Obesity: the perfect storm for heart failure.

Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi-imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost-effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium-glucose co-transporter-2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF.

Incidence of new-onset hypertension before, during, and after the COVID-19 pandemic: a 7-year longitudinal cohort study in a large population.

BACKGROUND: While the augmented incidence of diabetes after COVID-19 has been widely confirmed, controversial results are available on the risk of developing hypertension during the COVID-19 pandemic. METHODS: We designed a longitudinal cohort study to analyze a closed cohort followed up over a 7-year period, i.e., 3 years before and 3 years during the COVID-19 pandemic, and during 2023, when the pandemic was declared to be over. We analyzed medical records of more than 200,000 adults obtained from a cooperative of primary physicians from January 1, 2017, to December 31, 2023. The main outcome was the new diagnosis of hypertension. RESULTS: We evaluated 202,163 individuals in the pre-pandemic years and 190,743 in the pandemic years, totaling 206,857 when including 2023 data. The incidence rate of new hypertension was 2.11 (95% C.I. 2.08-2.15) per 100 person-years in the years 2017-2019, increasing to 5.20 (95% C.I. 5.14-5.26) in the period 2020-2022 (RR = 2.46), and to 6.76 (95% C.I. 6.64-6.88) in 2023. The marked difference in trends between the first and the two successive observation periods was substantiated by the fitted regression lines of two Poisson models conducted on the monthly log-incidence of hypertension. CONCLUSIONS: We detected a significant increase in new-onset hypertension during the COVID-19 pandemic, which at the end of the observation period affected ~ 20% of the studied cohort, a percentage higher than the diagnosis of COVID-19 infection within the same time frame. This observation suggests that increased attention to hypertension screening should not be limited to individuals who are aware of having contracted the infection but should be extended to the entire population.

Pro-inflammatory cells sustain leukemic clonal expansion in T-cell large granular lymphocyte leukemia.

T-cell large granular lymphocyte leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by the clonal expansion of T-cell large granular lymphocytes (T-LGL). Immunophenotypic and genotypic features contribute to discriminate symptomatic (CD8+ STAT3-mutated T-LGLL) from clinically indolent patients, this latter group including CD8+ wildtype (wt), CD4+ STAT5B-mutated and wt cases. T-LGL lymphoproliferation is sustained both by somatic gain-offunction mutations (i.e., STAT3 and STAT5B) and by pro-inflammatory cytokines, but little information is available on the activity of T-LGLL non-leukemic cells. In this study, we characterized pro-inflammatory cells in the peripheral blood of T-LGLL patients and analyzed their role in supporting the leukemic growth. In symptomatic patients we found that cell populations not belonging to the leukemic component showed a discrete pro-inflammatory pattern. In particular, CD8+ STAT3-mutated cases showed a skewed Th17/Treg ratio and an abnormal distribution of monocyte populations characterized by increased intermediate and non-classical monocytes. We also demonstrated that monocytes released high levels of interleukin-6 after CCL5 stimulation, a chemokine specifically expressed only by leukemic LGL. Conversely, in asymptomatic cases an altered distribution of monocyte populations was not detected. Moreover, T-LGLL patients' monocytes showed abnormal activation of signaling pathways, further supporting the different pathogenic role of monocytes in patients in discrete clinical settings. Altogether, our data contribute to deepening the knowledge on the different cell subtypes in T-LGLL, focusing particularly on non-leukemic cell populations and thus offering the rationale for new therapeutic strategies.

Long-Lasting Control of LDL Cholesterol Induces a 40% Reduction in the Incidence of Cardiovascular Events: New Insights from a 7-Year Study.

Recent studies have yielded controversial results on the long-term effects of statins on the risk of cardiovascular (CV) events. To fill this knowledge gap, we assessed the relationship between low-density lipoprotein cholesterol (LDL-C) levels and CV events in hypertensive patients without previous CV events and naïve to antidyslipidemic treatment within the "Campania Salute Network" in Southern Italy. We studied 725 hypertensive patients with a mean follow-up of 85.4 ± 25.7 months. We stratified our cohort into three groups based on LDL cholesterol (LDL-C) levels in mg/dl: group 1) patients showing during the follow-up a mean LDL-C value ≤100 mg/dl in absence of statin therapy; group 2) statin-treated patients with LDL ≤100 mg/dl; and group 3) patients with LDL-C >100 mg/dl. No significant difference among the groups was observed in terms of demographic and clinical characteristics and medications. The incidence of first CV events was 5.7% in group 1, 6.0% in group 2, and 11.9% in group 3 (P < 0.05 vs. group 1 and group 2). A stable long-term satisfactory control of LDL-C plasma concentration (≤100 mg/dl) reduced the incidence of major CV events from one event every 58.6 patients per year to one event every 115.9 patients per year. These findings were confirmed in a Cox regression analysis, adjusting for potential confounding factors. Collectively, our data demonstrate that a 7-year stable control of LDL-C reduces the incidence of CV events by 40%. SIGNIFICANCE STATEMENT: There are several discrepancies between Mendelian studies and other investigations concerning the actual effects of reduction of plasma concentration of low-density lipoprotein (LDL) cholesterol on the incidence of major cardiovascular events. Taken together, our data in nondiabetic subjects show that a 7-year stable control of LDL cholesterol induces a ∼40% reduction of the incidence of cardiovascular events.

The Environmental Pollution and Cardiovascular Risk: The Role of Health Surveillance and Legislative Interventions in Cardiovascular Prevention.

Environmental pollution in considered an established determinant of non-communicable illness, including cardiovascular diseases (CVDs). Air pollution is the result of a complex combination of chemical, physical, and biological agents, and represents one of the main causes of mortality and morbidity in the world population. It is responsible for 7.6% of global mortality. In this regard, it has been documented that it increases the risk of CVDs and major adverse cardiovascular and cerebrovascular events. In northern regions of China, long-term exposures to the particulate matter < 2.5 µm (PM2.5) increase in the risk of ischemic heart disease by almost two-folds. Similarly, the additional risk for stroke, increases by almost 10% for long-term exposure to PM2.5. The detrimental effects of air pollution on cardiovascular system are particularly manifest in vulnerable subjects, such as the elderly, patients with heart disease, and obese individuals. Therefore, nowadays, cardiovascular prevention strategies, in addition to controlling traditional risk factors, should also include measures to improve the environment. This goal can be achieved by the implementation of the health surveillance in occupational medicine and by the extensive application of the national and international legislative measures. In fact, the health surveillance represents a crucial preventive measure for workers exposed to health risks (chemical, physical agents, etc.) that may lead to occupational diseases after long-term exposure. On the other hand, since environmental pollution does not recognize well-defined boundaries, only the implementation of regulations among large territorial areas can be useful to improve the quality of environment.

Achieving a Systolic Blood Pressure Below 130 mmHg Reduces the Incidence of Cardiovascular Events in Hypertensive Patients with Echocardiographic Left Ventricular Hypertrophy.

Background: Recent reports have evidenced an increased mortality rate in hypertensive patients with electrocardiographic left ventricular hypertrophy (ECG-LVH) achieving systolic blood pressure (SBP) <130mmHg. However, to the best of our knowledge, the actual effects of BP reduction to the {less than or equal to}130/80mmHg target on the incidence of cardiovascular events in hypertensive patients with a diagnosis of LVH based on echocardiographic-criteria (Echo-LVH) have never been determined. Methods: In order to fill this long-standing knowledge gap, we harnessed a population of 9511 hypertensive patients, followed-up for 33.6 [IQR 7.9-72.7] months. The population was divided into six groups according to the average SBP achieved during the follow-up ({less than or equal to}130, 130-to-139, and {greater than or equal to}140mmHg) and absence/presence of Echo-LVH. The primary endpoint was a composite of fatal or non-fatal myocardial infarction and stroke, sudden cardiac death, heart failure requiring hospitalization, revascularization, and carotid stenting. Secondary endpoints included atrial fibrillation and transient ischemic attack. Results: During the follow-up, achieved SBP and diastolic BP (DBP) were comparable between patients with and without Echo-LVH. Strikingly, the rate of primary and secondary endpoints was significantly higher in patients with Echo-LVH and SBP>130mmHg, reaching the highest rate in the Echo-LVH group with SBP{greater than or equal to}140mmHg. By separate Cox multivariable regressions, after adjusting for potential confounders, both primary and secondary endpoints were significantly associated with SBP{greater than or equal to}140mmHg and Echo-LVH. Instead, DBP reduction {less than or equal to}80mmHg was associated with a significant increased rate of secondary events. Conclusions: In hypertensive patients with Echo-LVH, achieving an average in-treatment SBP target {less than or equal to}130mmHg has a beneficial prognostic impact on incidence of cardiovascular events. Significance Statement In contrast with recent reports, achieving in-treatment SBP≤130mmHg reduces the incidence of CV events in hypertensive patients with Echo-LVH. Reducing DBP≤80mmHg is instead associated with a higher rate of CV complications. By Cox multivariable regression models, adjusting for potential confounders, the rate of hard and soft CV events was significantly associated with Echo-LVH and SBP≥140mmHg. Our data indicate that therapeutic strategies in patients with Echo-LVH should aim at reducing SBP≤130mmHg paying attention to not reducing DBP≤80mmHg.

Incidence of type 2 diabetes before and during the COVID-19 pandemic in Naples, Italy: a longitudinal cohort study.

Background: The association of COVID-19 with the development of new-onset diabetes has been recently investigated by several groups, yielding controversial results. Population studies currently available in the literature are mostly focused on type 1 diabetes (T1D), comparing patients with a SARS-CoV-2 positive test to individuals without COVID-19, especially in paediatric populations. In this study, we sought to determine the incidence of type 2 diabetes (T2D) before and during the COVID-19 pandemic. Methods: In this longitudinal cohort study, we analysed a cohort followed up over a 6-year period using an Interrupted Time Series approach, i.e. 3-years before and 3-years during the COVID-19 pandemic. We analysed data obtained from >200,000 adults in Naples (Italy) from January 1st 2017 to December 31st 2022. In this manner, we had the opportunity to compare the incidence of newly diagnosed T2D before (2017-2019) and during (2020-2022) the COVID-19 pandemic. The key inclusion criteria were age >18-year-old and data availability for the period of observation; patients with a diagnosis of diabetes obtained before 2017 were excluded. The main outcome of the study was the new diagnosis of T2D, as defined by the International Classification of Diseases 10 (ICD-X), including prescription of antidiabetic therapies for more than 30 days. Findings: A total of 234,956 subjects were followed-up for at least 3-years before or 3-years during the COVID-19 pandemic and were included in the study; among these, 216,498 were analysed in the pre-pandemic years and 216,422 in the pandemic years. The incidence rate of T2D was 4.85 (95% CI, 4.68-5.02) per 1000 person-years in the period 2017-2019, vs 12.21 (95% CI, 11.94-12.48) per 1000 person-years in 2020-2022, with an increase of about twice and a half. Moreover, the doubling time of the number of new diagnoses of T2D estimated by unadjusted Poisson model was 97.12 (95% CI, 40.51-153.75) months in the prepandemic period vs 23.13 (95% CI, 16.02-41.59) months during the COVID-19 pandemic. Interestingly, these findings were also confirmed when examining patients with prediabetes. Interpretation: Our data from this 6-year study on more than 200,000 adult participants indicate that the incidence of T2D was significantly higher during the pandemic compared to the pre-COVID-19 phase. As a consequence, the epidemiology of the disease may change in terms of rates of outcomes as well as public health costs. COVID-19 survivors, especially patients with prediabetes, may require specific clinical programs to prevent T2D. Funding: The US National Institutes of Health (NIH: NIDDK, NHLBI, NCATS), Diabetes Action Research and Education Foundation, Weill-Caulier and Hirschl Trusts.

Hypertension-mediated organ damage involving multiple sites is an independent risk factor for cardiovascular events.

Aims: Chronic pressure overload determines functional and structural alterations, leading to hypertension-mediated organ damage (HMOD), affecting multiple districts. We aim at evaluating the prognostic impact of the absence vs. presence of HMOD in one or more sites and of blood pressure (BP) and metabolic control in hypertensive patients. Methods and results: The study included 7237 hypertensive patients from the Campania Salute Network Registry, followed up for 5.3 ± 4.5 years. As HMOD, we analysed the presence of left ventricular hypertrophy, carotid plaques, and chronic kidney disease (CKD-EPI ≥3 stage) and evaluated the impact of zero vs. one vs. two vs. three sites of HMOD on the occurrence of major adverse cardiovascular events (MACEs). Blood pressure control and Metabolic Score for Insulin Resistance (METS-IR) were also considered. Optimal BP control was achieved in 57.3% patients. Major adverse cardiovascular events occurred in 351 (4.8%) patients. The MACE rate in patients without HMOD was 2.7%, whereas it was 4.7, 7.9, and 9.8% in patients with one, two, and three sites with HMOD, respectively. By using Cox multivariate models, adjusted for age, BP control, mean heart rate, mean METS-IR, number of HMOD sites, and drugs, MACE was found to be significantly associated with ageing, mean METS-IR, anti-platelet therapy, and multiple sites with HMOD, whereas a negative association was found with renin-angiotensin system inhibitor drugs. Conclusion: In hypertensive patients, the risk of MACE increases with the incremental number of districts involved by HMOD, independent of BP control and despite the significant impact of metabolic dysregulation. Hypertension-mediated organ damage involving multiple sites is the deleterious consequence of hypertension and dysmetabolism but, when established, it represents an independent cardiovascular risk factor for MACE occurrence.

A Pharmacovigilance Study on the Safety of Axicabtagene Ciloleucel Based on Spontaneous Reports from the EudraVigilance Database.

During pre-approval clinical trials, the safety of axi-cel, a second-generation CAR-T-cell therapy directed against CD19, which dramatically improved the prognosis of intractable B-cell lymphomas, has been investigated only in about 400 patients. Therefore, additional information on this issue is urgently needed. In the present paper, we evaluated the 2905 ICSRs with axi-cel as the suspected drug that had been uploaded in the EudraVigilance database from 1 January 2018 to 31 December 2022. About 80% of the reported adverse events were serious, and about 20% of them did not fully resolve or caused death. The adverse events most-frequently reported were Nervous system disorders (25.6%) and, among them, immune-effector-cell-associated neurotoxicity syndrome, followed by Immune system disorders (23.1%), General disorders and administration site conditions (12.0%), Blood and lymphatic system disorders (7.2%), and Infections and infestations (5.8%). Disproportionality analysis showed that the frequency of reported adverse events related to the nervous system was higher with axi-cel than with the other approved CAR-T-cells, except brexu-cel. In conclusion, real-world pharmacovigilance data showed that nervous system and immune system disorders are the adverse events most reported in axi-cel-related ICSRs and suggest that axi-cel could be more neurotoxic than other CAR-T-cells.

Focal adhesion kinase activation by calcium-dependent calpain is involved in chronic lymphocytic leukaemia cell aggressiveness.

Signalling events downstream the B-cell receptor (BCR) are central for the survival and progression of chronic lymphocytic leukaemia (CLL) cells. Focal adhesion kinase (FAK), regulated through calpain, interacts with molecules of BCR signalling, cytoskeletal modelling and disease progression, such as Src/Lyn, cortactin and HS1. Hypothesizing that FAK might play a key role in CLL pathogenesis, we observed a down-modulation of FAK whole form, associated with FAK cleavage due to calpain activity upon BCR stimulation. Patients, whose cells were able to release Ca++ after BCR stimulation, had less amount of full-length FAK, which translated into a higher presence of cleaved/activated form of the protein phosphorylated at Y397, these features being mostly shown by immunoglobulin heavy chain (IGHV)-unmutated poor-prognosis patients. Moreover, we found that cortactin and HS1 proteins were overexpressed in those cells, suggesting a possible interplay with FAK. Treatment with the FAK inhibitor Defactinib was able to induce apoptosis in CLL cells. In conclusion, the malignant phenotype in unfavourable-prognosis patients seems to be encouraged by the overexpression of cortactin and HS1, that, together with FAK, may be involved in a druggable pathogenetic pathway in CLL.

The therapeutic concordance approach reduces adverse drug reactions in patients with resistant hypertension.

Background: Adverse drug reactions (ADRs) remain among the leading causes of therapy-resistant hypertension (TRH) and uncontrolled blood pressure (BP). We have recently reported beneficial results in BP control in patients with TRH adopting an innovative approach, defined as therapeutic concordance, in which trained physicians and pharmacists reach a concordance with patients to make them more involved in the therapeutic decision-making process. Methods: The main scope of this study was to investigate whether the therapeutic concordance approach could lead to a reduction in ADR occurrence in TRH patients. The study was performed in a large population of hypertensive subjects of the Campania Salute Network in Italy (ClinicalTrials.gov Identifier: NCT02211365). Results: We enrolled 4,943 patients who were firstly followed-up for 77.64 ± 34.44 months, allowing us to identify 564 subjects with TRH. Then, 282 of these patients agreed to participate in an investigation to test the impact of the therapeutic concordance approach on ADRs. At the end of this investigation, which had a follow-up of 91.91 ± 54.7 months, 213 patients (75.5%) remained uncontrolled while 69 patients (24.5%, p < 0.0001) reached an optimal BP control. Strikingly, during the first follow-up, patients had complained of a total of 194 ADRs, with an occurrence rate of 68.1% and the therapeutic concordance approach significantly reduced ADRs to 72 (25.5%). Conclusion: Our findings indicate that the therapeutic concordance approach significantly reduces ADRs in TRH patients.

L-Arginine in diabetes: clinical and preclinical evidence.

L-Arginine (L-Arg), is a semi-essential amino acid involved in the formation of nitric oxide. The functional relevance of L-Arg in diabetes mellitus has been evaluated both in animal models and in human subjects. In the literature there are several lines of evidence indicating that L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients. Here we present a comprehensive overview of the main studies exploring the effects of L-Arg in diabetes, including preclinical and clinical reports on this topic.

Choline supplements: An update.

In this comprehensive review, we examine the main preclinical and clinical investigations assessing the effects of different forms of choline supplementation currently available, including choline alfoscerate (C8H20NO6P), also known as alpha-glycerophosphocholine (α-GPC, or GPC), choline bitartrate, lecithin, and citicoline, which are cholinergic compounds and precursors of acetylcholine. Extensively used as food supplements, they have been shown to represent an effective strategy for boosting memory and enhancing cognitive function.

Beneficial effects of L-Arginine in patients hospitalized for COVID-19: New insights from a randomized clinical trial.

We have recently demonstrated in a double-blind randomized trial the beneficial effects of L-Arginine in patients hospitalized for COVID-19. We hypothesize that one of the mechanisms underlying the favorable effects of L-Arginine is its action on inflammatory cytokines. To verify our hypothesis, we measured longitudinal plasma levels of pro-inflammatory and anti-inflammatory cytokines implied in the pathophysiology of COVID-19 in patients randomized to receive oral L-Arginine or placebo. The study was successfully completed by 169 patients. Patients in the L-Arginine arm had a reduced respiratory support evaluated at 10 and 20 days; moreover, the time to hospital discharge was significantly shorter in the L-Arginine group. The assessment of circulating cytokines revealed that L-Arginine significantly reduced the circulating levels of pro-inflammatory IL-2, IL-6, and IFN-γ and increased the levels of the anti-inflammatory IL-10. Taken together, these findings indicate that adding L-Arginine to standard therapy in COVID-19 patients markedly reduces the need of respiratory support and the duration of in-hospital stay; moreover, L-Arginine significantly regulates circulating levels of pro-inflammatory and anti-inflammatory cytokines.