Stem cell genes in atheromatosis: The role of Klotho, HIF1α, OCT4, and BMP4.

During fetal development, shear stress regulates several aspects of vascular development. Alterations in signaling pathways due to disturbed flow in atheroprone regions closely mirror phenomena seen during embryogenesis. This flow-dependent dysregulation of developmental genes appears to promote atherogenesis by mediating inflammatory phenomena, cell cycle progression, apoptosis, cell migration, and oxidative stress. Indeed, several stem cell genes have been implicated in vascular health and atheromatosis. Klotho is key in maintaining endothelial integrity, reducing oxidative stress, and sustaining endothelial nitric oxide production. In atherosclerotic lesions, OCT4 mediates the conversion of vascular smooth muscle cells from contractile to a de-dedifferentiated proliferative phenotype with phagocytic ability. HIF1α drives atherosclerotic plaque progression by promoting intraplaque angiogenesis. BMP4 promotes osteochondrogenic development and arterial calcification. Strategic extracellular matrix changes are also seen during the various phases of atherosclerosis. The aforementioned conceptual framework explains how proatherogenic inflammation develops in response to low shear stress. In the present review, we explored the effect of cardinal atheroprotective (Klotho, OCT4) and proatherogenic (HIF1α, BMP4) genes in mediating proatherogenic inflammation.

Angiotensin Receptor Neprilysin Inhibitors-2019 Update.

An abundance of new data regarding the use of the novel drug compound sacubitril/valsartan in chronic heart failure (CHF) patients is published every year since the initial publication of the PARADIGM-HF study in 2014. This review summarises the most recent evidence (2019 and onwards) of sacubitril/valsartan in CHF patients as well as provides a critical appraisal of these data. New data are grouped in categories such as real-world data, randomised controlled trials, surrogate end-points, cost-effectiveness, use of sacubitril/valsartan as an anti-hypertensive treatment, effect on diuretic dosing and implementation of this novel compound in other populations. This review of recent literature identified important messages such as early initiation during index hospitalisation or immediately post-discharge, barriers against implementation of this novel treatment modality, analytical issues regarding measuring natriuretic peptides in patients under treatment and extrapolated use of sacubitril/valsartan in other than PARADIGM-HF populations. This update may serve as a very helpful evidence-based resource for practising clinicians, future research planning and health-related policy makers.

The Incidence and the Prognostic Impact of Acute Kidney Injury in Acute Myocardial Infarction Patients: Current Preventive Strategies.

Acute kidney injury (AKI) is one of the most common complications during hospitalization in various clinical settings. The goal of this review was to assess the incidence of AKI in acute myocardial infarction patients (AMI), how this incidence is affected by the diverse definitions, and if there is variability in the reported rates over recent years. Additionally, we sought to appraise the impact of AKI on short- and long-term prognosis of these patients. Finally, we report on the current preventive measures as they are suggested in the current guidelines of various societies, we comment on the evidence that support them, and we review the literature for other proposed therapeutic strategies, which either failed to prove their efficacy or they are not adequately confirmed yet. Due to the heterogeneity in AKI definition and in the population studied of the published data, the incidence of AKI ranged from 5.2 to 59%. A recent meta-analysis reported a median value of 15.8%. All studies assessing AKI-related prognosis in AMI patients suggested that presence of AKI has detrimental effect on patients prognosis, raising mortality two- to threefold not only during the 30 first days but also during the first year after the acute event. Various treatment modalities have been proposed for prevention of AKI in AMI patients; however, the majority of them failed to prove their efficacy in the clinical trial arena. Hydration, use of iso- or low-osmolar agents at the lowest possible dose during coronary interventions, and use of statins have been proposed among others. Nonetheless, the prevalence of AKI after an AMI still remains high today and therefore it is crucial for the practicing physician to be aware of its presence and for the scientific community to identify novel measures for a more efficacious prevention.

Novel echocardiographic prognostic markers for cardiac tamponade in patients with large malignant pericardial effusions: A paradigm shift from flow to tissue imaging.

BACKGROUND: With this study, we sought to investigate the prognostic value of echocardiographic tissue imaging markers in predicting tamponade among patients with large malignant pericardial effusion compared to routinely used echocardiographic signs. METHODS: A total of 96 consecutive patients with large malignant pericardial effusion, not in clinical cardiac tamponade, underwent an echocardiographic examination and were prospectively assessed for 1 month. Clinically evident cardiac tamponade was considered as the study endpoint. The prognostic performance of tricuspid valve annular plane systolic excursion (TAPSE) and peak systolic annular velocity at the lateral margin of the tricuspid valve annulus (STV ) was assessed and compared to routinely used imaging signs. RESULTS: During follow-up, 37 patients (39%) developed clinically evident cardiac tamponade. TAPSE (area under the curve [AUC] 0.958) and STV (AUC 0.948) had excellent predictive accuracy for tamponade. Multivariate analysis showed that TAPSE (Hazard ratio [HR] 3.03; 95% CI 1.60-5.73, P=.001) and STV (HR 1.17; 95% CI 1.05-1.29, P=.005) remained independent significant predictors of cardiac tamponade. Reclassification analysis and decision curve analysis showed additive prognostic value and adjunct clinical benefit of these markers when added to a recently published triage pericardiocentesis score. CONCLUSION: Echocardiographic tissue imaging markers such as TAPSE and STV are characterized by an excellent prognostic ability for development of cardiac tamponade and better prognostic value compared to routine echocardiographic signs in patients with large malignant pericardial effusion. Incorporating these markers to a recent triage pericardiocentesis score resulted in additional prognostic value and increased clinical benefit.

Contrast-Induced Acute Kidney Injury: An Update.

Contrast-induced acute kidney injury (CI-AKI) is defined as an abrupt deterioration in renal function associated with the administration of iodinated contrast media. This type of acute kidney injury is frequently encountered as a complication of percutaneous coronary intervention (PCI) and is associated with adverse short- and long-term outcomes including mainly mortality, cardiovascular morbidity and prolongation of hospitalization. The incidence of CI-AKI after PCI ranges from 2 to 20 % according to baseline kidney function. It may also range according to the clinical setting, being higher after emergency PCI. The primary manifestation is a small decline in kidney function, occurring 1 to 3 days after the procedure. Kidney function usually returns to preexisting levels within 7 days. Incidence of acute renal failure requiring dialysis following PCI is rare (<1 %). The present article aims to review up-to-date published data concerning diagnosis, definition, epidemiology and prognosis of this novel in-hospital epidemic.

Prevention of Contrast-Induced Acute Kidney Injury: an Update.

Contrast-induced acute kidney injury (CI-AKI) is a common complication of intravascular administration of contrast media used in coronary angiography, percutaneous coronary intervention and other diagnostic and interventional procedures. This review article aims at summarizing the published literature regarding the prevention of CI-AKI, by focusing on available high-quality meta-analyses addressing this matter. Apart from adequate hydration, a number of pharmacologic agents have been proposed as potential candidates to be included in the routine preparation, prior to the patient's arrival in the cardiac catheterization laboratory. Among them, statins and N-acetylcysteine appear to be the most extensively studied ones. Throughout this article we present the available data on CI-AKI prevention and provide a critical clinical appraisal, as well as a summary of currently available guidelines.

An Armored Heart: A Diagnosis Hidden in Plain Sight.

We report a case of an overtly symptomatic patient with delayed diagnosis of massive (>25-mm thickness), circular, constrictive pericarditis. Our patient underwent a successful surgical pericardiectomy-a high-risk procedure-revealing an armored heart, with an impressive clinical improvement. Diagnosis of constrictive pericarditis is challenging and requires high clinical suspicion.

Coronary Artery Ectasia as an Autoimmune Disease Paradigm in a Cross-Sectional Case-Control Study.

Coronary artery ectasia (CAE) is defined as local or generalized aneurysmal dilatation of the coronary arteries. CAE likely represents an exaggerated form of excessive vascular wall remodeling in different clinical settings such as atherosclerosis, vasculitides, connective tissue disorders, hereditary collagen defects, bacterial infections, and congenital malformations. In the present case-control study, we investigated whether the incidental finding of CAE in patients who undergo coronary angiography is associated with presence of autoimmune reactivity. From 2019 to 2022, we identified all consecutive patients with CAE (n = 319) on elective or emergency coronary angiography (n = 7,458). We furthermore included 90 patients with nonectatic coronary arteries as a control group. Antinuclear antibody (ANA) titer was measured in both groups using the indirect immunofluorescence method from peripheral blood samples. The prevalence of CAE in our study cohort was 4.3%. Among patients with CAE (n = 319), presence of positive Antinuclear antibody (ANA) titer was identified in 128 patients (40%). Only 18 patients (20%) from the control group had positive ANA titer. There was a statistically significant greater percentage of patients with positive ANA titer among patients with CAE than among controls (chi-square = 12.39; p <0.001), with an odds ratio of 2.68. Among patients with CAE, there is an increased prevalence of positive ANA titer, suggesting an underlying autoimmune disease. Screening for autoimmune reactivity could be a reasonable diagnostic strategy in patients who undergo coronary angiography with an incidental finding of coronary ectasia because the number needed to screen for positive ANA titer in this subgroup of patients is only 5.

Plasma leptin and adiponectin concentrations in healthy, non-obese children.

BACKGROUND: Alterations in plasma leptin and adiponectin concentrations are associated with an adverse metabolic profile in obese children. OBJECTIVE: To simultaneously assess multiple factors with possible effects on plasma leptin and adiponectin concentrations in healthy, non-obese children. SUBJECTS: We studied 170 healthy non-obese children (86 males, age 10+1.5 years), with available medical records from birth. METHODS: Plasma leptin and adiponectin concentrations were assessed by immunoassay. The ratio of current weight/birth weight (WBWR) was used as an index of children growth from birth. Children's intensity of physical activity and parental characteristics were also assessed. RESULTS: Leptin was positively associated with WBWR (p<0.0001); parental smoking (analysis of variance, ANOVA; p-=0.03) and parental obesity (ANOVA; p<0.001) were negatively associated with breastfeeding (p<0.01) and children's access to exercise (p<0.0001). Adiponectin was negatively associated with WBWR (p<0.0001) and parental smoking (p=0.04), with an additive negative effect of parental smoking status and parental obesity on children's adiponectin levels (ANOVA; p=0.02). CONCLUSIONS: Children's and parental factors are related and could possibly influence leptin and adiponectin concentrations in healthy non-obese children. Early preventive strategies that target both children and parents could improve the profile of adipocytokine in these children.

Slow Coronary Flow: Pathophysiology, Clinical Implications, and Therapeutic Management.

Coronary slow flow (CSF) is an angiographic phenomenon with specific epidemiologic characteristics, associated clinical presentation, and prognosis. Although patients with CSF are diagnosed as having "normal coronary arteries," it seems appropriate to consider CSF as a distinct disease entity requiring specific treatment. The patient with CSF is usually male, smoker, obese, with a constellation of risk factors suggestive of metabolic syndrome. Unstable angina is the most common clinical presentation, with recurrent episodes of chest pain at rest associated with electrocardiographic changes often requiring readmission and reevaluation. Regarding definition and diagnosis, interventionists should first exclude possible "secondary" causes of CSF, use objective means for definition and then differentiate from other similar conditions such as microvascular angina. Although the phenomenon is generally benign, patients with CSF are severely symptomatic with recurrent episodes of chest pain and poor quality of life. Furthermore, acute presentation of the phenomenon is commonly life-threatening with ventricular tachyarrhythmias, conduction abnormalities, or cardiogenic shock. Acute treatment of CSF includes, but is not restricted to, intracoronary infusion of dipyridamole, adenosine, or atropine. Chronic management of patients with CSF encompasses dipyridamole, diltiazem, nebivolol, telmisartan, and/or atorvastatin associated with amelioration of angina symptoms, improved quality of life, and good prognosis.

Total coronary occlusion in non ST elevation myocardial infarction: Time to change our practice?

Based on 12­lead electrocardiogram (ECG) findings, myocardial infarction (MI) patients are dichotomized to ST-elevation MI (STEMI) and non ST-elevation MI (NSTEMI) in terms of management strategy. NSTEMI patients are increasing in numbers worldwide, among which an approximately 30% are associated with a total occlusion of a coronary artery. This review summarizes recent evidence in epidemiology, clinical, laboratory, ECG and prognostic characteristics of this NSTEMI sub-group. Patients with a diagnosis of NSTEMI and a total occluded coronary artery (TOCA) represent a sub-group of NSTEMI patients with total occlusion of coronary arteries and associated high-risk that are frequently not managed according to a STEMI-like pathway. The present review echoes a call for action in changing our everyday clinical practice. Therefore, we propose a new triage algorithm by which recognition of high-risk features in NSTEMI patients is central in order to identify STEMI 'equivalents' among NSTEMI patients in terms of similar pathology and high-risk who may benefit from immediate invasive strategy (<2 h).

Effect of Sacubitril/Valsartan on circulating catecholamine levels during a 6-month follow-up in heart failure patients. Timeo Danaos et dona ferentes?

We assessed the effect of Sacubitril/Valsartan on circulating catecholamine levels in patients with HF in an observational cohort study. We included 108 consecutive HF patients attending our HF Outpatients Clinic who were eligible to Sacubitril/Valsartan according to the PARADIGM-HF inclusion and exclusion criteria. We furthermore included 58 stable HF patients under optimal medical therapy as a control group. Norepinephrine and epinephrine were measured with immunoradiometric assays at baseline, at 3- and at 6-month time follow-up. Compared to baseline levels there was no change at three months in epinephrine (p = 0.177) or norepinephrine (p = 0.815) concentrations. At 6 months norepinephrine remained unchanged (p = 0.359). However, at 6 months we observed a significant increase in epinephrine levels compared to baseline [66 pg/mL (37-93) vs 38 pg/mL (18-74), p < 0.001]. In the control group no change was observed in epinephrine levels compared to baseline (p = 0.838). This study is the first to report on the effect of the new drug Sacubitril/Valsartan on circulating catecholamine levels in HF patients. Our data show a significant increase in epinephrine levels during a 6 month follow up in stable HF patients.

ISCHEMIA trial: Is there enough evidence to drive a change in clinical practice? A critical appraisal.

Recently, ISCHEMIA trial was published in order to determine the effect of adding cardiac catheterization and revascularization when feasible to medical therapy in patients with stable CAD and moderate or severe ischemia. Over a median of 3.2 years of follow-up, among patients with stable CAD who had moderate or severe ischemia on stress testing, an initial invasive strategy, as compared with an initial conservative strategy, did not reduce the rates of the primary or key secondary composite outcomes. The primary outcome was the composite of death from cardiovascular causes, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. The key secondary outcomes were the composite of death from cardiovascular causes or MI and angina-related quality of life. Patients in the invasive-strategy group had more procedural myocardial MIs, and they had fewer spontaneous infarctions during follow-up. The incidence of death from any cause was low and similar in the two groups. However, the ISCHEMIA trial was challenging to implement, event rates were low and enrollment fell behind initial milestones. Furthermore, power of the study was compromised, composite end-point definition as well as definitions of crucial individual components were changed amid study progression. There was a "heterobaric" combined end-point with procedural MIs favoring the conservative arm and spontaneous MIs favoring the invasive arm. Finally, the duration of reported follow-up showed signals that findings may shift in favor of invasive treatment and results were sensitive to definition and type of MIs. Therefore, we believe that it is premature to change clinical practice in view of the results of ISCHEMIA trial. As stable CAD patients is a vastly heterogenous patient group, it may be prudent to apply common clinical judgement and individual decision-making according to current guidelines before changing our management strategies.

Comparison of novel LDL cholesterol equations in myocardial infarction patients: Clinical impact on risk re-classification and lipid treatment goals on secondary prevention.

BACKGROUND AND AIMS: Numerous low-density lipoprotein (LDL) calculating equations for more accurate estimation have emerged. With the present study, we assessed the clinical impact of implementing novel equations in terms of risk reclassification and LDL treatment goals in myocardial infarction (MI) patients. METHODS: This was a post-hoc analysis of a prospective acute MI cohort study. We enrolled 805 consecutive patients presenting with acute MI. Patients with high triglyceride levels (>400 mg/dL) were excluded. In the remaining 773 acute MI patients, LDL cholesterol levels were calculated using 12 different equations including the Friedewald equation. Each patient was categorized into a 5-scale risk strata scheme according to baseline LDL cholesterol levels. Moreover, ΔLDL cholesterol (change in LDL cholesterol levels to achieve the <55 mg/dL LDL treatment goal) was calculated for each patient. RESULTS: Mean levels and distribution of LDL cholesterol were significantly different compared to those derived from the Friedewald equation. Net reclassification improvement (NRI) analysis, as well as heat maps, showed that this re-categorization had no significant impact on prognostic terms (NRI ranged from -6.1% to 5.9% with p values > 0.05 for each comparison). Statistically significant differences were observed in ΔLDL cholesterol levels between each one of the novel equations and the Friedewald equation. CONCLUSIONS: Novel LDL cholesterol calculating equations are not associated with a clinically significant risk re-classification in MI patients. In addition, use of these novel equations may have an impact on assessing potency of hypolipidemic therapy use in secondary prevention as far as succeeding lipid treatment goals in MI patients.

Application of 17 Contrast-Induced Acute Kidney Injury Risk Prediction Models.

INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is a frequent complication of percutaneous coronary interventions (PCI). Various groups have developed and validated risk scores for CI-AKI. Although the majority of these risk scores achieve an adequate accuracy, their usability in clinical practice is limited and greatly debated. OBJECTIVE: With the present study, we aimed to prospectively assess the diagnostic performance of recently published CI-AKI risk scores (up to 2018) in a cohort of patients undergoing PCI. METHODS: We enrolled 1,247 consecutive patients (80% men, mean age 62 ± 10 years) treated with elective or urgent PCI. For each patient, we calculated the individual CI-AKI risk score based on 17 different risk models. CI-AKI was defined as an increase of ≥25% (liberal) or ≥0.5 mg/dL (strict) in pre-PCI serum creatinine 48 h after PCI. RESULTS: CI-AKI definition and, therefore, CI-AKI incidence have a significant impact on risk model performance (median negative predictive value increased from 85 to 99%; median c-statistic increased from 0.516 to 0.603 using more strict definition criteria). All of the 17 published models were characterized by a weak-to-moderate discriminating ability mainly based on the identification of "true-negative" cases (median positive predictive value 19% with liberal criterion and 3% with strict criterion). In none of the models, c-statistic was >0.800 with either CI-AKI definition. Novel, different combinations of the >35 independent variables used in the published models either by down- or by up-scaling did not result in significant improvement in predictive performance. CONCLUSIONS: The predictive ability of all models was similar and only modest, derived mainly by identifying true-negative cases. A new approach is probably needed by adding novel markers or periprocedural characteristics.

Oxidised low-density lipoprotein and arterial function in beta-thalassemia major.

OBJECTIVES: Vascular abnormalities such as endothelial dysfunction and arterial stiffness have been described in patients with beta-thalassemia major (beta-TM). Increased concentrations of oxidised low-density lipoprotein cholesterol (oxLDL) have been observed in those patients, but possible associations between oxLDL and arterial function in beta-TM have not been defined. METHODS: Twenty-six patients (11 males) with beta-TM (age 23 +/- 4 yr) and 30 age and gender-matched healthy subjects were studied. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (PWVc-f) using applanation tonometry; brachio-radial artery stiffness was assessed by carotid-radial PWV (PWVc-r). Flow-mediated dilatation (FMD) of the brachial artery and oxLDL (ELISA) were also measured. RESULTS: Patients with beta-TM had higher oxLDL levels (68.6 +/- 13.7 mU/mg vs. 50.0 +/- 12.6 mU/mg, P = 0.005), decreased FMD (3.6 +/- 2.5% vs. 7.3 +/- 3.5%, P = 0.001) and higher PWVc-f compared with controls (8.4 +/- 1.7 vs. 7.2 +/- 1.1. P < 0.002). FMD of the brachial artery was negatively associated with OxLDL concentrations in simple linear (r(2) = -0.25, P = 0.001) and multiple linear regression analysis (beta = -0.242, P = 0.03, R(2) = 0.43, P = 0.0002). PWVc-r was positively associated with OxLDL (r(2) = 0.23, P = 0.003) and showed a tendency in multiple regression analysis (beta = 0.18, P = 0.05). PWVc-r and FMD were also significantly correlated (beta = -0.213, P = 0.04) in beta-TM patients. There was no association between oxLDL and PWVc-f. CONCLUSION: An association between oxLDL, arterial elastic properties and endothelial dysfunction of muscular arteries was found. OxLDL may represent a contributing factor for the vascular manifestations described in beta-TM patients.

Cardiovascular Implications of Sphingomyelin Presence in Biological Membranes.

Sphingomyelin (SM) is a type of sphingolipid found within plasma, cellular membranes and plasma lipoproteins. Here we highlight the basic biochemical features of SMs and their role in biological membranes. We further discuss evidence of the association between SM and cardiovascular diseases such as atherosclerosis, valvular disease, heart failure and diabetes mellitus.

Serum calcification propensity is independently associated with disease activity in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with severe cardiovascular complications. The T50 score is a novel functional blood test quantifying calcification propensity in serum. High calcification propensity (or low T50) is a strong and independent determinant of all-cause mortality in various patient populations. METHODS: A total of 168 patients with ≥ 4 American College of Rheumatology (ACR) diagnostic criteria from the Swiss Systemic lupus erythematosus Cohort Study (SSCS) were included in this analysis. Serum calcification propensity was assessed using time-resolved nephelometry. RESULTS: The cohort mainly consisted of female (85%), middle-aged (43±14 years) Caucasians (77%). The major determinants of T50 levels included hemoglobin, serum creatinine and serum protein levels explaining 43% of the variation at baseline. Integrating disease activity (SELENA-SLEDAI) into this multivariate model revealed a significant association between disease activity and T50 levels. In a subgroup analysis considering only patients with active disease (SELENA-SLEDAI score ≥4) we found a negative association between T50 and SELENA-SLEDAI score at baseline (Spearman's rho -0.233, P = 0.02). CONCLUSIONS: Disease activity and T50 are closely associated. Moreover, T50 levels identify a subgroup of SLE patients with ongoing systemic inflammation as mirrored by increased disease activity. T50 could be a promising biomarker reflecting SLE disease activity and might offer an earlier detection tool for high-risk patients.