Despite major advances in prevention and treatment, cardiac and cerebral atherothrombotic complications still account for substantial morbidity and mortality worldwide. In this context, inflammation is involved in the chronic process leading atherosclerotic plaque formation and its complications, as well as in the maladaptive response to acute ischemic events. For this reason, modulation of inflammation is nowadays seen as a promising therapeutic strategy to counteract the burden of cardio- and cerebrovascular disease. Being produced and recognized by both inflammatory and vascular cells, the complex network of cytokines holds key functions in the crosstalk of these two systems and orchestrates the progression of atherothrombosis. By binding to membrane receptors, these soluble mediators trigger specific intracellular signaling pathways eventually leading to the activation of transcription factors and a deep modulation of cell function. Both stimulatory and inhibitory cytokines have been described and progressively reported as markers of disease or interesting therapeutic targets in the cardiovascular field. Nevertheless, cytokine inhibition is burdened by harmful side effects that will most likely prevent its chronic use in favor of acute administrations in well-selected subjects at high risk. Here, we summarize the current state of knowledge regarding the modulatory role of cytokines on atherosclerosis, myocardial infarction, and stroke. Then, we discuss evidence from clinical trials specifically targeting cytokines and the potential implication of these advances into daily clinical practice.

Very low-carbohydrate ketogenic diets (VLCKDs) are an emerging nutritional treatment for severe obesity and are associated with a significant improvement in non-alcoholic fatty liver disease (NAFLD). Little is known about the effect of sex differences on weight loss induced by following a VLCKD. The aim of this study was to investigate the effects of sex differences on weight loss and NAFLD improvement in patients with severe obesity undergoing a VLCKD. Forty-two females and 28 males with severe obesity underwent a 25-day VLCKD. Anthropometric parameters, bioimpedentiometry, degree of liver steatosis measured by ultrasonography, liver function tests, and glucose homeostasis were measured before and after the VLCKD. Males experienced a significantly larger excess body weight loss (EBWL) and a greater reduction in γ-glutamyl transferase (γGT) than females. Dividing the female group by menopausal status, a significant difference between males and pre-menopausal females was found for both EBWL and γGT. No significant difference between groups was observed for improvement in the Edmonton stage or in the degree of steatosis. We conclude that the efficacy of following a VLCKD in severe obesity is affected by sex differences and, for females, by menopausal status. Males seem to experience larger benefits than females in terms of EBWL and NAFLD improvement. These differences are attenuated after menopause, probably because of changes in hormonal profile and body composition.

Accumulation of fat in renal sinus and hilum is associated with hypertension development. We evaluated the relationship between perirenal fat and hypertension in a population of morbidly obese patients and the potential variations after sleeve‐gastrectomy. Two hundred and eighty‐four morbidly obese patients were included in the study, and 126 underwent sleeve‐gastrectomy. At baseline and 10‐12 months after surgery, we evaluated anthropometric parameters, blood pressure, glycometabolic, and lipidic assessment, and performed an ultrasonographic evaluation of visceral fat area and perirenal fat thickness. The perirenal fat thickness in hypertensive obese was higher than in nonhypertensive (13.6 ± 4.8 vs 11.6 ± 4.1, P = 0.001). It showed a significant direct correlation with age, waist circumference, BMI, systolic blood pressure (SBP), insulinemia, HOMA‐IR, glycated hemoglobin, and creatinine. The independent predictors (R² = 0.129) of SBP were perirenal fat thickness (β = 0.160, P = 0.022) and age (β = 0.175, P = 0.011). After surgery, perirenal fat thickness significantly decreased (from 13 ± 4 to 9 ± 4 mm, P <0.001). In the 89 hypertensive obese patients who underwent sleeve‐gastrectomy, we observed a significant decrease in antihypertensive medications needed. Sixteen patients suspended therapy. The perirenal fat thickness in obese patients could be a valuable tool to define the risk of developing hypertension, providing the clinician with an additional parameter to define those who need a more aggressive treatment and could benefit most from bariatric surgery.

In preclinical studies, fasting was found to potentiate the effects of several anticancer treatments, and early clinical studies indicated that patients may benefit from regimes of modified fasting. However, concerns remain over possible negative impact on the patients’ nutritional status. We assessed the feasibility and safety of a 5-day “Fasting-Mimicking Diet” (FMD) as well as its effects on body composition and circulating growth factors, adipokines and cyto/chemokines in cancer patients. In this single-arm, phase I/II clinical trial, patients with solid or hematologic malignancy, low nutritional risk and undergoing active medical treatment received periodic FMD cycles. The body weight, handgrip strength and body composition were monitored throughout the study. Growth factors, adipokines and cyto/chemokines were assessed by ELISA. Ninety patients were enrolled, and FMD was administered every three weeks/once a month with an average of 6.3 FMD cycles/patient. FMD was largely safe with only mild side effects. The patients’ weight and handgrip remained stable, the phase angle and fat-free mass increased, while the fat mass decreased. FMD reduced the serum c-peptide, IGF1, IGFBP3 and leptin levels, while increasing IGFBP1, and these modifications persisted for weeks beyond the FMD period. Thus, periodic FMD cycles are feasible and can be safely combined with standard antineoplastic treatments in cancer patients at low nutritional risk. The FMD resulted in reduced fat mass, insulin production and circulating IGF1 and leptin. This trial was registered on Clinicaltrials.gov in July 2018 with the identifier NCT03595540.

Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left ventricular function. This study examined the relationship of circulating DPP3 (cDPP3) with cardiogenic shock (CS) and mortality in patients presenting with acute coronary syndromes (ACS). Plasma cDPP3 levels were assessed at baseline and 12–24 h after presentation in patients with ACS prospectively enrolled into the multi-centre SPUM-ACS study (n = 4787). Circulating DPP3 levels were associated with in-hospital CS when accounting for established risk factors including the ORBI risk score [per log-2 increase, hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.05–1.82, P = .021]. High cDPP3 was an independent predictor of mortality at 30 days (HR 1.87, 95% CI 1.36–2.58, P < .001) and at one year (HR 1.61, 95% CI 1.28–2.02, P < .001) after adjustment for established risk factors and the GRACE 2.0 score. Compared to values within the normal range, persistently elevated cDPP3 levels at 12–24 h were associated with 13.4-fold increased 30-day mortality risk (HR 13.42, 95% CI 4.86–37.09, P < .001) and 5.8-fold increased 1-year mortality risk (HR 5.79, 95% CI 2.70–12.42, P < .001). Results were consistent across various patient subgroups. This study identifies cDPP3 as a novel marker of CS and increased mortality in patients with ACS. Circulating DPP3 offers prognostic information beyond established risk factors and improves early risk assessment. Circulating dipeptidyl peptidase 3 (cDPP3) was identified as a novel marker of cardiogenic shock (CS) and increased mortality risk in patients with acute coronary syndromes (ACS). Upon ischaemic cell death, the intracellular aminopeptidase DPP3 is released in the circulation where it cleaves angiotensin II (ATII) and exerts negative inotropic effects on the left ventricle. Circulating DPP3 levels were measured at presentation and after 12–24 h in patients enrolled into the multi-centre prospective SPUM-ACS study. High baseline levels of cDPP3 were independently associated with in-hospital CS, mortality risk at 30 days, and mortality risk at 1 year beyond established risk factors. Patients with persistently high cDPP3 levels at 12–24 h displayed substantially increased 30-day and 1-year mortality risk, whereas normalization of initially high cDDP3 levels was associated with a decrease in mortality risk. In a subcohort of patients undergoing cardiac magnetic resonance imaging (MRI), cDPP3 trajectories were associated with infarct size at 30 days of follow-up. Circulating DPP3 provides prognostic information beyond established risk factors in patients with ACS.