Circulating Biomarkers of Endothelial Dysfunction and Inflammation in Predicting Clinical Outcomes in Diabetic Patients with Critical Limb Ischemia.

Critical limb ischemia (CLI) is a severe manifestation of peripheral artery disease characterized by ischemic pain, which is frequently associated with diabetes and non-healing lesions to inferior limbs. The clinical management of diabetic patients with CLI typically includes percutaneous transluminal angioplasty (PTA) to restore limb circulation and surgical treatment of diabetic foot ulcers (DFU). However, even after successful treatment, CLI patients are prone to post-procedure complications, which may lead to unplanned revascularization or foot surgery. Unfortunately, the factors predicting adverse events in treated CLI patients are only partially known. This study aimed to identify potential biomarkers that predict the disease course in diabetic patients with CLI. For this purpose, we measured the circulating levels of a panel of 23 molecules related to inflammation, endothelial dysfunction, platelet activation, and thrombophilia in 92 patients with CLI and DFU requiring PTA and foot surgery. We investigated whether these putative biomarkers were associated with the following clinical endpoints: (1) healing of the treated DFUs; (2) need for new revascularization of the limb; (3) appearance of new lesions or relapses after successful healing. We found that sICAM-1 and endothelin-1 are inversely associated with DFU healing and that PAI-1 and endothelin-1 are associated with the need for new revascularization. Moreover, we found that the levels of thrombomodulin and sCD40L are associated with new lesions or recurrence, and we show that the levels of these biomarkers could be used in a decision tree to assign patients to clusters with different risks of developing new lesions or recurrences.

Bleeding Risk Scores and Scales of Frailty for the Prediction of Haemorrhagic Events in Older Adults with Acute Coronary Syndrome: Insights from the FRASER study.

PURPOSE: Hitherto, no study has yielded important information on whether the scales of frailty may improve the ability to discriminate the risk of haemorrhages in older adults admitted to hospital for acute coronary syndrome (ACS). The aim of this study is to investigate whether frailty scales would predict the 1-year occurrence of haemorrhagic events and if they confer a significant incremental prognostic value over the bleeding risk scores. METHODS: The present study involved 346 ACS patients aged ≥ 70 years enrolled in the FRASER study. Seven different scales of frailty and PARIS, PRECISE-DAPT and BleeMACS bleeding risk scores were available for each patient. The outcomes were the 1-year BARC 3-5 and 2 bleeding events. RESULTS: Adherence to antiplatelet treatment at 1, 6 and 12 months was 98%, 87% and 78%, respectively. At 1-year, 14 (4%) and 30 (9%) patients presented BARC 3-5 and 2 bleedings, respectively. Bleeding risk scores and four scales of frailty (namely Short Physical Performance Battery, Columbia, Edmonton and Clinical Frailty Scale) significantly discriminated the occurrence of BARC 3-5 events. The addition of the scales of frailty to bleeding risk scores did not lead to a significant improvement in the ability to predict BARC 3-5 bleedings. Neither the bleeding risk scores nor the scales of frailty predicted BARC 2 bleedings. CONCLUSIONS: Both the bleeding risk scores and the scales of frailty predicted BARC 3-5 haemorrhages. However, integrating the scales of frailty with the bleeding risk scores did not improve their discriminative ability. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov: NCT02386124.

Renin-Angiotensin-Aldosterone System Inhibitors, Statins, and Beta-Blockers in Diabetic Patients With Critical Limb Ischemia and Foot Lesions.

Medical therapy for secondary prevention is known to be under-used in patients with peripheral artery disease (PAD). Few data are available on the subgroup with critical limb ischemia (CLI). Prescription of cardiovascular preventive therapies was recorded at discharge in a large, prospective cohort of patients admitted for treatment of CLI and foot lesions, stratified for coronary artery disease (CAD) diagnosis. All patients were followed up for at least 1 year. The primary endpoint was major adverse cardiovascular events (MACE). 618 patients were observed for a median follow-up of 981 days. Renin-angiotensin-aldosterone system (RAAS) inhibitors, statins, beta-blockers, and antithrombotic drugs were prescribed in 52%, 80%, 51%, and 99% of patients, respectively. However, only 43% of patients received optimal medical therapy (OMT), defined as the combination of RAAS inhibitor plus statin plus at least one antithrombotic drug. It was observed that the prescription of OMT was not affected by the presence of a CAD diagnosis. On the other hand, it was noticed that the renal function affected the prescription of OMT. OMT was independently associated with MACE (HR 0.688, 95%CI 0.475-0.995, P = .047) and, after propensity matching, also with all-cause mortality (HR 0.626, 95%CI 0.409-0.958, P = .031). Beta-blockers prescription was not associated with any outcome. In conclusion, patients with critical limb ischemia are under-treated with cardiovascular preventive therapies, irrespective of a CAD diagnosis. This has consequences on their prognosis.

High-Sensitivity Cardiac Troponin Predicts Major Cardiovascular Events in Diabetic Patients With Critical Limb Ischemia and Foot Lesions.

Background: Diabetic patients with critical limb ischemia (CLI) and foot lesions show a poor prognosis. Optimal risk stratification to guide tailored intervention is still uncertain. The aim of the present study was to assess the prognostic role of high-sensitivity cardiac troponin T (hs-TnT) in such a high-risk population. Methods and Results: Clinical, laboratory, and interventional data, as well as the SPINACH score, were collected. Hs-TnT was measured at hospital admission. All patients were followed up for at least 1 year. The primary endpoint was the cumulative occurrence of major cardiovascular events (MACEs, all-cause death, myocardial infarction, or stroke). The secondary endpoint was all-cause mortality. Overall, 618 patients were included and followed for a median of 981 (557-1,325) days. Diagnosis of coronary artery disease (CAD) was established in 270 (43.7%) patients. Median hs-TnT at admission was 31 (20-59) ng/L, with 525 (85%) patients over the upper reference limit. Hs-TnT values were significantly higher in patients with established CAD (39 vs. 29 ng/L, p < 0.01). Hs-TnT was an independent predictor of MACE (HR 2.440, 95% CI 1.706-3.489, p < 0.001). The best cut-offs were 40 ng/L (AUC 0.711) for patients with established CAD and 25 ng/L (AUC 0.725) for those without. Hs-TnT emerged also as an independent predictor of all-cause mortality. The addition of hs-TnT improved prognostic value of the SPINACH score. Conclusions: Hs-TnT is a powerful biomarker for prognostic stratification of diabetic CLI patients with foot lesions. This is confirmed independently to CAD diagnosis and permits the identification of higher risk patients requiring tailored intervention.

Lipid plaque burden in NSTE-ACS patients with or without COPD: insights from the SCAP Trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients have higher recurrence of adverse events and worse prognosis after acute coronary syndrome (ACS). The underlying pathophysiological mechanism is not fully elucidated. METHODS: In screening for COPD in ACS (SCAP) Trial (NCT02324660), ACS patients with smoking habit underwent a predischarge screening procedure to detect undiagnosed chronic obstructive pulmonary disease (UCOPD) confirmed with spirometry at 60 days. Patients were then categorized as UCOPD or no-COPD. In 65 NSTE-ACS patients, we performed near infrared spectroscopy (NIRS) in the culprit and at least one non-culprit vessel (151 vessels overall), and we calculated the SYNTAX I Score. Primary endpoint was max lipid core burden index (LCBI) 4 mm. Secondary endpoints were SYNTAX Score I and vessel LCBI. RESULTS: Max LCBI 4 mm and vessel LCBI were significantly higher in the UCOPD compared to the no-COPD group (UCOPD 388±122, no-COPD 264±131, P<0.001; UCOPD 118±50, no-COPD 82±42, P<0.001, respectively). UCOPD patients showed higher max LCBI 4 mm and LCBI vessel both in culprit and non-culprit vessels. SYNTAX Score I was comparable between the two groups (UCOPD: 13.5 [5.5-24], no-COPD: 12.5 [5-24.5], P=0.7). CONCLUSIONS: NSTE-ACS patients with UCOPD showed a higher LCBI compared to those without COPD, while SYNTAX Score I was comparable between the two groups.

[Early invasive strategy (<24 h) in high-risk non-ST-elevation acute coronary syndrome: when the guideline recommendations need to be contextualized]. / Strategia invasiva precoce (<24 h) nelle sindromi coronariche acute senza sopraslivellamento del tratto ST ad alto rischio, ovvero quando le raccomandazioni delle linee guida dovrebbero essere contestualizzate.

The advantages of an early invasive strategy in non-ST-elevation acute coronary syndromes (NSTE-ACS) are well documented. Less clear is the ideal time to perform it (within 24 h, within 72 h, or during hospitalization after positive non-invasive testing for ischemia). In particular, the class IA recommendation for coronary angiography within 24 h in patients with high-risk NSTE-ACS is controversial. Randomized clinical trials and meta-analyses show neutral effects on mortality, while significant positive results are observed only for secondary outcomes (mainly ischemic recurrences). Favorable effects on major cardiovascular events are reported only in the subgroup analysis of a single randomized trial (TIMACS) or in several trials included in the meta-analyses. Thus, these results are far from conclusive and should stimulate new randomized clinical studies to support them. In fact, the logistical implications that this recommendation implies deserve stronger evidence. It is clear that all patients with NSTE-ACS, especially if high-risk, should have the opportunity to undergo a coronary angiogram during hospitalization. However, in the real world, the strict timeline of the international guidelines may be difficult to follow. Therefore, indications that take into account resource availability and the organizational context should be developed. Several regional indications suggest that even in high-risk patients the 24 h time limit for the invasive strategy should not be mandatory, but timing of angiography should be calibrated on clinical presentation and logistical resources, without any a priori automatism.

[Primary percutaneous coronary angioplasty in octogenarians and over. The experience of a high-volume hub center]. / L'angioplastica primaria nei grandi anziani. Esperienza di un centro di riferimento ad alto volume.

BACKGROUND: Primary coronary angioplasty (PCI) is the reference treatment for acute ST-elevation myocardial infarction (STEMI), but elderly patients (>80 years) are underrepresented in clinical trials that support the guideline recommendations. The aim of this study was to assess in-hospital and 1-year total mortality of octogenarians and over treated with primary PCI at a large referral center. METHODS: Single-center analysis of all consecutive patients with STEMI aged ≥80 years treated with primary PCI between 2010 and 2016. Patients were divided into three age groups: 80-84 years, 85-89 years, and ≥90 years. For each group, clinical and procedural data, in-hospital and 1-year mortality were analyzed. RESULTS: During the study period, 2127 patients were treated with primary PCI, 463 of them (22%) were aged ≥80 years (mean 85 ± 3 years). Of these, 51% were aged ≥80 and ≤84 years, 32% were aged ≥85 and ≤89 years, and 17% were aged ≥90 years. An increase of female gender prevalence and a decrease of risk factor prevalence as well as PCI success were observed with ageing. In-hospital and 1-year total death rates increased with age as well, mainly after 85 years. CONCLUSIONS: Primary PCI for STEMI among octogenarians and over is feasible and has good procedural results. Nevertheless, in-hospital and 1-year total mortality is high, with a marked deterioration after 85 years of age, when it doubles. Considering population demographics, specific studies in this very elderly population are needed to improve treatment and outcomes.

Nutritional status and all-cause mortality in older adults with acute coronary syndrome.

BACKGROUND & AIMS: The present analysis investigated the prevalence and the prognostic implication of nutritional status in older adults hospitalized for acute coronary syndrome (ACS). METHODS: The analysis is based on older ACS patients included in the FRASER and LONGEVO SCA studies. The Global Risk of Acute Coronary Events (GRACE) risk score was computed in all patients. Nutritional status was assessed with the Mini Nutritional Assessment-Short Form (MNA-SF, normal for values between 12 and 14, at risk of malnutrition for values between 8 and 11, and malnutrition for values ≤ 7). Physical performance was assessed with the Short Physical Performance Battery (SPPB). Primary outcome was all-cause mortality. RESULTS: The study included 908 patients. Overall, 35 patients (4%) were malnourished and 361 (40%) were at risk of malnutrition. After a median follow-up of 288 [187-370] days, the primary endpoint occurred in 94 (10.5%) patients. The mortality rate was 31% in malnourished subjects, 19% in at-risk patients, 3% in patients with a normal nutritional status (p < 0.001). MNA-SF emerged as an independent predictor of all-cause mortality (HR 0.76, 95%CI 0.68-0.84 for single change unit). The MNA-SF score improved the GRACE score's ability to discriminate subjects at risk of death (ΔC-statistic = 0.076, p < 0.001; ΔBIC -28; IDI 0.052, p < 0.001; NRI 0.793, p < 0.001). The prognostic value of MNA-SF was maintained also by including the SPPB score in the predictive model. CONCLUSION: s: The MNA-SF helped to identify malnutrition in older ACS patients. Moreover, the MNA-SF value is an independent predictor of all-cause mortality and it improves the predictive value of the GRACE risk score.

Limb salvage in diabetic patients with no-option critical limb ischemia: outcomes of a specialized center experience.

Objective: To describe the characteristics, the management and the outcome of a consecutive series of patients with diabetic foot lesions (DF) and no-option critical limb ischemia (CLI) treated with a multidimensional, interdisciplinary approach in a dedicated center. Research Design and Methods: The prospective database of the Diabetic Foot Unit of the Maria Cecilia Hospital (Cotignola, Italy) collects medical history, risk factors, chemistry values, angiographic data, characteristic of foot lesions, medical and surgical therapies of all patients admitted with a diagnosis of DF and CLI. All patients were followed-up for at least 1 year and/or total recovery. The primary endpoint was 1-year amputation-free survival (AFS), secondary endpoints were limb salvage and survival. Results: Between October 2014 and October 2017, 1024 patients with DF and CLI were admitted to the center. Eighty-four of them (8.2%) fulfilled the criteria for no-option CLI. At 1 year, AFS, limb salvage, and survival rates were 34%, 34%, and 83%, respectively. Lesions located proximal to the Lisfranc joint were associated with major amputation (HR 2.1 [1.2-3.6]). One-year survival of patients treated with minor procedures was significantly higher compared to patients treated with major amputation (96% vs 76%, log-rank p = 0.019). Major amputation was independently associated with mortality (HR 7.83 [1.02-59.89]). Conclusions: The application of dedicated and standardized strategies permitted limb salvage in one-third of patients with no-option CLI. Patients with stable lesions limited to the forefoot and without ischaemic pain had a greater probability to successfully receive conservative treatments. Limb salvage was associated with subsequent higher one-year survival.

Effectiveness of a Novel Nutraceutical Compound Containing Red Yeast Rice, Polymethoxyflavones and Antioxidants in the Modulation of Cholesterol Levels in Subjects With Hypercholesterolemia and Low-Moderate Cardiovascular Risk: The NIRVANA Study.

Background: Red yeast rice supplements are broadly accepted as treatment for dyslipidaemia in subjects without high cardiovascular (CV) risk. Their effect on lipid profile is well known, but few data are available on their effect on endothelial function. Objectives: To study the effect of a novel nutraceutical compound (NC) containing low monacolin K dose, polymethoxyflavones and antioxidants on lipid profile, endothelial function and oxidative stress. Methods: Fifty-two subjects with low-moderate CV risk and dyslipidaemia (according to European guidelines) were enrolled and treated for 8 weeks with the NC. Blood samples were collected at baseline and at the end of treatment to assess changes in lipid profile, endothelial function and oxidative stress. The primary endpoint was the reduction of low density lipoprotein (LDL) cholesterol. Endothelial function was assessed through measurement of rate of apoptosis and nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) treated with subject's serum. High-sensitivity C-reactive protein, 4-hydroxynonenal (HNE) and oxidized LDL (oxLDL) were markers of oxidative stress. Results: Fifty subjects completed the study. The treatment caused a significant decrease in LDL (-15.6%, p < 0.001), oxLDL (-21.5%, p < 0.001), total cholesterol (TC), triglycerides, and ApoB. Apoptosis rate of HUVECs significantly decreased (-15.9%, p < 0.001). No changes were noted for NO levels and 4-HNE protein adducts. The reduction of the apoptosis rate was correlated to the reduction of oxLDL. Conclusion: An 8-week treatment based on a novel NC containing low manocolin K dose, polymethoxyflavones and antioxidants improved lipid profile in subjects with dyslipidaemia and low-moderate CV risk. Secondarily, we observed an improvement in surrogate markers of endothelial function that may result from the reduction of oxLDL (Registered at www.clinicaltrials.gov, NCT03216811).

Ticagrelor Improves Endothelial Function by Decreasing Circulating Epidermal Growth Factor (EGF).

Ticagrelor is one of the most powerful P2Y12 inhibitor. We have recently reported that, in patients with concomitant Stable Coronary Artery Disease (SCAD) and Chronic Obstructive Pulmonary Disease (COPD) undergoing percutaneous coronary intervention (PCI), treatment with ticagrelor, as compared to clopidogrel, is associated with an improvement of the endothelial function (Clinical Trial NCT02519608). In the present study, we showed that, in the same population, after 1 month treatment with ticagrelor, but not with clopidogrel, there is a decrease of the circulating levels of epidermal growth factor (EGF) and that these changes in circulating levels of EGF correlate with on-treatment platelet reactivity. Furthermore, in human umbilical vein endothelial cells (HUVEC) incubated with sera of the patients treated with ticagrelor, but not with clopidogrel there is an increase of p-eNOS levels. Finally, analyzing the changes in EGF and p-eNOS levels after treatment, we observed an inverse correlation between p-eNOS and EGF changes only in the ticagrelor group. Causality between EGF and eNOS activation was assessed in vitro in HUVEC where we showed that EGF decreases eNOS activity in a dose dependent manner. Taken together our data indicate that ticagrelor improves endothelial function by lowering circulating EGF that results in the activation of eNOS in the vascular endothelium.

BRS implantation in long lesions requiring device overlapping: myth or reality?

Dealing with bioresorbable vascular scaffolds (BVS) implantation in long lesions requiring device overlapping in this particular moment might seem a little provocative for several reasons. First, most studies testing BVS have focused on their safety and efficacy profile in simple patients with simple lesions. Second, ABSORB II did not meet its primary endpoint, while ABSORB III showed a higher rate of target vessel-myocardial infarction (TV-MI) at 2 years. Third, data on porcine model showed that overlapping zone has delayed but greater neointimal proliferation with consequent higher risk for scaffold thrombosis in the short-term and of in-scaffold restenosis in the long-term. Fourth, recently published data showed higher risk of TVF in patients treated with ≥60 mm BVS. Given all these premises, it may seem right to put aside this technology, while it may seem inappropriate to hypothesize the use of BVS in long lesions. The aim of the present review is precisely to critically review the available evidences regarding BVS with particular regard to overlapping BVS in order to understand whether this technology has a future per se and especially in long coronary lesions requiring overlap.

Accuracy of Lung Ultrasound in Patients with Acute Dyspnea: The Influence of Age, Multimorbidity and Cognitive and Motor Impairment.

Discriminating between causes of dyspnea may be difficult, particularly in the elderly. The aim of this retrospective study of 83 inpatients with acute dyspnea was to assess the influence of age, multimorbidity and cognitive or motor impairment on the diagnostic accuracy of lung ultrasound (LUS) in discriminating acute heart failure (AHF) from noncardiogenic dyspnea (NCD). Univariate analysis indicates that LUS misdiagnosis was associated with the following parameters: history of stroke (p = 0.037), lower activity of daily living (p = 0.039), higher modified-Rankin scale (mRS) (p = 0.027) and need of two operators to complete LUS because of reduced patient compliance (p = 0.030). Regression analysis identified only history of stroke (p = 0.048) as an independent predictor of LUS misdiagnosis. This study supports LUS usefulness to differentiate AHF from NCD. Our data suggest that diagnostic accuracy of LUS is affected by history of stroke as a proxy for severe motor impairment but not by age, cognitive impairment and multimorbidity.