Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure.

Heart failure is a complex medical syndrome that is attributed to a number of risk factors; nevertheless, its clinical presentation is quite similar among the different etiologies. Heart failure displays a rapidly increasing prevalence due to the aging of the population and the success of medical treatment and devices. The pathophysiology of heart failure comprises several mechanisms, such as activation of neurohormonal systems, oxidative stress, dysfunctional calcium handling, impaired energy utilization, mitochondrial dysfunction, and inflammation, which are also implicated in the development of endothelial dysfunction. Heart failure with reduced ejection fraction is usually the result of myocardial loss, which progressively ends in myocardial remodeling. On the other hand, heart failure with preserved ejection fraction is common in patients with comorbidities such as diabetes mellitus, obesity, and hypertension, which trigger the creation of a micro-environment of chronic, ongoing inflammation. Interestingly, endothelial dysfunction of both peripheral vessels and coronary epicardial vessels and microcirculation is a common characteristic of both categories of heart failure and has been associated with worse cardiovascular outcomes. Indeed, exercise training and several heart failure drug categories display favorable effects against endothelial dysfunction apart from their established direct myocardial benefit.

Lipoprotein(a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment.

Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) cholesterol-like particle bound to apolipoprotein(a). Increased Lp(a) levels are an independent, heritable causal risk factor for atherosclerotic cardiovascular disease (ASCVD) as they are largely determined by variations in the Lp(a) gene (LPA) locus encoding apo(a). Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), and its role adversely affects vascular inflammation, atherosclerotic lesions, endothelial function and thrombogenicity, which pathophysiologically leads to cardiovascular (CV) events. Despite this crucial role of Lp(a), its measurement lacks a globally unified method, and, between different laboratories, results need standardization. Standard antilipidemic therapies, such as statins, fibrates and ezetimibe, have a mediocre effect on Lp(a) levels, although it is not yet clear whether such treatments can affect CV events and prognosis. This narrative review aims to summarize knowledge regarding the mechanisms mediating the effect of Lp(a) on inflammation, atherosclerosis and thrombosis and discuss current diagnostic and therapeutic potentials.

Performance of Thyme Oil@Na-Montmorillonite and Thyme Oil@Organo-Modified Montmorillonite Nanostructures on the Development of Melt-Extruded Poly-L-lactic Acid Antioxidant Active Packaging Films.

Today, the use of natural biodegradable materials in the production processes is more and more adopted by industry to achieve cyclic economy targets and to improve environmental and human health indexes. Active packaging is the latest trend for food preservation. In this work, nanostructures were prepared by incorporation of thyme oil with natural natrium-montmorillonite and organo-montmorillonite with two different techniques, direct impregnation and the green evaporation-adsorption process. Such nanostructures were mixed with poly-L-lactic-acid for the first time via an extrusion molding process to develop a new packaging film. Comparisons of morphological, mechanical, and other basic properties for food packaging were carried out via XRD, FTIR, TG, SEM/EDS, oxygen and water vapor permeation, and antimicrobial and antioxidant activity for the first time. Results showed that poly-L-lactic-acid could be modified with clays and essential oils to produce improved active packaging films. The final product exhibits food odor prevention characteristics and shelf-life extension capabilities, and it could be used for active packaging. The films based on OrgMt clay seems to be more promising, while the thyme oil addition improves their behavior as active packaging. The PLLA/3%TO@OrgMt and PLLA/5%TO@OrgMt films were qualified between the tested samples as the most promising materials for this purpose.

Arterial stiffness and microvascular disease in type 2 diabetes.

BACKGROUND: The clustering of arterial stiffness with microvascular disease (MD) and their effects on the clinical outcome of patients with type 2 diabetes (T2D) remains not fully clarified. METHODS: In a prospective study of 414 patients with T2D, we investigated the prognostic value of arterial stiffness and MD for clinical outcomes. Participants were assessed for the presence of MD (ie diabetic retinopathy, nephropathy and neuropathy) and arterial stiffness by pulse wave velocity (PWV) and followed-up for a median of 30 (range 1-60) months. The primary endpoint of the study was the composite endpoint of major adverse cardiovascular events, that is, cardiovascular and non-cardiovascular mortality and non-fatal myocardial infarction/stroke. RESULTS: A total of 146 (35.3%) patients had evidence of MD at baseline. In cox regression models, MD and PWV were independently associated with the composite clinical endpoint; for MD hazard ratio (HR), 3.24, 95%CI, 1.10-9.54, P=.032, and for PWV HR, 1.20, 95%CI, 1.06-1.36, P=.004) after adjustment for traditional risk factors, and enhanced risk discrimination and reclassification. The subgroup of patients with MD and high PWV was associated with increased incidence of the composite clinical endpoint (20.9% vs 1.8% in those with no MD & low PWV, P=.001). Importantly, absence of MD at baseline was associated with no mortality events during the follow-up period. PWV at baseline was not associated with MD progression during follow-up. CONCLUSIONS: These findings support that screening for arterial stiffness and MD in the routine clinical assessment of patients with T2D may enhance prognostication and cardiovascular risk reclassification.

Association of Soluble Suppression of Tumorigenesis-2 (ST2) with Endothelial Function in Patients with Ischemic Heart Failure.

Soluble suppression of tumorigenesis-2 (sST2) has been introduced as a marker associated with heart failure (HF) pathophysiology and status. Endothelial dysfunction is a component underlying HF pathophysiology. Therefore, we examined the association of arterial wall properties with sST2 levels in patients with HF of ischemic etiology. We enrolled 143 patients with stable HF of ischemic etiology and reduced left ventricular ejection fraction (LVEF) and 77 control subjects. Flow-mediated dilation (FMD) was used to evaluate endothelial function and pulse wave velocity (PWV) to assess arterial stiffness. Although there was no significant difference in baseline demographic characteristics, levels of sST2 were increased in HF compared to the control (15.8 (11.0, 21.8) ng/mL vs. 12.5 (10.4, 16.3) ng/mL; p < 0.001). In the HF group, there was a positive correlation of sST2 levels with age (rho = 0.22; p = 0.007) while there was no association of LVEF with sST2 (rho = -0.119; p = 0.17) nor with PWV (rho = 0.1; p = 0.23). Interestingly, sST2 was increased in NYHA III [20.0 (12.3, 25.7) ng/mL] compared to patients with NYHA II (15.0 (10.4, 18.2) ng/mL; p = 0.003) and inversely associated with FMD (rho = -0.44; p < 0.001) even after adjustment for possible confounders. In patients with chronic HF of ischemic etiology, sST2 levels are increased and are associated with functional capacity. There is an inverse association between FMD and sST2 levels, highlighting the interplay between the dysfunctional endothelium and HF pathophysiologic mechanisms.

Prognostic significance of arterial stiffness and osteoprotegerin in patients with stable coronary artery disease.

BACKGROUND: Arterial stiffness and vascular calcification significantly contribute to coronary atherosclerosis progression. The prognostic value of increased arterial stiffness and vascular calcification in subjects with stable coronary artery disease (CAD) after percutaneous coronary intervention(PCI) is currently under question. MATERIALS AND METHODS: We randomly enrolled 262 patients with stable CAD 1 month after successful PCI. Carotid-femoral pulse wave velocity (PWV) was measured as a well-established index of central aortic stiffness. Osteoprotegerin (OPG) plasma levels were measured as a biomarker of vascular calcification. Patients were followed up prospectively up to 52 months. The primary endpoint was the composite of death from cardiovascular causes, myocardial infarction, stroke or hospitalization for cardiovascular causes. RESULTS: During the follow-up period, 48 patients presented the primary composite endpoint. Subjects who presented the primary endpoint, compared to subjects free of cardiovascular events, had significantly increased PWV (9.45 ± 2.19 m/s vs 8.73 ± 2.07 m/s, P = .04) and OPG levels (4.21 ± 2.19 pmol/L vs 3.18 ± 1.74 pmol/L, P = .003). Survival analysis indicated that PWV predicted adverse cardiac events MACE (Hazard ratio = 1.29 95%CI: 1.07-1.57, P = .008) independently from confounders such as age, sex, smoking habits, ejection fraction, extent of coronary artery disease, hypertension and diabetes mellitus. Interestingly, for every increase in pulse wave velocity by 1 m/s, there is an anticipated increase in the risk of major adverse cardiovascular event (MACE) by 29%. CONCLUSIONS: These findings extend the current knowledge concerning the role of arterial stiffness as powerful biomarkers in cardiovascular disease. Measurement of PWV might have a role in ascertaining prognosis and managing treatment in patients with stable CAD after PCI.

Role of local coronary blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and coronary plaque.

PURPOSE OF REVIEW: The natural history of coronary atherosclerosis is complex and atherosclerotic plaques exhibit large morphologic and functional variability within the same individual as well as over time. The purpose of this article is to review the role of blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and atherosclerosis progression. RECENT FINDINGS: Recent breakthroughs in cardiovascular imaging have facilitated in-vivo characterization of the anatomic and functional characteristics of atherosclerotic plaques and have highlighted the role of endothelial shear stress and epicardial and microvascular endothelial dysfunction in the natural history of coronary atherosclerosis. SUMMARY: There is an important need to identify individual lesions which may progress to vulnerable plaque in order to provide early therapeutic management. Evaluation of endothelial shear stress, local blood flow patterns, epicardial and microvascular endothelial dysfunction, as well as their complex associations might indicate those patients who have microvascular endothelial dysfunction and increased risk for upstream epicardial endothelial dysfunction and plaque progression. Such high-risk patients could potentially be targeted for more intensive therapeutic strategies to prevent the progression of both microvascular and epicardial atherosclerotic manifestations.

Genotyping, Platelet Activation, and Cardiovascular Outcome in Patients after Percutaneous Coronary Intervention: Two Pieces of the Puzzle of Clopidogrel Resistance.

OBJECTIVES: Individual platelet responses to antiplatelet therapy depend on genetic, cellular, and clinical factors. CYP2C19 and P2Y12 receptor polymorphisms are implicated in platelet responses to antiplatelet treatment. We aimed to evaluate the impact of CYP2C19 and C34T P2Y12 genotyping on platelet reactivity and cardiovascular outcome in patients after percutaneous coronary intervention (PCI) on clopidogrel treatment. METHODS: We enrolled 408 patients with stable coronary artery disease (CAD) receiving aspirin and clopidogrel (75 mg/day) 1 month after PCI. High on-treatment platelet reactivity was evaluated using the VerifyNow Assay in a subset of patients. CYP2C19*2 and C34T P2Y12 genotyping was performed by real-time polymerase chain reaction. The primary end point was the composite of death or hospitalization for cardiovascular causes, and patients were followed for a median time of 13 months. RESULTS: In the total study population, 37% were carriers of at least 1 CYP2C19*2 loss-of-function allele, and 53% were carriers of at least 1 C34T loss-of-function allele. Interestingly, homozygotes of the CYP2C19*2 loss-of-function allele had significantly increased P2Y12 reaction units (PRU) (p = 0.007). However, PRU did not differ between carriers and noncarriers of the C34T loss-of-function allele (p = 0.41). Moreover, carriers of CYP2C19*2 had an increased hazard ratio (HR) for the occurrence of the primary end point (for carriers HR = 1.96, 95% CI 1.05-3.66, p = 0.03), whereas the C34T polymorphism had no impact on the cardiovascular outcome (p = 0.17). Finally, PRU was associated with cardiovascular outcome even after adjustment for the presence of any reduced function allele polymorphism. CONCLUSIONS: We documented a different effect of CYP2C19 and P2Y12 receptor polymorphisms on platelet reactivity and cardiovascular outcome in CAD patients after PCI on clopidogrel treatment. Importantly, increased platelet reactivity adversely affects the cardiovascular outcome independently of the studied polymorphisms.

Different Prognostic Significance of Cardiac Troponin at Presentation and Peak Cardiac Troponin in Patients with Non-ST Segment Elevation Myocardial Infarction.

OBJECTIVES: Non-ST elevation myocardial infarction (NSTEMI) is one of the most common manifestations of acute coronary syndromes (ACS). We evaluated the prognostic role of cardiac troponin I (cTnI) at presentation and peak cardiac troponin I in patients with NSTEMI. METHODS: We consecutively enrolled 215 subjects presenting with NSTEMI. Subjects were followed up for 1 year. cTnI at presentation and the peak value of cTnI were measured. The primary end point was defined as cardiovascular death, readmission to hospital with heart failure and new ACS. RESULTS: The subjects who presented the primary end point (49 subjects) had significantly increased values of peak cTnI compared to subjects free of cardiovascular events [7.19 (2.97-21.32) vs. 4.09 (1.18-11.85) ng/l; p = 0.002]. Nevertheless, cTnI at presentation did not differ between subjects who presented the primary end point and those free of events (p = 0.39). Multivariate Cox regression analysis after adjustment for confounders revealed by the univariate analysis showed that for an increase in peak cTnI from 1 to 10 ng/l, there is a 60% anticipated increase in the relative risk to present the primary end point (p = 0.04). CONCLUSION: These findings documented the different prognostic significance of cTnI at presentation and peak cTnI in patients presenting with NSTEMI, and highlighted the importance of monitoring the levels of cTnI in this high-risk population.

Markers of Vascular Dysfunction in Hypertension.

Hypertension is a modifiable cardiovascular risk factor and displays a rapidly growing incidence due to aging and the acquisition of an unhealthy lifestyle. Hypertension is linked to the development of target organ damage in several vascular beds such as coronary arteries, peripheral, cerebral, and renal arteries. Besides, along with the presence of other cardiovascular risk factors, it aggravates vascular dysfunction due to the aging process. The mechanisms of vascular dysfunction in hypertension are complex and involve excessive salt intake and water retention, activation of neurohormonal systems, induction of endothelial dysfunction of large arteries and microcirculation, development of arterial stiffness, and complex interactions with cellular pathways of inflammation, oxidative stress, and thrombosis. The extent of vascular dysfunction in patients with hypertension can be assessed by evaluating endothelial function, measuring arterial stiffness, and testing the levels of circulating biomarkers of oxidative stress, pro-inflammatory cytokines, and thrombosis. Assessing these markers in subjects with and without hypertension could aid in identifying those at risk of vascular damage and improving risk prediction for future cardiovascular events. While several lifestyle and pharmacological therapies have shown promise in addressing vascular dysfunction in hypertension, none of these biomarkers have been established as an independent risk factor or treatment target. Therefore, in this article, we review the literature on the evidence that exists regarding the role of vascular dysfunction in the pathophysiology, diagnosis, progression, and treatment of hypertension, highlighting the lack of conclusive evidence in this field.

Impairment in Right Ventricular-Pulmonary Arterial Coupling in Overweight and Obesity.

Background: The association of obesity with right ventricular function and the interplay between right heart and pulmonary circulation is incompletely understood. We evaluate the role of obesity as a determinant of right ventricular-pulmonary artery coupling (RVAC). Methods: We retrospectively studied consecutive subjects without overt cardiovascular or pulmonary disease. Subjects were stratified according to body mass index (BMI) as normal weight, overweight, or obese. A transthoracic echocardiographic study was used to assess left and right heart functional and structural parameters. RVAC was assessed using the ratio of peak systolic velocity of the tricuspid annulus to pulmonary artery systolic pressure (PASP). Results: A total of 145 subjects were enrolled with diabetes mellitus incidence higher in obese. There was no difference in left ventricular global longitudinal strain and in PASP or markers of right ventricular systolic function based on BMI. RVAC was significantly lower in the presence of obesity (normal weight: 0.52 (0.19) cm·(sec·mmHg)-1 vs. overweight: 0.47 (0.16) cm·(sec·mmHg)-1 vs. obese: 0.43 (0.14) cm·(sec·mmHg)-1, p = 0.03), even after adjustment for confounders (ß: -0.085, 95% confidence interval: -0.163, -0.009, p = 0.029). Conclusions: Our findings highlight the relationship between metabolic impairment and RVAC, suggesting additional mechanisms for heart failure development observed in obese subjects.

Semaglutide Concurrently Improves Vascular and Liver Indices in Patients With Type 2 Diabetes and Fatty Liver Disease.

Context: The cardiovascular benefits of semaglutide are established; however, its effects on surrogate vascular markers and liver function are not known. Objective: To investigate the effects of semaglutide on vascular, endothelial, and liver function in patients with type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD). Methods: Overall, 75 consecutive subjects with T2DM and NAFLD were enrolled: 50 patients received semaglutide 1 mg (treatment group) and 25 patients received dipeptidyl peptidase 4 inhibitors (control group). All patients underwent a clinical, vascular, and hepatic examination with Fibroscan elastography at 4 and 12 months after inclusion in the study. Results: Treatment with semaglutide resulted in a reduction of Controlled Attenuation Parameter (CAP) score, E fibrosis score, NAFLD fibrosis score, Fibrosis-4 (FIB-4) score and perfused boundary region (PBR) at 4 and at 12 months (P < .05), contrary to controls. Patients treated with semaglutide showed a greater decrease of central systolic blood pressure (SBP) (-6% vs -4%, P = .048 and -11% vs -9%, P = .039), augmentation index (AIx) (-59% vs -52%, P = .041 and -70% vs -57%, P = .022), and pulse wave velocity (PWV) (-6% vs -3.5%, P = .019 and -12% vs -10%, P = .036) at 4 and at 12 months, respectively. In all patients, ΔPWV and ΔPBR were correlated with a corresponding reduction of CAP, E fibrosis, NAFLD fibrosis, and FIB-4 scores. Conclusion: Twelve-month treatment with semaglutide simultaneously improves arterial stiffness, endothelial function, and liver steatosis and fibrosis in patients with T2DM and NAFLD.

The Role of Shear Stress in Coronary Artery Disease.

Coronary artery disease is the leading cause of morbidity and mortality worldwide, especially in developed countries, with an increasing incidence in developing countries. Despite the advances in cardiology, there are yet many unanswered questions about the natural history of coronary atherosclerosis. However, it has not been fully explained why some coronary artery plaques remain quiescent over time, whereas others evolve to a high-risk, "vulnerable" plaque with a predisposition to destabilize and induce a cardiac event. Furthermore, approximately half of the patients with acute coronary syndromes demonstrate no prior symptoms of ischemia or angiographically evident disease. Recent findings have indicated that apart from cardiovascular risk factors, genetics, and other unknown factors, local hemodynamic forces, such as endothelial shear stress, blood flow patterns, and endothelial dysfunction of the epicardial and microvascular coronary arteries, are associated with the progression of coronary plaque and the development of cardiovascular complications with complex interactions. In this review article, we summarize the mechanisms that affect coronary artery plaque progression, indicating the importance of endothelial shear stress, endothelial dysfunction of epicardial and microvascular vessels, inflammation, and their complex associations, underlying in parallel the clinical perspectives of these findings.

Antithrombotic Treatment in Coronary Artery Disease.

Coronary artery disease exhibits growing mortality and morbidity worldwide despite the advances in pharmacotherapy and coronary intervention. Coronary artery disease is classified in the acute coronary syndromes and chronic coronary syndromes according to the most recent guidelines of the European Society of Cardiology. Antithrombotic treatment is the cornerstone of therapy in coronary artery disease due to the involvement of atherothrombosis in the pathophysiology of the disease. Administration of antiplatelet agents, anticoagulants and fibrinolytics reduce ischemic risk, which is amplified early post-acute coronary syndromes or post percutaneous coronary intervention; though, antithrombotic treatment increases the risk for bleeding. The balance between ischemic and bleeding risk is difficult to achieve and is affected by patient characteristics, procedural parameters, concomitant medications and pharmacologic characteristics of the antithrombotic agents. Several pharmacological strategies have been evaluated in patients with coronary artery disease, such as the effectiveness and safety of antithrombotic agents, optimal dual antiplatelet treatment schemes and duration, aspirin de-escalation strategies of dual antiplatelet regimens, dual inhibition pathway strategies as well as triple antithrombotic therapy. Future studies are needed in order to investigate the gaps in our knowledge, including special populations.

The Role of Ranolazine in Heart Failure-Current Concepts.

Heart failure is a complex clinical syndrome with a detrimental impact on mortality and morbidity. Energy substrate utilization and myocardial ion channel regulation have gained research interest especially after the introduction of sodium-glucose co-transporter 2 inhibitors in the treatment of heart failure. Ranolazine or N-(2,6-dimethylphenyl)-2-(4-[2-hydroxy-3-(2-methoxyphenoxy) propyl] piperazin-1-yl) acetamide hydrochloride is an active piperazine derivative which inhibits late sodium current thus minimizing calcium overload in the ischemic cardiomyocytes. Ranolazine also prevents fatty acid oxidation and favors glycose utilization ameliorating the "energy starvation" of the failing heart. Heart failure with preserved ejection fraction is characterized by diastolic impairment; according to the literature ranolazine could be beneficial in the management of increased left ventricular end-diastolic pressure, right ventricular systolic dysfunction and wall shear stress which is reflected by the high natriuretic peptides. Fewer data is evident regarding the effects of ranolazine in heart failure with reduced ejection fraction and mainly support the control of the sodium-calcium exchanger and function of sarcoendoplasmic reticulum calcium adenosine triphosphatase. Ranolazine's therapeutic mechanisms in myocardial ion channels and energy utilization are documented in patients with chronic coronary syndromes. Nevertheless, ranolazine might have a broader effect in the therapy of heart failure and further mechanistic research is required.

Novel Biomarkers and Their Role in the Diagnosis and Prognosis of Acute Coronary Syndrome.

The burden of cardiovascular diseases and the critical role of acute coronary syndrome (ACS) in their progression underscore the need for effective diagnostic and prognostic tools. Biomarkers have emerged as crucial instruments for ACS diagnosis, risk stratification, and prognosis assessment. Among these, high-sensitivity troponin (hs-cTn) has revolutionized ACS diagnosis due to its superior sensitivity and negative predictive value. However, challenges regarding specificity, standardization, and interpretation persist. Beyond troponins, various biomarkers reflecting myocardial injury, neurohormonal activation, inflammation, thrombosis, and other pathways are being explored to refine ACS management. This review article comprehensively explores the landscape of clinically used biomarkers intricately involved in the pathophysiology, diagnosis, and prognosis of ACS (i.e., troponins, creatine kinase MB (CK-MB), B-type natriuretic peptides (BNP), copeptin, C-reactive protein (CRP), interleukin-6 (IL-6), d-dimers, fibrinogen), especially focusing on the prognostic role of natriuretic peptides and of inflammatory indices. Research data on novel biomarkers (i.e., endocan, galectin, soluble suppression of tumorigenicity (sST2), microRNAs (miRNAs), soluble oxidized low-density lipoprotein receptor-1 (sLOX-1), F2 isoprostanes, and growth differentiation factor 15 (GDF-15)) are further analyzed, aiming to shed light on the multiplicity of pathophysiologic mechanisms implicated in the evolution of ACS. By elucidating the complex interplay of these biomarkers in ACS pathophysiology, diagnosis, and outcomes, this review aims to enhance our understanding of the evolving trajectory and advancements in ACS management. However, further research is necessary to establish the clinical utility and integration of these biomarkers into routine practice to improve patient outcomes.

The prognostic role of galectin-3 and endothelial function in patients with heart failure.

BACKGROUND: Heart failure (HF) is nowadays classified as HF with reduced ejection fraction (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF). Endothelial dysfunction (assessed by flow-mediated dilatation [FMD]), increased arterial stiffness (assessed by carotid-femoral pulse-wave velocity [PWV]), and galectin-3, a biomarker of myocardial fibrosis, have been linked to major adverse cardiovascular events (MACE) in patients with ischemic HF. METHODS: In this study we prospectively enrolled 340 patients with stable ischemic HF. We assessed the brachial artery FMD, carotid-femoral PWV, and galectin-3 levels, and patients were followed up for MACE according to HF group. RESULTS: Interestingly, the FMD values exhibited a stepwise improvement according to left ventricular ejection fraction (LVEF) (HFrEF: 4.74 ± 2.35% vs. HFmrEF: 4.97 ± 2.81% vs. HFpEF: 5.94 ± ± 3.46%, p = 0.01), which remained significant after the evaluation of possible confounders including age, sex, cardiovascular risk factors, and number of significantly stenosed epicardial coronary arteries (b coefficient: 0.990, 95% confidence interval: 0.166-1.814, p = 0.019). Single-vessel coronary artery disease was more frequent in the group of HFpEF (HFrEF: 56% vs. HFmrEF: 64% vs. HFpEF: 73%, p = 0.049). PWV did not display any association with LVEF. Patients who presented MACE exhibited worse FMD values (4.51 ± 2.35% vs. 5.32 ± 2.67%, p = 0.02), and the highest tertile of galectin-3 was linked to more MACEs (36% vs. 5.9%, p = 0.01). CONCLUSIONS: Flow-mediated dilatation displayed a linear improvement with LVEF in patients with ischemic HF. Deteriorated values are associated with MACE. Higher levels of galectin-3 might be used for risk stratification of patients with ischemic HF.

"Heart failure in COVID-19 patients: Critical care experience": A letter to the editor.

Coronavirus disease 2019 (COVID-19) is associated with poor cardiovascular outcomes in patients with heart failure (HF) of all categories of ejection fraction (EF), but mainly in patients with HF with reduced EF. Moreover, cardiac transplant patients exhibit worse cardiovascular prognosis, high mortality, and more admissions to the intensive care unit. In general, COVID-19 seems to de-teriorate the clinical status of HF and favors the development of acute respiratory distress syndrome and multiorgan failure, especially in the presence of cardiovascular comorbidities such as diabetes mellitus, kidney dysfunction, and older age. COVID-19 may induce new-onset HF with complex mechanisms that involve myocardial injury. Indeed, myocardial injury comprises a large category of detrimental effects for the myocardium, such as myocardial infarction type 1 or type 2, Takotsubo cardiomyopathy, microvascular dysfunction and myocarditis, which are not easily distinguished by HF. The pathophysiologic mechanisms mainly involve direct myocardial damage by severe acute respiratory syndrome coronavirus 2, cytokine storm, hypercoagulation, inflammation, and endothelial dysfunction. The proper management of patients with COVID-19 involves careful patient evaluation and ongoing monitoring for complications such as HF.

Association of Growth Differentiation Factor 15 with Arterial Stiffness and Endothelial Function in Subpopulations of Patients with Coronary Artery Disease: A Proof-of-Concept Study.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) is a biomarker belonging to the transforming growth factor-beta cytokine superfamily, which is linked to many pathological conditions, including inflammation and myocardial injury. Pulse wave velocity (cfPWV) and augmentation index (AIx) are indices of arterial stiffness, which are associated with the severity of coronary artery disease (CAD). Flow-mediated dilatation (FMD) is a well-studied surrogate marker of endothelial-dependent dysfunction and systemic inflammation. OBJECTIVE: In this proof-of-concept study, we aimed to investigate the relationship between circulating GDF-15, endothelial dysfunction, and indices of arterial stiffness in different settings of coronary artery disease and myocardial injury. METHODS: In this cross-sectional single-center study, we enrolled patients (n = 22) after interventional treatment for acute myocardial infarction (AMI), patients (n = 11) admitted with chest pain and elevated cardiac enzymes but without evidence of obstructing CAD (MI-NOCAD) in percutaneous coronary angiography (CAG), and patients (n = 20) who underwent CAG according to indications without evident obstructive CAD in CAG (NOCAD). FMD was assessed at the brachial artery. AIx of the central aortic pressure and cfPWV were estimated by applanation tonometry at the radial and carotid-femoral site, respectively, with a validated acquisition system (Sphygmo- Cor, AtCor Medical, Sydney (NSW), Australia). ELISA was used to determine circulating GDF- 15 serum levels (R&D Systems, Minneapolis, MN). Clinical and demographic data and values of routine biochemical biomarkers were obtained. The highest high-sensitive cardiac Troponin I (hsTpnI) value during hospitalization was also recorded. Left ventricular ejection fraction (LVEF) was assessed with a transthoracic echocardiogram. RESULTS: Patients with AMI were older, had worse LVEF, higher values of hsTpnI and increased circulating GDF-15 levels. Importantly, AMI patients had increased cfPWV values, deteriorated AIx values, blunted FMD and worse serum creatinine levels compared to MI-NOCAD and NOCAD patients, respectively, whereas MI-NOCAD and NOCAD did not differ from each other significantly on these biomarkers. Both AMI and MI-NOCAD patients presented a higher but comparable white blood cell count than NOCAD patients. A strong linear correlation between GDF-15 and cfPWV, hsTpnI, AIx, white blood cell count and creatinine but not with FMD was demonstrated in the general study population. CONCLUSION: This proof-of-concept study showed that higher circulating levels of GDF-15, an inflammatory biomarker, were associated significantly with increased arterial stiffness only in AMI patients, whereas elevated GDF-15 demonstrated a linear relationship with the severity of the myocardial injury.

The effect of allopurinol on cardiovascular outcomes in patients with type 2 diabetes: a systematic review.

BACKGROUND: Cardiovascular disease (CVD) remains the main cause of death in patients with type 2 diabetes (T2D). Although hyperuricemia has been associated with multiple CV complications, it is not officially recognized as a target parameter for CVD risk reduction. AIM: To systematically review the literature in order to determine whether treating hyperuricemia with allopurinol in patients with T2D reduces CVD risk. METHODS: A thorough literature search in the PubMed, CENTRAL, and EMBASE databases from inception to August 2022 was performed. After application of selection criteria, 6 appropriate studies were identified. RESULTS: Detailed analysis of the data derived indicated that there is an association between allopurinol treatment and CV benefits, resulting in a reduced risk of CVD events and mortality rates. This association can be attributed mainly to the reduction of inflammation and oxidative burden, as well as to the improvement of glycemic and lipid profiles. CONCLUSIONS: This systematic review provides evidence that allopurinol may reduce CVD risk in patients with T2D. Randomized, placebo-controlled trials should be performed in order to confirm these findings and identify specific subgroups of patients who will benefit most.