiology and cardiac surgery, namely, the Endocarditis Team, is highly recommended by the current guidelines.