Cardiopulmonary Exercise Testing in Patients with Heart Failure: Impact of Gender in Predictive Value for Heart Transplantation Listing.

BACKGROUND: Exercise testing is key in the risk stratification of patients with heart failure (HF). There are scarce data on its prognostic power in women. Our aim was to assess the predictive value of the heart transplantation (HTx) thresholds in HF in women and in men. METHODS: Prospective evaluation of HF patients who underwent cardiopulmonary exercise testing (CPET) from 2009 to 2018 for the composite endpoint of cardiovascular mortality and urgent HTx. RESULTS: A total of 458 patients underwent CPET, with a composite endpoint frequency of 10.5% in females vs. 16.0% in males in 36-month follow-up. Peak VO2 (pVO2), VE/VCO2 slope and percent of predicted pVO2 were independent discriminators of the composite endpoint, particularly in women. The International Society for Heart Lung Transplantation recommended values of pVO2 ≤ 12 mL/kg/min or ≤14 if the patient is intolerant to ß-blockers, VE/VCO2 slope > 35, and percent of predicted pVO2 ≤ 50% showed a higher diagnostic effectiveness in women. Specific pVO2, VE/VCO2 slope and percent of predicted pVO2 cut-offs in each sex group presented a higher prognostic power than the recommended thresholds. CONCLUSION: Individualized sex-specific thresholds may improve patient selection for HTx. More evidence is needed to address sex differences in HF risk stratification.

Age Differences in Cardiopulmonary Exercise Testing Parameters in Heart Failure with Reduced Ejection Fraction.

Background and Objectives: Cardiopulmonary exercise testing (CPET) is a cornerstone of risk stratification in heart failure with reduced ejection fraction (HFrEF). However, there is a paucity of evidence on its predictive power in older patients. The aim of this study was to evaluate the prognostic power of current heart transplantation (HTx) listing criteria in HFrEF stratified according to age groups. Materials and Methods: Consecutive patients with HFrEF undergoing CPET between 2009 and 2018 were followed-up for cardiac death and urgent HTx. Results: CPET was performed in 458 patients with HFrEF. The composite endpoint occurred in 16.8% of patients ≤50 years vs. 14.1% of patients ≥50 years in a 36-month follow-up. Peak VO2 (pVO2), VE/VCO2 slope and percentage of predicted pVO2 were strong independent predictors of outcomes. The International Society for Heart and Lung Transplantation thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to ß-blockers), VE/VCO2 slope > 35 and percentage of predicted pVO2 ≤ 50% presented a higher overall diagnostic effectiveness in younger patients (≤50 years). Specific thresholds for each age subgroup outperformed the traditional cut-offs. Conclusions: Personalized age-specific thresholds may contribute to an accurate risk stratification in HFrEF. Further studies are needed to address the gap in evidence between younger and older patients.

Cardiopulmonary Exercise Testing in the Age of New Heart Failure Therapies: Still a Powerful Tool?

BACKGROUND: New therapies with prognostic benefits have been recently introduced in heart failure with reduced ejection fraction (HFrEF) management. The aim of this study was to evaluate the prognostic power of current listing criteria for heart transplantation (HT) in an HFrEF cohort submitted to cardiopulmonary exercise testing (CPET) between 2009 and 2014 (group A) and between 2015 and 2018 (group B). METHODS: Consecutive patients with HFrEF who underwent CPET were followed-up for cardiac death and urgent HT. RESULTS: CPET was performed in 487 patients. The composite endpoint occurred in 19.4% of group A vs. 7.4% of group B in a 36-month follow-up. Peak VO2 (pVO2) and VE/VCO2 slope were the strongest independent predictors of mortality. International Society for Heart and Lung Transplantation (ISHLT) thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to ß-blockers) and VE/VCO2 slope > 35 presented a similar and lower Youden index, respectively, in group B compared to group A, and a lower positive predictive value. pVO2 ≤ 10 mL/kg/min and VE/VCO2 slope > 40 outperformed the traditional cut-offs. An ischemic etiology subanalysis showed similar results. CONCLUSION: ISHLT thresholds showed a lower overall prognostic effectiveness in a contemporary HFrEF population. Novel parameters may be needed to improve risk stratification.

Threading the needle: a case report of double-wiring technique and double intracoronary imaging guidance for a multifenestrated iatrogenic coronary artery dissection.

Background: Iatrogenic coronary artery dissection (ICAD) may represent a serious complication of percutaneous coronary intervention. Stenting the dissected segment is recommended in large dissections with compromised distal blood flow, although wiring the true lumen is often difficult. Case summary: A 64-year-old woman with effort angina was submitted to invasive coronary angiography that revealed a severe stenosis in the distal right coronary artery. A large spiral ICAD occurred after pre-dilatation and guidewire position is lost. We report the treatment of this multifenestrated dissection using combined intracoronary imaging guidance with angiographic co-registered optical coherence tomography and real-time intravascular ultrasound, which were crucial to achieve a successful outcome. Discussion: A double-wiring technique with double intracoronary imaging guidance enables a comprehensive depiction of the compromised artery and should be considered in selected cases to guide true lumen wiring and stent implantation.

Sacubitril/Valsartan Improves Left Atrial and Ventricular Strain and Strain Rate in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Data on the impact of sacubitril/valsartan (SV) therapy on phasic left atrial (LA) and left ventricular (LV) strain in heart failure with reduced ejection fraction (HFrEF) are limited. The aim of this study was to evaluate changes in two-dimensional speckle tracking (2D-STE) parameters with SV therapy in HFrEF patients. METHODS: Prospective evaluation of HFrEF patients receiving optimized medical therapy. Two-dimensional speckle tracking (2D-STE) parameters were assessed at baseline and after 6 months of SV therapy. LA strain and strain rate (SR) in reservoir, conduit, and contraction phases were compared with LV longitudinal, radial, and circumferential strain and SR and stratified according to heart rhythm and HFrEF etiology. RESULTS: A total of 35 patients completed the 6-month follow-up, with a mean age of 59 ± 11 years, 40% in atrial fibrillation, 43% with ischemic etiology, and LVEF of 29 ± 6%. There were significant improvements in LA reservoir, conduit, and contractile strain and SR following SV therapy, particularly among patients in sinus rhythm. There were significant improvements in longitudinal, radial, and circumferential LV function indices. CONCLUSION: SV therapy in HFrEF was associated with improved longitudinal, radial, and circumferential function, particularly among patients in sinus rhythm. These findings can provide insights into the mechanisms underlying the improvement of cardiac function and help assess subclinical responses to the treatment.

Dilated Cardiomyopathy: A Comprehensive Approach to Diagnosis and Risk Stratification.

Dilated cardiomyopathy (DCM) represents one of the most common causes of non-ischemic heart failure, characterised by ventricular dilation alongside systolic dysfunction. Despite advances in therapy, DCM mortality rates remain high, and it is one of the leading causes of heart transplantation. It was recently recognised that many patients present minor structural cardiac abnormalities and express different arrhythmogenic phenotypes before overt heart-failure symptoms. This has raised several diagnostic and management challenges, including the differential diagnosis with other phenotypically similar conditions, the identification of patients at increased risk of malignant arrhythmias, and of those who will have a worse response to medical therapy. Recent developments in complementary diagnostic procedures, namely cardiac magnetic resonance and genetic testing, have shed new light on DCM understanding and management. The present review proposes a comprehensive and systematic approach to evaluating DCM, focusing on an improved diagnostic pathway and a structured stratification of arrhythmic risk that incorporates novel imaging modalities and genetic test results, which are critical for guiding clinical decision-making and improving outcomes.

Initial single-center experience of a standardized protocol for invasive assessment of ischemia and non-obstructive coronary artery disease.

INTRODUCTION: Coronary vasomotion disorders (CVDs), including microvascular angina (MVA) and vasospastic angina (VSA), account for significant morbidity among patients with non-obstructive coronary artery disease (NOCAD). However, protocols for CVD assessment in clinical practice are seldom standardized and may be difficult to implement. PURPOSE: To assess the safety and feasibility of a comprehensive coronary function test (CFT) protocol for assessment of CVD and the prevalence of different phenotypes of CVD in patients with angina and NOCAD (ANOCA). METHODS: Patients with persistent angina referred for invasive coronary angiogram and found to have NOCAD were prospectively recruited and underwent a CFT. Functional parameters (fractional flow reserve, coronary flow reserve and index of myocardial resistance) and coronary vasoreactivity were assessed in all patients. RESULTS: Of the 20 patients included, the mean age was 63±13 years and 50% were females. Most patients had persistent typical angina and evidence of ischemia in noninvasive tests (75%). The CFT was successfully performed in all subjects without serious complications. Isolated MVA was found in 25%, isolated VSA in 40%, both MVA and VSA in 10% and noncardiac chest pain in 25% of patients. Antianginal therapy was modified after the results of CFT in 70% of patients. CONCLUSION: A coronary function test was feasible and safe in a cohort of patients with ANOCA. CVD were prevalent in this selected group of patients, and some presented mixed CVD phenotypes. CFT may provide a definitive diagnosis in patients with persistent angina and prompt the stratification of pharmacological therapy.

Levosimendan in outpatients with advanced heart failure: Single-center experience of 200 intermittent perfusions.

INTRODUCTION: Patients with advanced heart failure (HF) have high morbidity and mortality, with only a small proportion being eligible for advanced therapies. Intermittent outpatient levosimendan infusion has been shown to provide symptomatic relief and reduce the rate of HF events. Our aim was to assess the safety and efficacy of outpatient levosimendan administration in an advanced HF population. METHODS: This is a report of a single-center experience of consecutive advanced HF patients referred for intermittent intravenous outpatient administration of levosimendan, between January 2018 and March 2021. Baseline and follow-up evaluation included clinical assessment, laboratory tests, transthoracic echocardiography and cardiopulmonary exercise testing. Baseline and clinical follow-up data were compared using the Wilcoxon signed-rank test. RESULTS: A total of 24 patients (60.8 years, 83% male, mean left ventricular ejection fraction [LVEF] 24%), with a median of 1.5 HF hospitalizations in the previous six months, were referred for outpatient levosimendan pulses, the majority as a bridge to transplantation or due to clinical deterioration. At six-month follow-up there was a significant reduction in HF hospitalizations to 0.4±0.7 (p<0.001). NYHA class IV (52.2% to 12.5%, p=0.025) and NT-proBNP (8812.5 to 3807.4 pg/ml, p=0.038) were also significantly reduced. Exercise capacity was significantly improved, including peak oxygen uptake (p=0.043) and VE/VCO2 slope (p=0.040). LVEF improved from 24.0% to 29.7% (p=0.008). No serious adverse events were reported. CONCLUSION: Repeated levosimendan administration in advanced HF patients is a safe procedure and was associated with a reduction in HF hospitalizations, functional and LVEF improvement, and reduction in NT-proBNP levels during follow-up.

The role of miRNAs in the diagnosis of stable atherosclerosis of different arterial territories: A critical review.

Atherosclerotic disease is a major cause of morbidity and mortality worldwide. Atherosclerosis may be present in different arterial territories and as a single- or multi-territorial disease. The different phenotypes of atherosclerosis are attributable only in part to acquired cardiovascular risk factors and genetic Mendelian inheritance. miRNAs, which regulate the gene expression at the post-transcriptional level, may also contribute to such heterogeneity. Numerous miRNAs participate in the pathophysiology of atherosclerosis by modulating endothelial function, smooth vascular cell function, vascular inflammation, and cholesterol homeostasis in the vessel, among other biological processes. Moreover, miRNAs are present in peripheral blood with high stability and have the potential to be used as non-invasive biomarkers for the diagnosis of atherosclerosis. However, the circulating miRNA profile may vary according to the involved arterial territory, considering that atherosclerosis expression, including the associated molecular phenotype, varies according to the affected arterial territory. In this review, we discuss the specific circulating miRNA profiles associated with atherosclerosis of different arterial territories, the common circulating miRNA profile of stable atherosclerosis irrespective of the involved arterial territory, and the circulating miRNA signature of multi-territorial atherosclerosis. miRNAs may consist of a simple non-invasive method for discriminating atherosclerosis of different arterial sites. The limitations of miRNA profiling for such clinical application are also discussed.

The prognostic value of the cardiorespiratory optimal point during submaximal exercise testing in heart failure.

INTRODUCTION: Peak oxygen consumption (pVO2) is a key parameter for assessing the prognosis of heart failure with reduced ejection fraction (HFrEF). However, it is less reliable when the cardiopulmonary exercise test (CPET) is not maximal. OBJECTIVE: To compare the prognostic power of various exercise parameters in submaximal CPET. METHODS: Adult patients with HFrEF undergoing CPET in a tertiary center were prospectively assessed. Submaximal CPET was defined as a respiratory exchange ratio ≤1.10. Patients were followed for one year for the primary endpoint of cardiac death and urgent heart transplantation (HT). Various CPET parameters were analyzed as potential predictors of the combined endpoint and their prognostic power (area under the curve [AUC]) was compared using the Hanley-McNeil test. RESULTS: CPET was performed in 442 HFrEF patients (mean age 56±12 years, 80% male), of whom 290 (66%) had a submaximal CPET. Seventeen patients (6%) reached the primary endpoint. The cardiorespiratory optimal point (COP) had the highest AUC value (0.989, p<0.001), and significantly higher prognostic power than other tested parameters, with pVO2 presenting an AUC of 0.753 (p=0.001). COP ≥36 had significantly lower survival free of HT during follow-up (p<0.001) and presented a sensitivity of 100% and a specificity of 89% for the primary endpoint. CONCLUSION: COP had the highest prognostic power of all parameters analyzed in a submaximal CPET. This parameter can help stratify HFrEF patients who are physiologically unable to reach a maximal level of exercise.

Remote invasive monitoring of pulmonary artery pressures in heart failure patients: Initial experience in Portugal in the context of the Covid-19 pandemic.

Background: Decompensated heart failure (HF) is associated with poor short- and long-term prognosis. Remote invasive monitoring of pulmonary artery pressures (PAP) enables early detection of HF decompensation before symptoms occur and may improve clinical outcomes. We aimed to describe our initial experience with the use of the CardioMEMS™ remote monitoring system in patients with HF, including its safety and effectiveness. Methods and results: Five patients with HF in New York Heart Association class III and at least one hospitalization due to decompensated HF in last 12 months, who underwent invasive remote monitoring of PAP, were included in this prospective registry. The median age was 66.0 years (interquartile range [IQR] 50.5-77.5 years), 80.0% were men and all had HF with reduced ejection fraction. The pulmonary artery (PA) sensor was placed in a left PA branch in all patients and no major procedural complications occurred. In median follow-up of 40 days (IQR 40-61 days), a total of 271 pressure readings were transmitted, patient compliance was 100% and freedom from sensor failure 98.1%. In three patients, PAP remained within the goal during follow-up. Two patients presented an increase in PAP to values above the targets, despite the absence of symptom worsening. These required dietary and diuretic dose adjustment, without the need for outpatient clinic visits, which reduced PAP. No hospitalizations for HF or deaths occurred during follow-up. Conclusion: Hemodynamic-guided HF monitoring was safe and effective and may be a useful adjunctive tool to the standard-of-care management in selected HF patients, particularly in the context of the COVID-19 pandemic, where a reduction in the number of health care visits may be desirable.

Introdução: A insuficiência cardíaca (IC) descompensada está associada a mau prognóstico em curto e longo prazo. A monitoração remota invasiva da pressão na artéria pulmonar (PAP) possibilita a deteção precoce da descompensação da IC, previamente ao início dos sintomas, pode melhorar os resultados clínicos. Descrevemos a experiência inicial com o uso do sistema de monitoração remota CardioMEMS™ em doentes com IC, inclusive a sua segurança e eficácia. Métodos e resultados: Foram incluídos prospetivamente cinco doentes com IC em classe III da New York Heart Association, com pelo menos uma hospitalização por IC descompensada nos últimos 12 meses, submetidos a implantação de sistema de monitoração remota invasiva da PAP. A mediana de idade foi de 66 anos (intervalo interquartil [IIQ] 50,5-77,5 anos), 80% eram do sexo masculino e todos apresentavam IC com fração de ejeção reduzida. O sensor de PAP foi colocado num ramo da artéria pulmonar esquerda em todos os doentes, não ocorreram complicações major. Durante o follow-up mediano de 40 dias (IIQ 40-61 dias), foram transmitidas 271 leituras, verificou-se uma adesão dos doentes de 100% e taxa de transmissão bem-sucedida de 98,1%. A PAP manteve-se dentro do objetivo em três doentes durante o follow-up. Apesar de continuarem assintomáticos, dois doentes apresentaram valores das PAP acima do alvo. Foi feito ajuste dietético e da dose de diurético, sem necessidade de visitas clínicas presenciais, objetivou-se uma redução efetiva das PAP. Durante o seguimento, não se registaram hospitalizações por IC ou óbitos. Conclusão: A monitoração da IC guiada pela hemodinâmica demonstrou ser segura e eficaz, pode assumir-se como uma ferramenta útil no manejo de doentes com IC, particularmente no contexto da pandemia Covid-19, quando é desejável uma redução do número de consultas presenciais hospitalares.

Association between miR-146a and Tumor Necrosis Factor Alpha (TNF-α) in Stable Coronary Artery Disease.

Background and Objectives: Tumor necrosis factor alpha (TNF-α) is proatherogenic and associated with the risk of acute ischemic events, although the mechanisms that regulate TNF-α expression in stable coronary artery disease (SCAD) are not fully understood. We investigated whether metabolic, inflammatory, and epigenetic (microRNA (miRNA)) markers are associated with TNF-α expression in SCAD. Materials and Methods: Patients with SCAD were prospectively recruited and their metabolic and inflammatory profiles were assessed. TNF-α levels were assessed using an enzyme-linked immunosorbent assay. The relative expression of six circulating miRNAs associated with the regulation of inflammation and/or atherosclerosis was determined. Results: Of the 24 included patients with the mean age of 65 (9) years, 88% were male, and 54% were diabetic. The TNF-α levels were (median (interquartile range)) 1.0 (0.7-1.1) pg/mL. The percentage of glycosylated hemoglobin (r = 0.418, p = 0.042), serum triglyceride levels (r = 0.429, p = 0.037), and C-reactive protein levels (r = 0.407, p = 0.048) were positively correlated with TNF-α levels. Of the candidate miRNAs, miR-146a expression levels were negatively correlated with TNF-α levels (as indicated by r = 0.500, p = 0.035 for correlation between delta cycle threshold (ΔCt) miR-146a and TNF-α levels). In multivariate analysis, serum triglyceride levels and miR-146a expression levels were independently associated with TNF-α levels. miR-146 expression levels were not associated with metabolic or other inflammatory parameters and were negatively correlated with the number of coronary vessels with obstructive disease (as indicated by r = 0.556, p = 0.017 for correlation between ΔCt miR-146a and number of diseased vessels). Conclusions: miR-146a expression levels were negatively correlated with TNF-α levels in patients with SCAD, irrespective of other metabolic or inflammatory markers, and with the severity of coronary artery disease. The results add to the knowledge on the role of miR-146a in TNF-α-based inflammation in SCAD and support future research on the potential therapeutic use of miR-146a in such a clinical scenario.

Prevalence and prognostic impact of apical sparing contractility pattern in patients with aortic stenosis referred for transcatheter aortic valve implantation.

INTRODUCTION: Prolonged afterload increase in aortic stenosis (AS) may alter left ventricular (LV) contractility, irrespective of LV ejection fraction (LVEF). The prevalence and morbimortality associated with the apical sparing strain pattern (ASP), a typical finding of cardiac amyloidosis (CA), are not fully understood in patients with AS. We assessed the prevalence of the ASP in patients with severe AS and its clinical impact after transcatheter aortic valve implantation (TAVI). METHODS: Eighty-nine consecutive patients with severe AS and LV hypertrophy referred for TAVI were included. Baseline clinical and echocardiographic data were assessed, including the ASP in bull's eye plots (ASPB), relative apical longitudinal strain (RALS) and EF to global longitudinal strain (EF/GLS) ratio. We analysed all-cause mortality; a composite of all-cause mortality, stroke, and heart failure hospitalizations; and the rate of pacemaker implantation, after TAVI. RESULTS: Mean age was 82 ± 6 years and mean LVEF was 57 ± 10%. ASPB and RALS >1 were present in 43.8% and 24.7% of patients, respectively. Over a median follow-up of 13 months (IQR 6-32), ASPB was associated with higher rates of all-cause mortality (log-rank P=0.001) and was an independent predictor of all-cause mortality in multivariate analysis. Combination of the ASPB and GLS or EF/GLS ratio improved the risk stratification. Patients with RALS >1 were more likely to have new BBB and an indication for pacemaker implantation (P=0.048). CONCLUSION: The ASP, as assessed by the ASPB and RALS, was frequent in patients with AS regardless of the diagnosis of CA. The ASPB may refine risk stratification in patients referred for TAVI.

Circulating miRNAs Are Associated with the Systemic Extent of Atherosclerosis: Novel Observations for miR-27b and miR-146.

The mechanisms that regulate the systemic extent of atherosclerosis are not fully understood. We investigated whether the expression of circulating miRNAs is associated with the extent of stable atherosclerosis to a single territory or multiple territories (polyvascular) and with the severity of atherosclerosis in each territory. Ninety-four participants were prospectively recruited and divided into five age- and sex-matched groups: presenting no atherosclerosis, isolated coronary atherosclerosis, coronary and lower extremity atherosclerosis, coronary and carotid atherosclerosis, and atherosclerosis of the coronary, lower extremity, and carotid territories. The expression of six circulating miRNAs with distinct biological roles was assessed. The expression of miR-27b and miR-146 differed across groups (p < 0.05), showing a decrease in the presence of atherosclerosis, particularly in the three territories. miR-27b and miR-146 expression decreased in association with a higher severity of coronary, lower extremity, and carotid atherosclerosis. Polyvascular atherosclerosis involving the three territories was independently associated with a decreased miR-27b and miR-146 expression. Both miRNAs presented an area under the curve of ≥0.75 for predicting polyvascular atherosclerosis involving the three territories. To conclude, miR-27b and miR-146 were associated with the presence of severe polyvascular atherosclerosis and with the atherosclerosis severity in each territory. Both are potential biomarkers of severe systemic atherosclerosis.

Cigarette Smoking, miR-27b Downregulation, and Peripheral Artery Disease: Insights into the Mechanisms of Smoking Toxicity.

Cigarette smoking is a risk factor for the development of peripheral artery disease (PAD), although the proatherosclerotic mediators of cigarette smoking are not entirely known. We explored whether circulating microRNAs (miRNAs) are dysregulated in cigarette smokers and associated with the presence of PAD. Ninety-four participants were recruited, including 58 individuals without and 36 with PAD, 51 never smokers, 28 prior smokers, and 15 active smokers. The relative expression of six circulating miRNAs with distinct biological roles (miR-21, miR-27b, miR-29a, miR-126, miR-146, and miR-218) was assessed. Cigarette smoking was associated with the presence of PAD in multivariate analysis. Active smokers, but not prior smokers, presented miR-27b downregulation and higher leukocyte, neutrophil, and lymphocyte counts; miR-27b expression levels were independently associated with active smoking. Considering the metabolic and/or inflammatory abnormalities induced by cigarette smoking, miR-27b was independently associated with the presence of PAD and downregulated in patients with more extensive PAD. In conclusion, the atheroprotective miR-27b was downregulated in active smokers, but not in prior smokers, and miR-27b expression was independently associated with the presence of PAD. These unreported data suggest that the proatherogenic properties of cigarette smoking are mediated by a downregulation of miR-27b, which may be attenuated by smoking cessation.

Soluble CD40 ligand expression in stable atherosclerosis: A systematic review and meta-analysis.

BACKGROUND AND AIMS: The role of inflammation in atherosclerosis development and expression in different arterial territories is unclear. Soluble CD40 ligand (sCD40L) mediates inflammation and atherogenesis. Through a systematic review and meta-analysis, we assessed whether sCD40L was dysregulated in stable atherosclerosis, irrespective of the diseased arterial territory, and whether this dysregulation differed according to the specific territory. METHODS: Systematic literature searches were performed in MEDLINE, Cochrane Library, Web of Science, and Embase for studies reporting circulating sCD40L levels in individuals with and without stable atherosclerosis. sCD40L levels were compared using random-effects meta-analysis, weighted by the inverse variance method (study protocol: PROSPERO CRD42020181392). RESULTS: Fifty-four studies (59 estimates) including 7705 patients and 7841 controls were analyzed. sCD40L levels were found to be increased in patients with atherosclerosis, irrespective of the territory (standardized mean difference [SMD] 0.43, 95% CI 0.29-0.57; 59 estimates; χ2 heterogeneity p < 0.001; I2 = 92%). SMD was greatest in carotid atherosclerosis (SMD 0.58, 95% CI 0.30-0.86; 17 estimates), followed by coronary (SMD 0.43, 95% CI 0.24-0.62; 33 estimates), lower extremity (SMD 0.26, 95% CI -0.02-0.54; 7 estimates), and renal atherosclerosis (SMD -0.07, 95% CI -2.77-2.64; 2 estimates) (χ2 heterogeneity p < 0.001; I2 ≥ 80% for all). Subgroup analysis revealed that sCD40L levels were increased in clinical, but not subclinical, atherosclerosis. CONCLUSIONS: sCD40L levels were increased in stable atherosclerosis, particularly in the carotid and coronary territories. These novel data support sCD40L as a marker of systemic atherosclerosis, possibly with differential roles in specific territories.

The Proinflammatory Soluble CD40 Ligand Is Associated with the Systemic Extent of Stable Atherosclerosis.

Background and objectives: Polyvascular atherosclerosis is frequent and associated with a high cardiovascular risk, although the mechanisms regulating the atherosclerosis extent to single or multiple arterial territories are still poorly understood. Inflammation regulates atherogenesis and soluble CD40 ligand (sCD40L) is an inflammatory mediator associated with the presence of single-territorial atherosclerosis. We assessed whether the sCD40L expression is associated with the atherosclerosis extent to single or multiple arterial territories and with the atherosclerosis severity in different territories. Materials and Methods: We prospectively enrolled 94 participants with no atherosclerosis (controls, n = 26); isolated coronary atherosclerosis (group 1, n = 20); coronary and lower extremity (LE) atherosclerosis (group 2, n = 18); coronary and carotid atherosclerosis (group 3, n = 12); and coronary, LE, and carotid atherosclerosis (group 4, n = 18). Serum sCD40L levels were quantified. Results: The sCD40L levels (ng/mL, mean (standard deviation)) were 4.0 (1.5), 5.6 (2.6), 7.2 (4.2), 5.9 (3.7), and 5.1 (2.4) in controls and groups 1 to 4, respectively (ANOVA p = 0.012). In nonrevascularized patients, the sCD40L levels were significantly higher in group 2 than in group 1 and were correlated with the number of LE diseased segments. Prior LE bypass surgery was associated with lower sCD40L levels. Coexistence of coronary and LE atherosclerosis was independently associated with the sCD40L levels. Conclusions: The sCD40L levels were increased in stable atherosclerosis, particularly in polyvascular coronary and LE atherosclerosis. The number of LE diseased segments and prior LE revascularization were associated with sCD40L expression. To our knowledge, these are novel data, which provide insights into the mechanisms underlying multi-territorial atherosclerosis expression. sCD40L may be a promising noninvasive tool for refining the stratification of the systemic atherosclerotic burden.