Leptin as predictor of cardiovascular events and high platelet reactivity in patients undergoing percutaneous coronary intervention.

BACKGROUND AND AIMS: Leptin is a hormone involved in the regulation of food intake. Previous studies suggested an interplay between leptin, platelet aggregation, and cardiovascular outcome but this issue was not investigated in vivo in patients treated with percutaneous coronary intervention (PCI). We designed a study to evaluate the possible relation between leptin, cardiovascular outcome, and platelet reactivity (PR) in patients undergoing PCI. METHODS: 155 PCI patients had preprocedural measurements of PR and leptin plasma levels. The latter were assessed by ELISA. Hyperleptinemia was defined as leptin levels ≥14 ng/ml. PR was evaluated by the VerifyNowP2Y12 assay and expressed as P2Y12 reaction units (PRU). Patients were divided into three groups based on PR values and defined as low (LPR), normal (NPR), and high (HPR). Patients were followed for up 8 years. The primary endpoint was the incidence of Major Acute Cardiac Events (MACE) at long-term follow-up according to leptin groups. Secondary endpoints were the evaluation of leptin levels according to PR groups and the incidence of periprocedural myocardial infarction (PMI) according to leptin groups. RESULTS: Long-term follow-up was completed in 140 patients. Patients with hyperleptinemia experienced a higher MACE rate than the normoleptinemic group (HR 2.3; CI 95% 1.14-4.6, P = 0.02). These results remained unchanged after adjusting for Body Mass Index, hypertension, and gender. Leptin levels were significantly different among groups of PR (P = 0.047). Leptin levels were higher in the HPR group (12.61 ± 16.58 ng/ml) compared to the LPR group (7.83 ± 8.87 ng/ml, P = 0.044) and NPR group (7.04 ± 7.03 ng/ml, P = 0.01). The rate of PMI was higher in hyperleptinemia patients (15.1% vs. 6.5%, P = 0.22). CONCLUSIONS: This study suggests that high leptin levels are associated with a worse clinical outcome in patients undergoing PCI and with HPR. Further studies are needed to define better the pathophysiological pathways underlying this association.

Impact of Endothelial Dysfunction on Long-Term Clinical Outcomes in Patients With Chronic Coronary Syndromes Treated With Second Generation Drug-Eluting Stent Implantation.

BACKGROUND: Studies investigating clinical outcomes of patients with or without endothelial disfunction (ED) treated with percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) using second generation drug eluting stents (DES) are lacking. METHODS: We prospectively collected data from 109 patients undergoing PCI with second generation DES due to stable CAD between December 2014 and September 2016. ED was evaluated evaluating the flow mediated dilation (FMD) at the brachial artery level and defined by an FMD < 7 %. Primary outcome were major adverse cardiovascular events (MACE), secondary outcomes were target vessel failure (TVR), myocardial infarction (MI) and all-cause death. RESULTS: Five-year follow-up was available in all patients. Median FMD didn't significantly differ between patients who experienced the outcome and those who didn't [no TVR vs. TVR: p = 0.358; no MI vs. MI: p = 0.157; no death vs. death: p = 0.355; no MACE vs. MACE: p = 0.805]. No association between ED and an increased risk for the primary outcome as well as for the secondary ones was evident [MACE: 17.0 % vs. 14.3 %, HR 0.87 (0.33-2.26), log rank p = 0.780; TVR: 9.4 % vs. 5.4 %, HR 0.53 (0.12-2.24), log rank p = 0.384; MI: 3.7 % vs. 8.9 %, HR 2.46 (0.47-12.76), log rank p = 0.265; death: 7.5 % vs. 3.6 %, HR 0.53 (0.09-2.90), log rank p = 0.458]. These findings were confirmed using a lower threshold of FMD to define ED and at one-year landmark analysis. CONCLUSIONS: ED is not associated with an increased risk of adverse events at long-term follow-up in a contemporary cohort of patients undergoing PCI with second generation DES.

Platelet reactivity and clinical outcomes following percutaneous coronary intervention in complex higher-risk patients.

AIMS: To investigate the levels of platelet reactivity and the impact of high platelet reactivity (HPR) on long-term clinical outcomes of complex higher-risk and indicated patients (CHIP) with stable coronary artery disease (CAD) treated with elective percutaneous coronary intervention (PCI). METHODS: We enrolled 500 patients undergoing elective PCI for stable CAD and treated with aspirin and clopidogrel. Patients were divided into four groups based on the presence of CHIP features and HPR. Primary endpoint was the occurrence of major adverse clinical events (MACE) at 5 years. RESULTS: The prevalence of HPR was significantly greater in the CHIP population rather than non-CHIP patients (39.9% vs 29.8%, P = 0.021). Patients with both CHIP features and HPR showed the highest estimates of MACE (22.1%, log-rank P = 0.047). At Cox proportional hazard analysis, the combination of CHIP features and HPR was an independent predictor of MACE (hazard ratio 2.57, 95% confidence interval 1.30-5.05, P = 0.006). CONCLUSION: Among patients with stable CAD undergoing elective PCI and treated with aspirin and clopidogrel, the combination of CHIP features and HPR identifies a cohort of patients with the highest risk of MACE at 5 years, who might benefit from more potent antiplatelet strategies.

Diagnosis, treatment and predictors of prognosis of myocarditis. A narrative review.

Although it has been recognized for almost two centuries, myocarditis is still a challenging diagnosis due to the wide heterogeneity of its clinical manifestations and evolution. Moreover, the diagnostic gold standard, endomyocardial biopsy (EMB), is infrequently used, making hard to determine the exact incidence of myocarditis. Clinical presentation includes a wide range of symptoms, ranging from asymptomatic or subclinical disease with mild dyspnea and chest pain to sudden death, due to cardiogenic shock or malignant ventricular arrhythmias. Equally, the evolution of myocarditis largely varies: albeit short-term prognosis is usually good, with complete or partial recovery, dilated cardiomyopathy with chronic heart failure is the major long-term consequence of myocarditis, developing often several years after the acute onset. This narrative review aims to summarize the current knowledge about myocarditis, with a particular attention to predictors of short- and long-term prognosis, in order to provide a rational and practical approach to the diagnosis, evaluation and treatment of suspected myocarditis.

Non-INvasive Functional and Anatomic vascular evaluation for the prediction of coronary artery disease: The NINFA study.

BACKGROUND: Endothelial function, as assessed with flow-mediated dilatation (FMD), and carotid intima-media thickness (IMT) correlate with the presence and extent of coronary artery disease (CAD). We investigated the incremental value of a combined evaluation of FMD and IMT in predicting the presence of CAD over traditional cardiovascular risk factors. METHODS: A total of 497 consecutive patients undergoing elective coronary angiography were enrolled in this study. Brachial artery FMD and ultrasound-based carotid IMT were evaluated prior to angiography. CAD was defined as the presence of a ≥ 50% stenosis in at least one coronary artery. SYNTAX score was also calculated. Patients were categorized based on the presence of FMD and IMT values below or above gender-specific median. RESULTS: Patients with both low FMD and high IMT presented the highest prevalence of CAD, number of diseased vessels, and SYNTAX score. At multivariate analysis, the combination of low FMD and high IMT was the strongest predictor of CAD (OR 3.63, 95% CI 2.19-6.02; p < .001). At ROC curve analysis, the addition of FMD and IMT to a model of traditional risk factors improved the predictive power for the presence of CAD (area under the curve [AUC] of risk factors model 0.715; AUC of risk factors + FMD + IMT 0.780; p < .001). The addition of FMD and IMT to the model of risk factors correctly reclassified 24.9% of patients. CONCLUSIONS: A combined evaluation of endothelial function and subclinical atherosclerosis at the carotid artery level improves the ability of traditional risk factors to identify patients with CAD.

REabsorbable vs. DUrable Polymer Drug-Eluting Stents in All-Comer PatiEnts: the REDUCE registry.

BACKGROUND: While the superiority of reabsorbable-polymer drug-eluting stents (RP-DES) over bare-metal stents and first-generation durable-polymer (DP)-DES has been largely established, their advantage compared with new-generation DP-DES is still controversial. This study aimed was to compare clinical outcomes of all-comer patients undergoing percutaneous coronary intervention (PCI) with new generation DP-DES or RP-DES implantation. METHODS: We prospectively enrolled 679 consecutive patients treated with PCI with RP-DES or DP-DES. The primary endpoint was the 1-year incidence of major adverse clinical events (MACE), a composite of death, myocardial infarction (MI), and target vessel revascularization (TVR). Target lesion revascularization (TLR) and definite stent thrombosis were also recorded. RESULTS: A total of 439 (64.6%) received RP-DES and 240 (36.4%) received DP-DES. No significant difference in the incidence of MACE (5.9 vs. 4.9%; hazard ratio, 1.23; 95% confidence interval (CI), 0.61-2.49; P = 0.569), death (1.8 vs. 1.7%; hazard ratio, 1.09; 95% CI, 0.33-3.64; P = 0.882), MI (2.3 vs. 2.1%; hazard ratio, 1.05; 95% CI, 0.36-3.08; P = 0.927), TVR (2.3 vs. 1.3%; hazard ratio, 1.70; 95% CI, 0.47-6.20; P = 0.418), TLR (1.4 vs. 0.4%; hazard ratio, 3.06; 95% CI, 0.37-25.40; P = 0.301), and definite stent thrombosis (0.5 vs. 0.4%; hazard ratio, 1.09; 95% CI, 0.10-12.10; P = 0.942) was observed between RP-DES and DP-DES patients at 1-year follow-up. These results were confirmed in a propensity score-matched cohort (n = 134 per group). CONCLUSION: In our registry including a real-world population of all-comer patients undergoing PCI, RP-DES, or durable polymer-DES showed similar efficacy and safety at a 1-year follow-up.

Characterization of inflammatory profile by breath analysis in chronic coronary syndromes.

AIMS: Exhaled breath contains thousands of volatile organic compounds (VOCs) produced during various metabolic processes both in health and disease.Analysis of breath with electronic nose BIONOTE-V allows modifications of exhaled VOCs to be studied, which are clinically recognized to be a marker for several disorders, including heart failure. New noninvasive tests based on VOCs analysis might be a useful tool for early detection of chronic coronary syndromes (CCS). METHODS: Exhaled air was collected and measured in individuals with an indication to perform invasive coronary angiography (ICA). All patients' samples were obtained before ICA. RESULTS: Analysis with BIONOTE-V was performed in a total cohort of 42 patients consecutively enrolled, of whom 19 did not require myocardial revascularization and 23 with indication for myocardial revascularization. BIONOTE-V was able to correctly identify 18 out of 23 patients affected by severe coronary artery disease (sensitivity = 78.3% and specificity = 68.4%). Our predicted model had a tight correlation with SYNTAX score (error of the BIONOTE-V = 15). CONCLUSION: CCS patients have a distinctive fingerprint of exhaled breath, and analysis by BIONOTE-V has the potential for identifying these patients. Moreover, it seems that this technique can correctly identify patients according to anatomical disease severity at ICA. If the preliminary data of this proof of concept study will be confirmed, this rapid and noninvasive diagnostic tool able to identify CCS might have an impact in routine clinical practice.

Acute Epstein-Barr related myocarditis: An unusual but life-threatening disease in an immunocompetent patient.

Myocarditis is an uncommon but potentially life-threatening disease. Clinical manifestations could range from subclinical disease to sudden death, due to fulminant heart failure and/or malignant ventricular arrhythmias. The most common cause of myocarditis is viral infection, including Epstein-Barr virus (EBV). Nevertheless, EBV rarely presents with cardiac involvement in immunocompetent hosts. We report a case of acute EBV-related myocarditis in a young female, complicated with malignant ventricular arrhythmias and cardiac arrest. After 20 days of hospitalization and treatment, the patient was fit for discharge on pharmacological therapy (tapering steroids, beta-blockers, amiodarone, angiotensin-converting enzyme inhibitors, and diuretics). Clinical course is described, cardiac magnetic resonance images are shown. This case underlines how myocarditis is a disease that should not be underestimated: it could present with life-threatening complications such as malignant arrhythmias and/or severe systolic dysfunction. .

Non-vitamin K oral anticoagulants at the time of cardiac rhythm device surgery: A systematic review and meta-analysis.

INTRODUCTION: Use of non-vitamin K oral anticoagulants (NOACs) has rapidly increased worldwide. We aimed to systematically assess the available evidence regarding the safety and efficacy of NOACs in patients undergoing cardiac implantable electronic device (CIED) surgery. METHODS: We performed a systematic literature search. Eligible randomised controlled trials and cohort studies were included. The primary outcome measures were clinically significant device-pocket haematoma and thromboembolic events. RESULTS: A total of 12 studies were included, equating to 2120 patients. The separate pooling of rate of events showed a low incidence of clinically significant device-pocket haematoma, although numerically higher in patients on continued (1.5%; CI95%0.8-3.0) versus interrupted NOAC (0.9%; CI95%0.5-1.7). The rate of any device-pocket haematoma was numerically higher in the continued versus interrupted NOAC group (5.4%; CI95%3.8-7.7 versus 2.4%; CI95%1.8-3.3). The incidence of thromboembolic events (0.4%; CI95%0.2-0.8) was low and comparable. From a meta-analysis of 3 studies (equating to 773 subjects) allowing for a comparison of continued versus interrupted NOAC, we found no significant difference between the 2 strategies in terms of clinically significant pocket haematoma (RR1.14; CI95%0.43-3.06, p = 0.79), thromboembolic complications (RR1.03; CI95%0.06-16.37, p = 0.98), and any pocket haematoma (RR1.19; CI95%0.65-2.20, p = 0.57). CONCLUSION: Use of NOACs at the time of CIEDs surgery appears to be safe, and either strategy of peri-procedure continuation or interruption might be reasonable. However, continuation of NOAC seems to be associated with a numerically higher rate of bleeding complications. Certainty of the evidence is low, and further studies are required to confirm these findings.

Endothelial Dysfunction, Fibrinolytic Activity, and Coagulation Activity in Patients With Atrial Fibrillation According to Type II Diabetes Mellitus Status.

Recent findings in atrial fibrillation (AF) patients receiving oral anticoagulation showed that diabetes without insulin therapy has a thromboembolic risk comparable to nondiabetic patients, whereas only diabetic patients on insulin have a heightened thromboembolic risk. We explored possible pathophysiological correlates of such finding on 90 AF patients on oral anticoagulation, divided according to diabetes status (n = 30 without diabetes; n = 29 with diabetes on oral antidiabetic drugs; n = 31 with insulin-requiring diabetes). We assessed von Willebrand Factor (VWF) concentration (VWF:Ag) and activity (VWF R:Co) as measures of endothelial dysfunction; and thrombin-activatable fibrinolysis inhibitor (TAFI) and prothrombin fragment 1 + 2 (F1+2) levels as markers of fibrinolytic activity and thrombin generation. Values of VWF:Ag, VWF:RCo, and TAFI were similar in the 3 groups. Patients with diabetes requiring insulin had significantly higher levels of F1+2 (median 23.1 pg/ml [interquartile range 17.6; 33.5]) than those without diabetes (16.3 pg/ml [11.5; 22.5], p = 0.036) and diabetic patients on oral antidiabetic drugs (20.6 pg/ml [13.3; 29], p = 0.046). Thus, in AF patients receiving oral anticoagulation, those with diabetes, regardless of the diabetes type (with or without insulin therapy), and those without diabetes have comparable indices of the explored parameters of endothelial dysfunction and fibrinolytic activity. Despite anticoagulant therapy, thrombin generation is selectively higher in diabetic patients' on insulin than in those without diabetes or with diabetes on oral antidiabetic drugs, with no differences between these latter 2 conditions. Thrombin generation might thus be a predominant contributor to the excess of thromboembolic risk in AF patients on insulin-requiring diabetes.

Interaction Between Diabetes Mellitus and Platelet Reactivity in Determining Long-Term Outcomes Following Percutaneous Coronary Intervention.

Diabetes mellitus (DM) is an independent predictor of adverse outcomes in patients with coronary artery disease (CAD). We investigated the interaction between DM and high platelet reactivity (HPR) in determining long-term clinical outcomes after percutaneous coronary intervention (PCI). We enrolled 500 patients who were divided based on the presence of DM and HPR. Primary endpoint was the occurrence of major adverse clinical events (MACE) at 5 years. Patients with both DM and HPR showed the highest estimates of MACE (37.9%, log-rank p < 0.001), all-cause death (15.5%, log-rank p = 0.022), and non-fatal myocardial infarction (25.9%, log-rank p < 0.001). At Cox proportional hazard analysis, the coexistence of DM and HPR was an independent predictor of MACE (HR 3.46, 95% CI 1.67-6.06, p < 0.001). Among patients with stable CAD undergoing elective PCI and treated with aspirin and clopidogrel, the combination of DM and HPR identifies a cohort of patients with the highest risk of MACE at 5 years.

Incremental role of glycaemic variability over HbA1c in identifying type 2 diabetic patients with high platelet reactivity undergoing percutaneous coronary intervention.

BACKGROUND: Diabetic patients with on-treatment high platelet reactivity (HPR) show an increased risk of thrombotic events. Whether measuring glycated haemoglobin (HbA1c) levels and/or glycaemic variability (GV) may help identifying diabetic patients at higher risk deserving tailored antiplatelet and/or glucose lowering strategies is unknown. We aimed to investigate the relationship between GV, HbA1c levels and platelet reactivity in patients with type 2 diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI). METHODS: Platelet reactivity was measured in type 2 DM patients using VerifyNow P2Y12 assay. HPR was defined as P2Y12 Reaction Unit (PRU) > 240. GV was expressed through mean amplitude of glycaemic excursions (MAGE) and coefficient of variance (CV) by using the iPro™ continuous glucose recorder. RESULTS: Thirty-five patients (age 70 ± 9 years, 86% male, mean HbA1c 7.2 ± 1.0%) on clopidogrel therapy were enrolled. HbA1c was independently associated with HPR (OR 7.25, 95% CI 1.55-33.86, p = 0.012). Furthermore, when factored into the model, GV indexes provided independent (OR 1.094, 95% CI 1.007-1.188, p < 0.034) and additional (p < 0.001) diagnostic significance in identifying diabetic patients with HPR. CONCLUSIONS: Glyco-metabolic state significantly correlates with HPR in well-controlled type 2 DM patients on clopidogrel therapy. HbA1c identifies patients at higher thrombotic risk but the highest diagnostic accuracy is achieved by combining GV and HbA1c. Whether individualized antithrombotic and glucose-lowering therapies based on the assessment of these parameters may reduce the incidence of thrombotic events in patients undergoing PCI should be further investigated.

Changes of the coronary arteries and cardiac microvasculature with aging: Implications for translational research and clinical practice.

Aging results in functional and structural changes in the cardiovascular system, translating into a progressive increase of mechanical vessel stiffness, due to a combination of changes in micro-RNA expression patterns, autophagy, arterial calcification, smooth muscle cell migration and proliferation. The two pivotal mechanisms of aging-related endothelial dysfunction are oxidative stress and inflammation, even in the absence of clinical disease. A comprehensive understanding of the aging process is emerging as a primary concern in literature, as vascular aging has recently become a target for prevention and treatment of cardiovascular disease. Change of life-style, diet, antioxidant regimens, anti-inflammatory treatments, senolytic drugs counteract the pro-aging pathways or target senescent cells modulating their detrimental effects. Such therapies aim to reduce the ineluctable burden of age and contrast aging-associated cardiovascular dysfunction. This narrative review intends to summarize the macrovascular and microvascular changes related with aging, as a better understanding of the pathways leading to arterial aging may contribute to design new mechanism-based therapeutic approaches to attenuate the features of vascular senescence and its clinical impact on the cardiovascular system.

Antiplatelet therapy in valvular and structural heart disease interventions.

Transcatheter interventions for valvular and structural heart diseases are rapidly expanding due to greater operators' experience and development of new generation devices associated with increased procedural safety. They represent the standard strategy for patients with prohibitive risk for open surgery. These procedures are associated with a significant occurrence of both thrombotic and bleeding complications, thus in this setting, even more than in other percutaneous procedures, the balance between thrombotic and bleeding risk is critical. This review describes the current data available on the antithrombotic management of patients undergoing transcatheter aortic valve implantation (TAVI), percutaneous mitral valve repair with the MitraClip system, percutaneous left atrial appendage occlusion and percutaneous patent foramen ovale (PFO)/atrial septal defects (ASD) closure.

[The hybrid strategy for complete myocardial revascularization in the frail elderly patient]. / La strategia "ibrida" per il conseguimento di una rivascolarizzazione miocardica completa nel paziente anziano fragile.

The hybrid strategy allows for a complete myocardial revascularization in patients with multivessel coronary artery disease and a high frailty index. These patients, due to their old age and multi-comorbidities, are evaluated with inadequate tools for their clinical complexity and destined to an incomplete revascularization for increased surgical or procedural risk. Hybrid revascularization enables to use the best techniques resulting from the surgical and percutaneous approach defining a tailored strategy for the patient. In the frail patient, this strategy is associated with favorable outcomes and a lower exposure to periprocedural complications.

Comparison of Lipid-Lowering Medications and Risk for Cardiovascular Disease in Diabetes.

PURPOSE OF THE REVIEW: To summarize available evidence regarding lipid-lowering interventions for the prevention of cardiovascular disease in patients with diabetes. RECENT FINDINGS: Statins and non-statin therapies that act through upregulation of LDL receptor expression are associated with similar cardiovascular risk reduction per decrease in LDL cholesterol. In subjects with diabetes, with or without established cardiovascular disease, each 39 mg/dl reduction in LDL cholesterol observed with statins is associated with a 21% relative reduction in the risk of major coronary events at 5 years. Statins remain the first-line lipid-lowering agents for the management of dyslipidemia in individuals with diabetes; however, the addition of non-statin therapies to lower LDL cholesterol, such as ezetimibe and PCSK-9 inhibitors, to maximally tolerated statin therapy is recommended in patients with atherosclerotic cardiovascular disease and baseline LDL cholesterol over 70 mg/dl. Recent data support even lower LDL cholesterol targets (< 55 mg/dl) to further reduce the risk of cardiovascular events especially in subjects with diabetes and documented cardiovascular disease.

Impact of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio on 5-Year Clinical Outcomes of Patients with Stable Coronary Artery Disease Undergoing Elective Percutaneous Coronary Intervention.

The prognostic role of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with stable coronary artery disease (CAD) is still unclear. We enrolled 500 patients undergoing elective percutaneous coronary intervention (PCI). Blood samples were drawn prior to PCI for NLR and PLR calculation. Major adverse clinical events (MACE), which included death, myocardial infarction (MI), and target vessel revascularization (TVR), were recorded up to 5 years. Patients in the higher tertile of NLR presented higher Kaplan-Meier estimates of MACE (26.0% vs. 16.9% in tertile 2 vs. 14.3% in tertile 1; p = 0.042) and death (12.0% vs 6.9% in tertile 2 vs. 4.6% in tertile 1; p = 0.040), whereas there were no significant differences in the estimates of MI and TVR. NLR in the higher tertile was an independent predictor of MACE (HR 1.65, 95% CI 1.07-2.55, p = 0.024). No significant difference was observed across tertiles of PLR. Unlike PLR, elevated pre-procedural NLR is associated with an increased risk of 5-year clinical adverse events.

Interrupted versus uninterrupted novel oral anticoagulant peri-implantation of cardiac device: A single-center randomized prospective pilot trial.

BACKGROUND: Many patients requiring cardiac implantable electronic device (CIED) implantation are on long-term oral anticoagulant therapy. While continuation of warfarin has been shown to be safe and reduce bleeding complications compared to interruption of warfarin therapy and heparin bridging, it is not known which novel oral anticoagulants (NOAC) regimen (interrupted vs uninterrupted) is better in this setting. METHODS: One-hundred and one patients were randomized to receive CIED implantation with either interrupted or uninterrupted/continuous NOAC therapy before surgery. No heparin was used in either treatment arm. The primary end-point was the presence of a clinically significant pocket hematoma after CIED implantation. The secondary end-point was a composite of other major bleeding events, device-related infection, thrombotic events, and device-related admission length postdevice implantation. RESULTS: Both treatment groups were equally balanced for baseline variables and concomitant medications. One clinically significant pocket hematoma occurred in the uninterrupted NOAC group and none in the interrupted group (P  =  0.320). There was no difference in other bleeding complications. No thrombotic events were observed in either of the two groups. CONCLUSIONS: Despite the paucity of bleeding events, data from this pilot study suggest that uninterrupted NOAC therapy for CIED implantation appears to be as safe as NOAC interruption and does not increase bleeding complications.