Biomarker-enhanced cardiovascular risk prediction in patients with cancer: a prospective cohort study.

BACKGROUND: Continuously improving cancer-specific survival puts a growing proportion of cancer patients at risk of major adverse cardiovascular events (MACE), but tailored tools for cardiovascular risk prediction remain unavailable. OBJECTIVES: To assess a broad panel of cardiovascular biomarkers and risk factors for the prediction of MACE and cardiovascular death in cancer patients. METHODS: In total, 2192 patients with newly diagnosed or recurrent cancer were followed prospectively for the occurrence of 2-year MACE and 5-year cardiovascular death. Univariable and multivariable risk models were fit to assess independent associations of cardiovascular risk factors and biomarkers with adverse outcomes, and a risk score was developed. RESULTS: Traditional cardiovascular risk factors and selected cancer types were linked to higher MACE risk. While levels of Lp(a), CRP, and GDF-15 did not associate with MACE, levels of ICAM-1, P-/E-/L-selectins, and NT-proBNP were independently linked to 2-year MACE risk. A clinical risk score was derived, assigning +1 point for male sex, smoking, and age of ≥60 years and +2 points for atherosclerotic disease, yielding a bootstrapped C-statistic of 0.76 (95% CI: 0.71-0.81) for the prediction of 2-year MACE. Implementation of biomarker data conferred improved performance (0.83, 95% CI: 0.78-0.88), with a simplified model showing similar performance (0.80, 95% CI: 0.74-0.86). The biomarker-enhanced and simplified prediction models achieved a C-statistic of 0.82 (95% CI: 0.71-0.93) and 0.74 (95% CI: 0.64-0.83) for the prediction of 5-year cardiovascular death. CONCLUSION: Biomarker-enhanced risk prediction strategies allow the identification of cancer patients at high risk of MACE and cardiovascular death. While external validation studies are ongoing, this first-of-its-kind risk score may provide the basis for personalized cardiovascular risk assessment across cancer entities.

The Need to Identify Novel Markers for Early Renal Injury in Cardiorenal Syndrome.

The term "Cardiorenal Syndrome" (CRS) refers to the complex interplay between heart and kidney dysfunction. First described by Robert Bright in 1836, CRS was brought to its modern view by Ronco et al. in 2008, who defined it as one organ's primary dysfunction leading to secondary dysfunction in the other, a view that led to the distinction of five different types depending on the organ of primary dysfunction and the temporal pattern (acute vs. chronic). Their pathophysiology is intricate, involving various hemodynamic, neurohormonal, and inflammatory processes that result in damage to both organs. While traditional biomarkers have been utilized for diagnosing and prognosticating CRS, they are inadequate for the early detection of acute renal damage. Hence, there is a pressing need to discover new biomarkers to enhance clinical outcomes and treatment approaches.

Navigating the autophagic landscape: Epigenetic modulation in gastrointestinal cancer.

This editorial comments on the manuscript by Chang et al, focusing on the still elusive interplay between epigenetic regulation and autophagy in gastrointestinal diseases, particularly cancer. Autophagy, essential for cellular homeostasis, exhibits diverse functions ranging from cell survival to death, and is particularly implicated in physiological gastrointestinal cell functions. However, its role in pathological backgrounds remains intricate and context-dependent. Studies underscore the dual nature of autophagy in cancer, where its early suppressive effects in early stages are juxtaposed with its later promotion, contributing to chemoresistance. This discrepancy is attributed to the dysregulation of autophagy-related genes and their intricate involvement in cellular processes. Epigenetic modifications and regulations of gene expression, including non-coding RNAs (ncRNAs), emerge as critical players in exerting regulatory control over autophagy flux, influencing treatment responses and tumor progression. Targeting epigenetic mechanisms and improving strategies involving the inhibition or induction of autophagy through pharmacological or genetic means present potential avenues to sensitize tumor cells to chemotherapy. Additionally, nanocarrier-based delivery of ncRNAs offers innovative therapeutic approaches. Understanding the intricate interaction between autophagy and ncRNA regulation opens avenues for the development of targeted therapies, thereby improving the prognosis of gastrointestinal malignancies with poor outcomes.

Mechanisms of damage and therapies for cardiac amyloidosis: a role for inflammation?

The term cardiac amyloidosis (CA) refers to the accumulation of extracellular amyloid deposits in the heart because of different conditions often affecting multiple organs including brain, kidney and liver. Notably, cardiac involvement significantly impacts prognosis of amyloidosis, with cardiac biomarkers playing a pivotal role in prognostic stratification. Therapeutic management poses a challenge due to limited response to conventional heart failure therapies, necessitating targeted approaches aimed at preventing, halting or reversing amyloid deposition. Mechanisms underlying organ damage in CA are multifactorial, involving proteotoxicity, oxidative stress, and mechanical interference. While the role of inflammation in CA remains incompletely understood, emerging evidence suggests its potential contribution to disease progression as well as its utility as a therapeutic target. This review reports on the cardiac involvement in systemic amyloidosis, its prognostic role and how to assess it. Current and emerging therapies will be critically discussed underscoring the need for further efforts aiming at elucidating CA pathophysiology. The emerging evidence suggesting the contribution of inflammation to disease progression and its prognostic role will also be reviewed possibly offering insights into novel therapeutic avenues for CA.

Ultrasound unveiling: Decoding venous congestion in heart failure for precision management of fluid status.

This editorial discusses the manuscript by Di Maria et al, published in the recent issue of the World Journal of Cardiology. We here focus on the still elusive pathophysiological mechanisms underlying cardio-renal syndrome (CRS), despite its high prevalence and the substantial worsening of both kidney function and heart failure. While the measure of right atrial pressure through right cardiac catheterization remains the most accurate albeit invasive and costly procedure, integrating bedside ultrasound into diagnostic protocols may substantially enhance the staging of venous congestion and guide therapeutic decisions. In particular, with the assessment of Doppler patterns across multiple venous districts, the Venous Excess Ultrasound (VExUS) score improves the management of fluid overload and provides insight into the underlying factors contributing to cardio-renal interactions. Integrating specific echocardiographic parameters, particularly those concerning the right heart, may thus improve the VExUS score sensitivity, offering perspective into the nuanced comprehension of cardio-renal dynamics. A multidisciplinary approach that consistently incorporates the use of ultrasound is emerging as a promising advance in the understanding and management of CRS.

Objective and subjective cognitive outcomes one year after COVID-19.

OBJECTIVE: This study aimed to evaluate subjective cognitive, physical, and mental health symptoms as well as objective cognitive deficits in COVID-19 patients 1 year after infection. METHODS: This was a cross-sectional study. Seventy-four patients, who contracted a SARS-CoV-2 infection in 2020, underwent an in-person neuropsychological assessment in 2021. This included standardized tests of memory, attention, and executive functions. In addition, participants also responded to scales on subjective attention deficits, mental health symptoms, and fatigue. Patients' scores were compared to published norms. RESULTS: Patients (N = 74) had a median age of 56 years (42% female). According to the initial disease severity, they were classified as mild (outpatients, 32%), moderate (hospitalized, non-ICU-admitted, 45%), or severe (ICU-admitted, 23%). Hospitalized patients were more often affected than outpatients. In general, deficits were most common in attention (23%), followed by memory (15%) and executive functions (3%). Patients reported increased levels of fatigue (51%), anxiety (30%), distractibility in everyday situations (20%), and depression (15%). An additional analysis suggested an association between lower scores in an attention task and hyperferritinemia. As indicated by a hierarchical regression analysis, subjective distractibility was significantly predicted by current anxiety and fatigue symptoms but not by objective attention performance (final model, adj-R2 = 0.588, P < 0.001). INTERPRETATION: One year after infection, COVID-19 patients can have frequent attention deficits and can complain about symptoms such as fatigue, anxiety, and distractibility. Anxiety and fatigue, more than objective cognitive deficits, have an impact on the patients' experienced impairments in everyday life.

Artificial intelligence in scientific medical writing: Legitimate and deceptive uses and ethical concerns.

The debate surrounding the integration of artificial intelligence (AI) into scientific writing has already attracted significant interest in medical and life sciences. While AI can undoubtedly expedite the process of manuscript creation and correction, it raises several criticisms. The crossover between AI and health sciences is relatively recent, but the use of AI tools among physicians and other scientists who work in the life sciences is growing very fast. Within this whirlwind, it is becoming essential to realize where we are heading and what the limits are, including an ethical perspective. Modern conversational AIs exhibit a context awareness that enables them to understand and remember any conversation beyond any predefined script. Even more impressively, they can learn and adapt as they engage with a growing volume of human language input. They all share neural networks as background mathematical models and differ from old chatbots for their use of a specific network architecture called transformer model [1]. Some of them exceed 100 terabytes (TB) (e.g., Bloom, LaMDA) or even 500 TB (e.g., Megatron-Turing NLG) of text data, the 4.0 version of ChatGPT (GPT-4) was trained with nearly 45 TB, but stays updated by the internet connection and may integrate with different plugins that enhance its functionality, making it multimodal.

Plasma levels of myeloperoxidase and resistin independently predict mortality in dialysis patients.

BACKGROUND: In patients with kidney failure (KF) undergoing dialysis, neutrophils are dysfunctionally activated. Such chronic activation does not correspond to increased protection against infections and is thought to cause direct vascular damage accounting for the higher incidence of cardiovascular (CV) events. We hypothesized that circulating levels of neutrophil degranulation products (i.e. myeloperoxidase (MPO) and resistin) can predict overall and CV-specific mortality in dialysis patients. METHODS: MPO and resistin levels were assessed in plasma samples from n = 1182 dialysis patients who were followed-up for median 2.9 years (IQR: 1.7-4.2). RESULTS: Patients were 65 ± 14 (SD) years old and 36 % women. Median value of MPO and resistin were 78 ng/mL (IQR: 54 - 123) and 72 ng/mL (IQR: 46 - 110), respectively. MPO and resistin levels correlated with biomarkers of organ damage, nutritional status and inflammation. Both MPO and resistin levels predicted all-cause mortality even after adjustment for traditional risk factors and inflammation, nutritional and KF-related indexes (MPO, HRfor 1 ln unit increase: 1.26, 95 %CI 1.11 - 1.42, P < 0.001; Resistin, HRfor 1 ln unit increase: 1.25, 95 %CI 1.09 - 1.44, P = 0.001). Similarly, their predictive ability held true also for CV death (MPO, HRfor 1 ln unit increase: 1.19, 95 %CI 1.01 - 1.41, P = 0.04; Resistin, HRfor 1 ln unit increase: 1.29, 95 %CI 1.07 - 1.56, P = 0.007). CONCLUSION: Plasma levels of MPO and resistin correlate with prospective overall and CV-specific mortality risk in KF patients undergoing dialysis and might be useful prognostic tools. Mediators of inflammation may be potential target to improve survival of those patients.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) and clinical outcomes in dialysis patients.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9), a factor accelerating the degradation of LDL receptors, was associated with a gender-dependent risk for cardiovascular (CV) events in the general population and with all-cause and CV mortality in two relatively small studies in black Africans and South Korean haemodialysis patients. The effect modification by gender was untested in these studies. METHODS: The study enrolled 1188 dialysis patients from the Prospective Registry of The Working Group of Epidemiology of Dialysis Region Calabria (PROGREDIRE) cohort. PCSK9 was measured by colorimetric enzyme-linked immunosorbent assay. The primary outcomes were all-cause and CV mortality. Statistical analysis included Cox regression analysis and effect modification analysis. RESULTS: During a median 2.9-year follow-up, out of 494 deaths, 278 were CV-related. In unadjusted analyses, PCSK9 levels correlated with increased all-cause (HRfor1ln unit increase: 1.23, 95% CI 1.06-1.43, p =.008) and CV mortality (HRfor1ln unit increase: 1.26, 95% CI 1.03-1.54, p =.03). After multivariate adjustment, these associations were no longer significant (all-cause mortality, HRfor 1 ln unit increase: 1.16, 95% CI .99-1.36, p =.07; CV mortality, HRfor1ln unit increase: 1.18, 95% CI .95-1.46, p =.14). However, in fully adjusted interaction analyses, a doubling in the risk of this outcome in women was registered (Women, HRfor1ln unit increase: 1.88, 95% CI 1.27-2.78, p =.002; Men, HRfor1ln unit increase: 1.07, 95% CI .83-1.38, p =.61; p for effect modification: .02). CONCLUSIONS: PCSK9 levels are unrelated to all-cause mortality in haemodialysis patients but, like in studies of the general population, independently of other risk factors, entail a doubling in the risk of CV events in women in this population.

SGLT2 inhibition to target kidney aging.

Anti-aging therapy is the latest frontier in the world of medical science, especially for widespread diseases such as chronic kidney disease (CKD). Both renal aging and CKD are characterized by increased cellular senescence, inflammation and oxidative stress. A variety of cellular signalling mechanisms are involved in these processes, which provide new potential targets for therapeutic strategies aimed at counteracting the onset and progression of CKD. At the same time, sodium-glucose co-transporter 2 inhibitors (SGLT2is) continuously demonstrate large beneficial effects at all stages of the cardiorenal metabolic continuum. The broad-spectrum benefits of SGLT2is have led to changes in several treatment guidelines and to growing scientific interest in the underlying working principles. Multiple mechanisms have been studied to explain these great renal benefits, but many things remain to be solved. With this in mind, we provide an overview of the experimental evidence for the effects of SGLT2is on the molecular pathway's ability to modulate senescence, aging and parenchymal damage, especially at the kidney level. We propose to shed some light on the role of SGLT2is in kidney care by focusing on their potential to reduce the progression of kidney disease across the spectrum of aging and dysregulation of senescence.

Inhibition of de novo ceramide synthesis by Sirtuin-1 improves beta-cell function and glucose metabolism in type 2 diabetes.

BACKGROUND: Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular diseases (CVD). Dysregulated pro-apoptotic ceramide synthesis reduces ß-cell insulin secretion, thereby promoting hyperglycemic states which may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor cardiovascular outcomes. Sirtuin-1 (SIRT1) is a NAD + - dependent deacetylase that protects against pancreatic ß-cell dysfunction; however, systemic levels are decreased in obese T2D mice and may promote pro-apoptotic ceramide synthesis and hyperglycemia. Herein, we aimed to assess the effects of restoring circulating SIRT1 levels to prevent metabolic imbalance in obese and diabetic mice. METHODS AND RESULTS: Circulating SIRT1 levels were reduced in obese diabetic mice (db/db) as compared to age-matched non-diabetic db/+ controls. Restoration of SIRT1 plasma levels with recombinant murine SIRT1 for 4-weeks prevented body weight gain, improved glucose tolerance, insulin sensitivity and vascular function in mice models of obesity and T2D. Untargeted lipidomics revealed that SIRT1 restored insulin-secretory function of ß-cells by reducing synthesis and accumulation of pro-apoptotic ceramides. Molecular mechanisms involved direct binding to and deacetylation of Toll-like receptor 4 (TLR4) by SIRT1 in ß-cells thereby decreasing the rate limiting enzymes of sphingolipid synthesis SPTLC1/2 via AKT/NF-κB. Among T2D patients, those with high baseline plasma levels of SIRT1 prior to metabolic surgery displayed restored ß-cell function (HOMA2- ß) and were more likely to have T2D remission during follow-up. CONCLUSION: Acetylation of TLR4 promotes ß-cell dysfunction via ceramide synthesis in T2D, which is blunted by systemic SIRT1 replenishment. Hence, restoration of systemic SIRT1 may provide a novel therapeutic strategy to counteract toxic ceramide synthesis and mitigate cardiovascular complications of T2D.

Baseline urinary osteopontin levels are associated with the improvement of metabolic syndrome.

BACKGROUND AND AIMS: While serum osteopontin (OPN)'s established role in cardiometabolic risk is recognized, its potential as a predictor of metabolic syndrome (MetS) improvement through a urine assay has not yet been demonstrated. In this study, we propose its potential predictive role over a 12-month period of standard care, with the ability to complement anthropometric measures. METHODS AND RESULTS: Hierarchical clustering revealed a notable association of urinary OPN (uOPN) with MetS criteria and overcame anthropometric measures in predicting the improvement at 12 months (OR of 2.74 [95% CI 1.32 to 6.29]). uOPN significantly contributed to the homogeneity of the nodes in the random forest and ultimately enhanced the performance of anthropometric measures when assessed for accuracy and area under the curve (AUC). CONCLUSION: Our findings offer insights into potential applications in cardiometabolic medicine for uOPN, which is easily detectable in non-invasive biological samples through an affordable assay.

Differential impact of fentanyl and morphine doses on ticagrelor-induced platelet inhibition in ST-segment elevation myocardial infarction: a subgroup analysis from the PERSEUS randomized trial.

Introduction: Among patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI), intravenous fentanyl does not enhance ticagrelor-induced platelet inhibition within 2 h compared to morphine. The impact of the total dose of fentanyl and morphine received on ticagrelor pharmacodynamic and pharmacokinetic responses in patients with STEMI remains however undetermined. Materials and methods: We performed a post-hoc subanalysis of the prospective, open-label, single-center, randomized PERSEUS trial (NCT02531165) that compared treatment with intravenous fentanyl vs. morphine among symptomatic patients with STEMI treated with primary PCI after ticagrelor pretreatment. Patients from the same population as PERSEUS were further stratified according to the total dose of intravenous opioids received. The primary outcome was platelet reactivity using P2Y12 reaction units (PRU) at 2 h following administration of a loading dose (LD) of ticagrelor. Secondary outcomes were platelet reactivity and peak plasma levels of ticagrelor and AR-C124910XX, its active metabolite, at up to 12 h after ticagrelor LD administration. Generalized linear models for repeated measures were built to determine the relationship between raw and weight-weighted doses of fentanyl and morphine. Results: 38 patients with STEMI were included between December 18, 2015, and June 22, 2017. Baseline clinical and procedural characteristics were similar between low- and high-dose opioid subgroups. At 2 h, there was a significant correlation between PRU and both raw [regression coefficient (B), 0.51; 95% confidence interval (CI), 0.02-0.99; p = 0.043] and weight-weighted (B, 0.54; 95% CI, 0.49-0.59; p < 0.001) doses of fentanyl, but not morphine. Median PRU at 2 h was significantly lower in patients receiving low, as compared to high, doses of fentanyl [147; interquartile range (IQR), 63-202; vs. 255; IQR, 183-274; p = 0.028], whereas no significant difference was found in those receiving morphine (217; IQR, 165-266; vs. 237; IQR, 165-269; p = 0.09). At 2 h, weight-weighted doses of fentanyl and morphine were significantly correlated to plasma levels of ticagrelor and AR-C124910XX. Conclusion: In symptomatic patients with STEMI who underwent primary PCI after ticagrelor pretreatment and who received intravenous opioids, we found a dose-dependent relationship between the administration of intravenous fentanyl, but not morphine, and ticagrelor-induced platelet inhibition.

Impulse Control Disorders in Parkinson's Disease: An Overview of Risk Factors, Pathogenesis and Pharmacological Management.

Impulse control disorders in Parkinson's disease are relatively common drug-induced addictive behaviours that are usually triggered by the dopamine agonists pramipexole, ropinirole and rotigotine. This narrative review aimed to provide a comprehensive overview of the current knowledge of impulse control disorders in Parkinson's disease. We summarised the prevalence, clinical features, risk factors and potential underlying mechanisms of impulse control disorders in Parkinson's disease. Moreover, recent advances in behavioural and imaging characteristics and management strategies are discussed. Early detection as well as a tailored multidisciplinary approach, which typically includes careful adjustment of the dopaminergic therapy and the treatment of associated neuropsychiatric symptoms, are necessary. In some cases, a continuous delivery of levodopa via a pump or the dopamine D1 receptor agonist, apomorphine, can be considered. In selected patients without cognitive or speech impairment, deep brain stimulation of the subthalamic nucleus can also improve addictions. Finding the right balance of tapering dopaminergic dose (usually dopamine agonists) without worsening motor symptoms is essential for a beneficial long-term outcome.

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.