Inflammation as a cause of acute myocardial infarction in patients with myeloproliferative neoplasm.

Myeloproliferative neoplasms (MPN) are a group of diseases characterized by the clonal proliferation of hematopoietic progenitor or stem cells. They are clinically classifiable into four main diseases: chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, and primary myelofibrosis. These pathologies are closely related to cardio- and cerebrovascular diseases due to the increased risk of arterial thrombosis, the most common underlying cause of acute myocardial infarction. Recent evidence shows that the classical Virchow triad (hypercoagulability, blood stasis, endothelial injury) might offer an explanation for such association. Indeed, patients with MPN might have a higher number and more reactive circulating platelets and leukocytes, a tendency toward blood stasis because of a high number of circulating red blood cells, endothelial injury or overactivation as a consequence of sustained inflammation caused by the neoplastic clonal cell. These abnormal cancer cells, especially when associated with the JAK2V617F mutation, tend to proliferate and secrete several inflammatory cytokines. This sustains a pro-inflammatory state throughout the body. The direct consequence is the induction of a pro-thrombotic state that acts as a determinant in favoring both venous and arterial thrombus formation. Clinically, MPN patients need to be carefully evaluated to be treated not only with cytoreductive treatments but also with cardiovascular protective strategies.

Facing ethical concerns in the age of precise gene therapy: Outlook on inherited arrhythmias.

This editorial, comments on the article by Spartalis et al published in the recent issue of the World Journal of Cardiology. We here provide an outlook on potential ethical concerns related to the future application of gene therapy in the field of inherited arrhythmias. As monogenic diseases with no or few therapeutic options available through standard care, inherited arrhythmias are ideal candidates to gene therapy in their treatment. Patients with inherited arrhythmias typically have a poor quality of life, especially young people engaged in agonistic sports. While genome editing for treatment of inherited arrhythmias still has theoretical application, advances in CRISPR/Cas9 technology now allows the generation of knock-in animal models of the disease. However, clinical translation is somehow expected soon and this make consistent discussing about ethical concerns related to gene editing in inherited arrhythmias. Genomic off-target activity is a known technical issue, but its relationship with ethnical and individual genetical diversity raises concerns about an equitable accessibility. Meanwhile, the cost-effectiveness may further limit an equal distribution of gene therapies. The economic burden of gene therapies on healthcare systems is is increasingly recognized as a pressing concern. A growing body of studies are reporting uncertainty in payback periods with intuitive short-term effects for insurance-based healthcare systems, but potential concerns for universal healthcare systems in the long term as well. Altogether, those aspects strongly indicate a need of regulatory entities to manage those issues.

CAR T therapy from haematological malignancies to aging-related diseases: An ever-expanding universe.

BACKGROUND: Short but impactful, the two-decade story of gene editing allowed a significant breakthrough in the treatment of haematological malignancies. However, despite different generations of chimeric antigen receptor T (CAR T), such a successful therapy has not yet been replicated in solid tumours and non-oncological diseases. METHODS: This narrative review discusses how CAR T therapy still faces challenges in overcoming the complexity of the solid tumour microenvironment and the concerns that its long-term activity raises about potential unknown and unpredictable consequences in non-oncological diseases. RESULTS: In the most recent studies, the senolytic potential of CAR T is becoming an exciting field of research. Still, experimental but promising results indeed indicate the clearance of senescent cells as an effective strategy to improve exercise capacity and metabolic dysfunction in physiological ageing, with long-term therapeutic and preventive effects. However, an effective expansion of a CAR T population requires a lympho-depleting chemotherapy prior to infusion. While this procedure sounds reasonable for rescue therapy of oncological diseases, it poses genotoxic risks that may not be justified for non-malignant diseases. Those represent the leading gaps for applying CAR T therapy in non-oncological diseases. CONCLUSION: More is expected from current studies on the other classes of CAR cells now under investigation. Engineering NK cells and macrophages are candidates to improve cytotoxic and immunomodulating properties, potentially able to broaden application in solid tumours and non-oncological diseases. Finally, engineering autologous T cells in old individuals may generate biologically deteriorated CAR T clones with impaired function and unpredictable effects on cytokine release.

Circulating Osteopontin Predicts Clinical and Radiological Response in First-Line Treatment of Advanced Non-Small Cell Lung Cancer.

PURPOSE: Pembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC). METHODS: Seventy-nine patients eligible to pembrolizumab regimens-alone or in combination with chemotherapy-as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS). RESULTS: High Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [-4.46 to -1.01]) and time-to death (-0.13 [-0.20 to -0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = -0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses. CONCLUSION: Baseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC.

SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits.

An increasing number of individuals is at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and premature death. The sodium-glucose cotransporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption, and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated view on the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With robust trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (ie, at cardiac, vascular, renal, and systemic levels), we provide insights into key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of vascular inflammation, oxidative stress, cellular energy metabolism and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrythmias are presented, and potential implications for future research and clinical practice are comprehensively reviewed.

Early diagnosis and management of cardiac amyloidosis: A clinical perspective.

Cardiac amyloidosis multidisciplinary team (MDT). We propose the creation of a multidisciplinary team (MDT) for cardiac amyloidosis in which internal medicine physicians could take a lead role in coordinating other specialists involved in patient care. Created with BioRender.com.

Sepsis in elderly patients: the role of neutrophils in pathophysiology and therapy.

Sepsis is among the most important causes of mortality, particularly within the elderly population. Sepsis prevalence is on the rise due to different factors, including increasing average population age and the concomitant rise in the prevalence of frailty and chronic morbidities. Recent investigations have unveiled a "trimodal" trajectory for sepsis-related mortality, with the ultimate zenith occurring from 60 to 90 days until several years after the original insult. This prolonged temporal course ostensibly emanates from the sustained perturbation of immune responses, persevering beyond the phase of clinical convalescence. This phenomenon is particularly associated with the aging immune system, characterized by a broad dysregulation commonly known as "inflammaging." Inflammaging associates with a chronic low-grade activation of the innate immune system preventing an appropriate response to infective agents. Notably, during the initial phases of sepsis, neutrophils-essential in combating pathogens-may exhibit compromised activity. Paradoxically, an overly zealous neutrophilic reaction has been observed to underlie multi-organ dysfunction during the later stages of sepsis. Given this scenario, discovering treatments that can enhance neutrophil activity during the early phases of sepsis while curbing their overactivity in the later phases could prove beneficial in fighting pathogens and reducing the detrimental effects caused by an overactive immune system. This narrative review delves into the potential key role of neutrophils in the pathological process of sepsis, focusing on how the aging process impacts their functions, and highlighting possible targets for developing immune-modulatory therapies. Additionally, the review includes tables that outline the principal potential targets for immunomodulating agents.

Role of glucagon-like peptide-1 receptor agonists in the treatment of obesity, cardiovascular disease, and cerebrovascular disease.

Worldwide prevalence of obesity is increasing dramatically, imposing a significant economic burden on our society. Treatment of obesity is challenging, potentially due to different disease phenotypes. Taking into consideration "obesities" rather than "obesity," and thus aiming to understand different pathophysiologic mechanisms of individual phenotypes, might help identify more tailored treatment strategies. Glucagon­like peptide­1 receptor agonists (GLP­1RAs), for example, dulaglutide and semaglutide, are routinely prescribed for the treatment of type 2 diabetes mellitus (T2DM) in patients with obesity or those at a high cardiovascular (CV) risk. Indeed, despite having been developed for T2DM, GLP­1RAs are being increasingly often recognized as antiobesity medications due to their weight loss effects. Furthermore, recent evidence has shown that the extent of CV prevention offered by these drugs goes beyond that associated with their weight loss and pleiotropic effects. For instance, they exert anti­inflammatory effects on vessels, enhance atherosclerotic plaque stability, reduce local advanced glycation end product receptor expression, lower monocyte­macrophage adhesion, and antagonize the effect of angiotensin II. In the heart, GLP­1RAs ameliorate cardiomyocyte survival and myocardial contractility, reduce cardiac hypertrophy, and are one of few drugs that can reduce epicardial fat thickness. In this review, we summarize recent evidence concerning the effects of GLP­1RAs on obesity / dysmetabolism and on cardio- / cerebrovascular health. We further highlight the possible role of GLP­1RAs in the treatment of obesity­related CV diseases by describing the principal molecular mechanisms reported in the current literature.

Adiponectin/leptin ratio predicts the remission of metabolic syndrome: A pilot study.

BACKGROUND: Adipokines are key mediators of inflammation in metabolic syndrome perpetuating the effect of excess nutrient intake by setting a self-maintaining vicious circle. Here, we assess levels of adiponectin and leptin in a cohort of individuals with MetS undergoing dietary and behavioral counselling. Specifically, we investigate their role as predictors of metabolic syndrome remission after 1 year. METHODS: Patients with MetS (n = 127) received behavioral and dietary recommendations and were followed-up for 1 year. Serum was available for 108 individuals, levels of adiponectin and leptin were tested at baseline, at 6 months (t1) and after 1 year (t2). Adiponectin/leptin (A/L) ratio was also calculated and tested for predictive ability. RESULT: At the end of the follow-up period, 59 patients did not show enough criteria to define MetS anymore. When considered alone, adiponectin and leptin levels did not show difference over follow-up. Their ratio instead was significantly reduced at t1 and t2 with respect to baseline. Remitters also showed lowers level of leptin and A/L ratio as compared to non-remitters at t1. At this timepoint, A/L ratio independently predicted MetS remission at 1 year [OR 9.082 95%CI (1.394-59.160), p = 0.021]. Bootstrap resampling analysis internally validated our findings. CONCLUSIONS: Preliminary results from our pilot study suggest that MetS remission after counselling associates with changes in adipokine balance. A/L ratio decreases overtime and its value at 6 months can independently predict MetS remission.

Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients.

BACKGROUND: Long COVID symptoms are widely diffused and have a poorly understood pathophysiology, with possible involvement of inflammatory cytokines. MATERIALS AND METHODS: A prospective follow-up study involved 385 unvaccinated patients, started 1 month after SARS-CoV-2 infection and continued for up to 12 months. We compared circulating biomarkers of neutrophil degranulation, endothelial and metabolic dysfunction in subjects with long COVID symptoms and in asymptomatic post-COVID controls. RESULTS: The highest occurrence of symptoms (71%) was after 3 months from the infection, decreasing to 62.3% and 29.4% at 6 and 12 months, respectively. Compared to controls, long COVID patients had increased levels of the neutrophilic degranulation indices MMP-8 and MPO, of endothelial dysfunction indices L-selectin and P-selectin. Among indices of metabolic dysfunction, leptin levels were higher in long COVID patients than in controls. CONCLUSION: In unvaccinated patients, symptoms may persist up to 1 year after acute COVID infection, with increased indices of neutrophil degranulation, endothelial and metabolic dysfunction. The clinical implications of specific inflammatory biomarkers require further attention, especially in individuals with fatigue and long COVID-linked cognitive dysfunctions.

Statin-Induced Necrotizing Autoimmune Myopathy: Case Report of a Patient under Chronic Treatment.

Introduction: 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors are widely used worldwide to treat dyslipidaemia and prevent cardiovascular events. Statins can cause a wide variety of muscle injuries ranging from myalgia to severe rhabdomyolysis. In most cases, these symptoms are mild and self-limiting and do not require specific treatment besides drug withdrawal. Statin-induced autoimmune necrotizing myopathy (SINAM) is a rare but potentially fatal complication, characterized by the subacute onset of progressive proximal muscle weakness and considerably high creatine phosphokinase (CK) levels in patients exposed to statins. The diagnosis is supported by the presence of antibodies HMGCR, which allows the differentiation from other forms of necrotizing autoimmune myopathies. Symptoms usually progress even after statin discontinuation and can determine severe muscle damage. Summary. We describe the case of a 77-year-old man who developed SINAM after 5 years of statin use. He suffered from muscle functional impairment mainly involving proximal lower limb muscles which progressed to the point that he almost became bedridden. Initial treatment with prednisone alone was not effective, and he required a combination therapy with steroids, methotrexate, and intravenous immunoglobulins. After 5 months of therapy and rehabilitation, he showed complete laboratory response and muscle strength recovery. Conclusion: Recognizing SINAM is paramount in order to promptly start treatment and avoid permanent muscle damage. Using a combination therapy from the beginning could contribute to a better outcome. Prompt statin cessation, categorization of the muscle disease by autoantibody testing, imaging, and histology, exclusion of malignancy, and anti-inflammatory therapy with corticosteroids, antimetabolites, immunoglobulins, and in some cases rituximab are currently accepted approaches to this entity.

Diagnosis of lung cancer following emergency admission: Examining care pathways, clinical outcomes, and advanced NSCLC treatment in an Italian cancer Center.

Background: Lung cancer patients diagnosed following emergency admission often present with advanced disease and poor performance status, leading to suboptimal treatment options and outcomes. This study aimed to investigate the clinical and molecular characteristics, treatment initiation, and survival outcomes of these patients. Methods: We retrospectively analyzed data from 124 patients diagnosed with lung cancer following emergency admission at a single institution. Clinical characteristics, results of molecular analyses for therapeutic purpose, systemic treatment initiation, and survival outcomes were assessed. Correlations between patients' characteristics and treatment initiation were analyzed. Results: Median age at admission was 73 years, and 79.0 % had at least one comorbidity. Most patients (87.1 %) were admitted due to cancer-related symptoms. Molecular analyses were performed in 89.5 % of advanced non-small cell lung cancer (NSCLC) cases. In this subgroup, two-thirds (66.2 %) received first-line therapy. Median overall survival (OS) was 3.9 months for the entire cohort, and 2.9 months for patients with metastatic lung cancer. Among patients with advanced NSCLC, OS was significantly longer for those with actionable oncogenic drivers and those who received first-line therapy. Improvement of performance status during hospitalization resulted in increased probability of receiving first-line systemic therapy. Discussion: Patients diagnosed with lung cancer following emergency admission demonstrated poor survival outcomes. Treatment initiation, particularly for patients with actionable oncogenic drivers, was associated with longer OS. These findings highlight the need for proactive medical approaches, including improving access to molecular diagnostics and targeted treatments, to optimize outcomes in this patient population.

Long non-coding RNAs H19 and NKILA are associated with the risk of death and lacunar stroke in the elderly population.

INTRODUCTION: Differential expression of long non-coding RNAs (lncRNAs) is a hallmark of cardiovascular aging, cerebrovascular diseases, and neurodegenerative disorders. This research article investigates the association between a panel of lncRNAs and the risk of death and ischemic stroke in a cohort of non-institutionalized elderly subjects. METHOD: A total of 361 healthy individuals aged 75 years old, prospectively recruited in the Vienna Transdanube Aging (VITA) cohort, were included. Expression of lncRNAs at baseline was assessed using quantitative polymerase chain reaction PCR with pre-amplification reaction, using 18S for normalization. The primary endpoint was all-cause mortality; the secondary endpoint was the incidence of new ischemic brain lesions. Death was assessed over a 14-year follow-up, and ischemic brain lesions were evaluated by magnetic resonance imaging (MRI) over a 90-month follow-up. Ischemic brain lesions were divided into large brain infarcts (Ø≥ 1.5 cm) or lacunes (Ø< 1.5 cm) RESULTS: The primary endpoint occurred in 53.5 % of the study population. The incidence of the secondary endpoint was 16 %, with a 3.3 % being large brain infarcts, and a 12.7 % lacunes. After adjustment for potential confounders, the lncRNA H19 predicted the incidence of the primary endpoint (HR 1.194, 95 % C.I. 1.012-1.409, p = 0.036), whereas the lncRNA NKILA was associated with lacunar stroke (HR 0.571, 95 % C.I. 0.375-0.868, p = 0.006). CONCLUSION: In a prospective cohort of non-institutionalized elderly subjects, high levels of lncRNA H19 are associated with a higher risk of death, while low levels of lncRNA NKILA predict an increased risk of lacunar stroke.

Antibody-mediated PCSK9 neutralization worsens outcome after bare-metal stent implantation in mice.

AIMS: Despite advances in pharmacotherapy and device innovation, in-stent restenosis (ISR) and stent thrombosis (ST) remain serious complications following percutaneous coronary intervention (PCI) procedure with stent implantation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme involved in plasma cholesterol homeostasis and recently emerged as a therapeutic target for hypercholesterolemia. Antibody-based PCSK9 inhibition is increasingly used in different subsets of patients, including those undergoing PCI. However, whether PCSK9 inhibition affects outcome after stent implantation remains unknown. METHODS AND RESULTS: 12 to 14 weeks old C57Bl/6 mice underwent carotid artery bare-metal stent implantation. Compared to sham intervention, stent implantation was associated with increased expression of several inflammatory mediators, including PCSK9. The increase in PCSK9 protein expression was confirmed in the stented vascular tissue, but not in plasma. To inhibit PCSK9, alirocumab was administered weekly to mice before stent implantation. After 6 weeks, histological examination revealed increased intimal hyperplasia in the stented segment of alirocumab-treated animals compared to controls. In vitro, alirocumab promoted migration and inhibited the onset of senescence in primary human vascular smooth muscle cells (VSMC). Conversely, it blunted the migration and increased the senescence of endothelial cells (EC). CONCLUSION: Antibody-based PCSK9 inhibition promotes in-stent intimal hyperplasia and blunts vascular healing by increasing VSMC migration, while reducing that of EC. This effect is likely mediated, at least in part, by a differential effect on VSMC and EC senescence. The herein-reported data warrant additional investigations concerning the use of PCSK9 inhibitors in patients undergoing PCI with stent implantation.

Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans.

AIMS: The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-ß superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing. METHODS AND RESULTS: In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. CONCLUSION: Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI.

Osteopontin levels correlate with severity of diabetic cardiomyopathy in early stage of diabetes.

Diabetic cardiomyopathy (DbCM) is characterized by restrictive pattern and consistent risk of overt heart failure. We here focused osteopontin (OPN), which was tested independently associated with left ventricular diastolic dysfunction (LVDD). Overall, OPN increased with DbCM severity according with the presence of left atrial dilatation, LV hypertrophy and LVDD.