Search

Pulmonary arterial hypertension (PAH) is a rare and progressive disorder that affects the pulmonary vasculature. Although recent developments in pharmacotherapy have extended the life expectancy of PAH patients, their 5-year survival remains unacceptably low, underscoring the need for multitarget and more comprehensive approaches to managing the disease. This should incorporate not only medical, but also lifestyle interventions, including dietary changes and the use of nutraceutical support. Among these strategies, n-3 polyunsaturated fatty acids (n-3 PUFAs) are emerging as promising agents able to counteract the inflammatory component of PAH. In this narrative review, we aim at analysing the preclinical evidence for the impact of n-3 PUFAs on the pathogenesis and the course of PAH. Although evidence for the role of n-3 PUFAs deficiencies in the development and progression of PAH in humans is limited, preclinical studies suggest that these dietary components may influence several aspects of the pathobiology of PAH. Further clinical research should test the efficacy of n-3 PUFAs on top of approved clinical management. These studies will provide evidence on whether n-3 PUFAs can genuinely serve as a valuable tool to enhance the efficacy of pharmacotherapy in the treatment of PAH., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Aims: Patients with heart failure (HF) remain often undertreated for multiple reasons, including treatment inertia, contraindications, and intolerance. The OPTIimal PHARMacological therapy for patients with Heart Failure (OPTIPHARM-HF) registry is designed to evaluate the prevalence of evidence-based medical treatment prescription and titration, as well as the causes of its underuse, in a broad real-world population of consecutive patients with HF across the whole ejection fraction spectrum and among different clinical phenotypes., Methods: The OPTIPHARM-HF registry (NCT06192524) is a prospective, multicenter, observational, national study of adult patients with symptomatic HF, as defined by current international guidelines, regardless of ejection fraction. Both outpatients and inpatients with chronic and acute decompensated HF will be recruited. The study will enroll up to 2500 patients with chronic HF at approximately 35 Italian HF centres. Patients will be followed for a maximum duration of 24 months. The primary objective of the OPTIPHARM-HF registry is to assess prescription and adherence to evidence-based guideline-directed medical therapy (GDMT) in patients with HF. The primary outcome is to describe the prevalence of GDMT use according to target guideline recommendation. Secondary objectives include implementation of comorbidity treatment, evaluation of sequence of treatment introduction and up-titration, description of GDMT implementation in the specific HF population, main causes of GDMT underuse, and assessment of cumulative rate of cardiovascular events., Conclusion: The OPTIPHARM-HF registry will provide important implications for improving patient care and adoption of recommended medical therapy into clinical practice among HF patients., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The identification of novel predictors of poor outcome may help stratify cardiovascular risk. Aim was to evaluate the individual contribution of blood cell count parameters, as well as their clustering, on the risk of death and cardiovascular events over the long term in the population-based Malmö Diet and Cancer Study cohort., Methods: In 30,447 individuals (age 57 ± 8 years), we assessed the incidence of all-cause death (primary endpoint) and major adverse cardiovascular events (MACE, secondary outcome measure) according to absence or presence of one, two and three factors at baseline out of the following: anaemia, leukocytosis and thrombocytosis. Median follow-up was 16 years., Results: The percentages of all-cause death were 19.5% in individuals without factors, 21.3% in those with one factor, 27.4% with two and 46.4% with three (log-rank test P < .001). The crude incidence of MACE was 28.0%, 29.2%, 35.5% and 57.1%, respectively (log-rank test P < .001). At multivariate analysis, we found a stepwise increase in overall mortality with increasing number of prevalent factors (one factor: HR 1.23, 95% CI 1.14-1.31, P < .001; two factors: 1.61, 1.37-1.89, P < .001; three factors: 2.69, 1.44-5.01, P = .002, vs no factor). Similar findings were observed for the incidence of MACE (one factor: adjusted HR 1.18, 95% CI 1.11-1.24, P < .001; two factors: 1.52, 1.33-1.76, P < .001; three factors: 2.03, 1.21-3.67, P < .001, vs no factor)., Conclusions: The easily assessable clustering of anaemia, leukocytosis and thrombocytosis heralds higher incidence of death and adverse cardiovascular events., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Immune checkpoint inhibitors (ICIs) are an emerging option for several advanced metastatic cancers, but may have cardiotoxic effects. The prognostic value of high-sensitivity troponin T (hs-TnT) before treatment start has never been investigated., Materials and Methods: Thirty consecutive patients underwent measurement of hs-TnT before starting ICI therapy (pembrolizumab, 23%; nivolumab, 12%; atezolizumab, 6%; durvalumab, 5%). The primary endpoint of cardiovascular death, stroke or transient ischaemic attack, pulmonary embolism and new-onset heart failure, and the secondary endpoint of progression of cardiac involvement according to the CARDIOTOX classification were evaluated after 3 months from the first cycle., Results: Patients (median age 68 years, 77% men, 13% with coronary artery disease, 90% current or former smokers, 67% overweight or obese and 43% hypertensive) had a median hs-TnT of 12 ng/L (interquartile interval 8-23). The primary endpoint occurred only in patients with hs-TnT ≥ 14 ng/L at baseline. Therefore, only patients who had hs-TnT ≥ 14 ng/L before the first cycle died had a stroke/TIA or new-onset HF. Furthermore, nine out of 13 patients with the secondary endpoint (progression of cardiac disease) had hs-TnT ≥ 14 ng/L before the first cycle (P = .012). AUC values were 0.909 for the primary endpoint and 0.757 for the secondary endpoint. The best cut-off was 14 ng/L for both the primary (100% sensitivity, 73% specificity) and secondary endpoints (sensitivity 75%, specificity 77%)., Conclusions: In patients on ICIs, baseline hs-TnT predicts a composite cardiovascular endpoint and the progression of cardiac involvement at 3 months, with 14 ng/L as the best cut-off., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is involved in cholesterol homeostasis. After binding to the complex low-density lipoprotein (LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance. In addition to the well-known activity on the hepatic LDL receptor-mediated pathway, PCSK9 has been, however, associated with vascular inflammation in atherogenesis. Indeed, PCSK9 is expressed by various cell types that are involved in atherosclerosis (e.g. endothelial cells, smooth muscle cells and macrophages) and is detected inside human atherosclerotic plaques. We here analyse the biology of PCSK9 and its possible involvement in molecular processes involved in atherosclerosis, beyond the regulation of circulating LDL cholesterol levels., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: ENSURE-AF (NCT02072434) assessed therapy with edoxaban vs enoxaparin-warfarin in patients with nonvalvular atrial fibrillation (AF) undergoing elective electrical cardioversion (ECV)., Objectives: To evaluate clinical features and primary efficacy (composite of stroke, systemic embolic events, myocardial infarction and cardiovascular mortality during study period) and safety endpoints (composite of major and clinically relevant nonmajor bleeding during on-treatment period) in patients awaiting ECV of AF with a transesophageal echocardiography (TEE)-guided vs a non-TEE-guided strategy., Methods: In this prospective, randomized, open-label, blinded endpoint study, 2199 patients were randomized to edoxaban 60 mg once-daily (30 mg for creatinine clearance 15-50 mL/min, weight ≤60 kg and/or concomitant use of P-glycoprotein inhibitor) or enoxaparin-warfarin. Primary efficacy endpoint and safety endpoint were reported. Associates of TEE use, efficacy endpoint and safety endpoint were explored using multivariable logistic regression., Results: In total, 589 patients from the edoxaban stratum and 594 from the enoxaparin-warfarin stratum were allocated to the TEE-guided strategy. Primary efficacy was similar regardless of TEE approach (P = .575). There were no significant differences in bleeding rates, regardless of TEE approach (P = .677). Independent predictors of TEE use were as follows: history of ischaemic stroke/ transient ischaemic attack, hypertension and valvular heart disease. Mean CHA 2 DS 2 VASc and HAS-BLED score were independent predictors of the efficacy endpoint whilst mean age was an independent predictor of the safety endpoint., Conclusions: Thromboembolic and bleeding events were not different between patients undergoing TEE-guided strategy and in those undergoing an optimized conventional anticoagulation approach for ECV of AF., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation.)

Aims: High-mobility group box-1 (HMGB1) is a ligand for the receptor for advanced glycation endproducts (RAGE). An HMGB1-RAGE interaction has been implicated in cardiac dysfunction. We assessed the association of HMGB1 and RAGE isoforms with heart failure (HF) in diabetic and non-diabetic patients., Methods and Results: We assayed serum levels of HMGB1, cleaved RAGE (cRAGE), endogenous secretory RAGE (esRAGE), high-sensitivity C-reactive protein (hsCRP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) in parallel with assessment of left ventricular volumes and function in 125 diabetic and 222 non-diabetic Chinese patients with chronic HF. Of the total, 79 diabetic patients without HF and 220 normal subjects served as diabetic and normal controls, respectively. Serum HMGB1, cRAGE, hsCRP, and NT-proBNP levels were higher and, in contrast, esRAGE levels lower in HF patients than in subjects without HF (for all; P < 0.01), with higher levels of cRAGE and hsCRP in diabetic HF vs. non-diabetic HF patients (P < 0.01). For HF patients-with or without diabetes-HMGB1 levels correlated positively with left ventricular end-diastolic and end-systolic volumes (r = 0.267 and r = 0.321, respectively) and NT-proBNP values (r = 0.497), and were inversely related to ejection fraction (r = -0.461; all P < 0.001). Serum cRAGE levels correlated with NT-proBNP values (r = 0.451) and New York Heart Association functional class (r = 0.402; both P < 0.001). Multivariable regression analysis revealed that HMGB1, cRAGE, and esRAGE were consistently associated with HF in diabetic and non-diabetic patients., Conclusion: Heart failure patients have increased serum HMGB1 and cRAGE and decreased esRAGE levels, and these are related to the severity of HF in both diabetic and non-diabetic patients. Such associations are worth further investigation.

Background: Adipose tissue-derived stromal cells (ADSCs) are being recognized as a source of stem cells potentially useful for cardiovascular repair. We analysed the abundance and angiogenic activity of adipose tissue-derived progenitor cells (PCs) in elderly patients most likely to benefit from this novel source of stem cells., Materials and Methods: Fifty-two subjects (aged 68 ± 13 years) with variable degrees of cardiovascular risk underwent abdominal surgery for intercurrent diseases. Visceral adipose tissue (3 ± 1 g visceral fat per patient) was processed with type-1 collagenase to obtain ADSCs from the stromal-vascular fraction. Adipose tissue-derived PCs were quantified by flow cytometry as %CD45(-)/CD34(+)/CD133(+) cells of total ADSCs. Matrigel angiogenesis assay was used to analyse the ability of ADSCs to form tubes or networks., Results: We found no correlations between number of CD45(-)/CD34(+)/CD133(+) or total ADSCs and quantitative risk parameters including total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, waist circumference, body mass index, and systolic and diastolic arterial pressure. However, increasing age (r = -0·31, P < 0·05) significantly and inversely correlated with levels of adipose tissue-derived CD45(-)/CD34(+)/CD133(+) cells in Matrigel angiogenesis assays; increasing age (r = -0·29, P < 0·05) was related to a reduction of ADSC-derived tubulization., Conclusions: Ageing may alter the availability of adipose tissue-derived CD45(-)/CD34(+)/CD133(+) cells and their angiogenic functional capacity. Such changes may impair the use of adipose tissue as source of autologous PCs in elderly patients., (© 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Urinary excretion of leukotriene (LT) E(4) is an index of LTC(4) biosynthesis and platelet-neutrophil interactions, which may occur in coronary heart disease and contribute to myocardial ischaemia. Enhanced LTC(4) biosynthesis may be a consequence of myocardial ischaemia or be linked to its pathogenetic substrate., Methods and Results: Overnight urine collections were obtained from 17 patients with chronic stable angina, three patients with Prinzmetal's angina, 16 patients with non ST-elevation acute coronary syndromes (NSTE-ACS) and six patients with acute ST-elevation myocardial infarction (STEMI). LTE(4) excretion was measured by enzyme immunoassay after HPLC separation. Compared with healthy controls (51.1 +/- 21.3 pg mg(-1) creatinine, mean +/- SD, n = 11) and with non-coronary cardiac controls (36.6 +/- 9.8 pg mg(-1) creatinine, n = 9), LTE(4) excretion was unchanged in stable angina (40.5 +/- 25.8 pg mg(-1) creatinine), but significantly (P < 0.01) increased in NSTE-ACS (122.7 +/- 137.2 pg mg(-1) creatinine) and STEMI (213.4 +/- 172.4 pg mg(-1) creatinine). In these patients, LTE(4) excretion rapidly dropped after day 1, consistent with effective coronary reperfusion. In patients with NSTE-ACS, the increase in LTE(4) excretion was entirely restricted to patients with recent (< 48 h) spontaneous anginal episodes. Myocardial ischaemia elicited by a positive exercise stress test was not accompanied by any detectable increase in LTE(4) excretion, while a significant (P < 0.01) increase was detected after a single-vessel percutaneous coronary interventions (PCI) procedure (n = 10), as compared with diagnostic angiography (n = 9)., Conclusions: In coronary heart disease, increased LTC(4) biosynthesis is restricted to ACS and not linked to myocardial ischaemia per se, but likely to the occurrence of plaque disruption.

Background: Advanced glycation endproducts (AGEs), particularly carboxymethyl(lysine)-adducts (CML), exert part of their cellular effects by binding to a receptor, named receptor for AGEs (RAGE). The soluble form of this receptor (sRAGE) has been shown to have an athero-protective role. We hypothesized the existence of a relationship between the AGE-RAGE axis and the occurrence of symptoms related to carotid atherosclerosis in nondiabetic conditions., Materials and Methods: We evaluated plasma levels of CML and sRAGE (by ELISA), and tissue levels (tAGEs and tRAGE, semiquantitatively, by immunohistochemistry) in endarterectomy carotid plaque tissue in 29 nondiabetic patients. At the time of surgery, 10 patients were asymptomatic and 19 were symptomatic., Results: Plasma levels of sRAGE were higher in symptomatic patients than in asymptomatic patients [median (interquartile range): 676 (394-858) pg mL(-1) vs. 347 (284-479) pg mL(-1), P = 0.009]. In symptomatic patients, plasma levels of sRAGE correlated positively with CML (r = 0.60, P < 0.01), C-reactive protein (CRP) (r = 0.618, P < 0.01) and fibrinogen (r = 0.522, P<0.005), while in asymptomatic patients, no correlation was observed. Although tissue and plasma levels of AGEs and RAGE did not correlate between each other, tAGEs and tRAGE were also positively correlated only in symptomatic patients (chi(2) = 8.93, P = 0.003)., Conclusions: Plasma levels of sRAGE are higher in symptomatic than asymptomatic carotid atherosclerosis. Higher levels of sRAGE in symptomatic patients may be markers of a higher degree of vascular inflammation in such patients.

Background and Objective: We performed a placebo-controlled, randomized study to address whether celecoxib or ibuprofen undermines the functional range of inhibition of platelet cyclooxygenase (COX)-1 activity by aspirin in patients with osteoarthritis and stable ischemic heart disease., Methods: Twenty-four patients who were undergoing long-term treatment with aspirin (100 mg daily) for cardioprotection were coadministered celecoxib, 200 mg twice daily, ibuprofen, 600 mg 3 times daily, or placebo for 7 days., Results: The coadministration of placebo or celecoxib did not undermine the aspirin-related inhibition of platelet COX-1 activity, as assessed by measurements of serum thromboxane B(2) (TXB(2)) levels, as well as platelet function. In contrast, a significant (P < .001) increase in serum TXB(2) level was detected on day 7 before drug administration (median, 19.13 ng/mL [range, 1-47.5 ng/mL]) and at 24 hours after the coadministration of aspirin and ibuprofen (median, 22.28 ng/mL [range, 4.9-44.4 ng/mL]) versus baseline (median, 1.65 ng/mL [range, 0.55-79.8 ng/mL]); this was associated with a significant increase in arachidonic acid-induced platelet aggregation (P < .01) and adenosine diphosphate-induced platelet aggregation (P < .05) and a decrease in the time to form an occlusive thrombus in the platelet function analyzer (P < .01). The urinary excretion of 11-dehydro-TXB(2), an index of systemic thromboxane biosynthesis, was not significantly affected by the coadministration of treatment drugs. At steady state, a comparable and persistent inhibition of lipopolysaccharide-stimulated prostaglandin E(2) generation, a marker of COX-2 activity ex vivo, was caused by ibuprofen (>or=80%) or celecoxib (>or=70%) but not placebo., Conclusions: Unlike ibuprofen, celecoxib did not interfere with the inhibition of platelet COX-1 activity and function by aspirin despite a comparable suppression of COX-2 ex vivo in patients with osteoarthritis and stable ischemic heart disease.

Several risk factors for coronary artery disease (CAD) induce atherosclerosis through endothelial activation and dysfunction, and ample evidence now suggests that the balance between production and removal of reactive oxygen species (ROS) - a condition termed oxidative stress - is implicated in such processes. A main source of ROS in vascular cells is the reduced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase system. This is a membrane-associated enzyme, composed of five subunits, catalyzing the one-electron reduction of oxygen, using NADH or NADPH as the electron donor. One of the system subunits, termed p22-phox, has a polymorphic site on exon 4, associated with variable enzyme activity. This polymorphism is generated by a point mutation (C(242)T) producing a substitution of histidine with tyrosine at position 72, which affects one of the heme binding sites essential for the NAD(P)H enzyme activity. The consequent decrease of superoxide production thus characterizes a phenotype candidate for conferring to the carrier a reduced susceptibility to CAD. At present, however, the body of evidence from current literature is not yet sufficient to confirm or exclude the hypothesis that the C(242)T polymorphism protects from CAD. The functional effects of this polymorphism and the potential and its pathophysiological consequences also need further investigation.

More than 100 years since their introduction in cardiovascular therapy, nitrates continue to be widely used in ischaemic heart disease despite incomplete knowledge of their intimate mechanism of action. Particularly, the development of a progressive attenuation of their efficacy over prolonged use (tolerance) continues to be the subject of current investigation. Newer findings point to the role of increased intracellular oxidative stress as a mechanism for tolerance and to folic acid derivatives as pharmacologic means to attenuate its development. This paper reviews nitrate mechanism of action, the history of nitrate tolerance and newer findings related to the use of folate to prevent this phenomenon.

Because of its high diffusing capacity through the alveolar-blood barrier and its high selectivity for the pulmonary vasculature, inhaled nitric oxide (NO) has been recently shown to be a viable and efficient approach to restore pulmonary NO deficiency. The most relevant applications of inhaled NO are in infants with primary pulmonary hypertension or hypoxia. In these patients, inhaled NO improves gas exchange and ventilation-perfusion matching, reduces the length of hospitalization and is without severe detrimental effects. The use of inhaled NO has also been extended to adults with pulmonary hypertension and the acute respiratory distress syndrome. In addition, recent clinical evidence supported by data from animal models, shows beneficial extra-pulmonary effects of inhaled NO, including protection against myocardial ischaemia-reperfusion injury.

The renin-angiotensin system (RAS) plays a central role in cardiovascular homeostasis. Angiotensin is the key peptide of the RAS, and exerts its influence on the heart and blood vessels both through its haemodynamic effects (via its influence on after-load and pre-load and determining coronary vasoconstriction) and through its direct cellular effects (via its actions on cell proliferation). Numerous studies in the past 10 years have demonstrated that the pharmacological inhibition of angiotensin converting enzyme (ACE), one of the two critical enzymes of the RAS, improves the outcome in patients with several cardiovascular disorders (hypertension, heart failure, ischaemic heart disease). These studies suggest a role of the RAS as a major determinant of cardiovascular risk. Recent data suggest that genetics may in turn contribute to modulating the effects of angiotensin on coronary vascular biology and ischaemia. This paper reviews the physiologic characteristics of the RAS and recent research developments related to angiotensin cell biology and pathobiology in heart disease. In particular, this review will cover the genetic aspects of RAS and their implications in cardiovascular disease.

Epidemiologic and biochemical studies have suggested an anti-inflammatory effect of n-3 fatty acids. Beneficial therapeutic effects reported from small patient groups need to be confirmed in large-cohort controlled clinical trials. There is a growing number of clinical trials of n-3 fatty acid supplementation in disease. Clinical benefits have been moderate in patients with rheumatoid arthritis and with arterial hypertension. Clearly negative results have been reported during the past 2 years for patients with lupus nephritis and for patients with psoriasis or with atopic dermatitis. Such trials have now been completed. For patients with coronary artery disease following coronary angioplasty, earlier results of a large meta-analysis, could not be confirmed. For patients with IgA-nephropathy and for patients following kidney transplantation, a clear benefit was seen in patients receiving fish oil. These promising results are currently pursued in follow-up phase III clinical trials.