Current Medical Therapy and Revascularization in Peripheral Artery Disease of the Lower Limbs: Impacts on Subclinical Chronic Inflammation.

Peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CeVD) are characterized by atherosclerosis and inflammation as their underlying mechanisms. This paper aims to conduct a literature review on pharmacotherapy for PAD, specifically focusing on how different drug classes target pro-inflammatory pathways. The goal is to enhance the choice of therapeutic plans by considering their impact on the chronic subclinical inflammation that is associated with PAD development and progression. We conducted a comprehensive review of currently published original articles, narratives, systematic reviews, and meta-analyses. The aim was to explore the relationship between PAD and inflammation and evaluate the influence of current pharmacological and nonpharmacological interventions on the underlying chronic subclinical inflammation. Our findings indicate that the existing treatments have added anti-inflammatory properties that can potentially delay or prevent PAD progression and improve outcomes, independent of their effects on traditional risk factors. Although inflammation-targeted therapy in PAD shows promising potential, its benefits have not been definitively proven yet. However, it is crucial not to overlook the pleiotropic properties of the currently available treatments, as they may provide valuable insights for therapeutic strategies. Further studies focusing on the anti-inflammatory and immunomodulatory effects of these treatments could enhance our understanding of the mechanisms contributing to the residual risk in PAD and pave the way for the development of novel therapies.

Sex-Based Differences in Clinical Characteristics and Outcomes among Patients with Peripheral Artery Disease: A Retrospective Analysis.

Peripheral arterial disease (PAD) is a prevalent medical condition associated with high mortality and morbidity rates. Despite the high clinical burden, sex-based differences among PAD patients are not well defined yet, in contrast to other atherosclerotic diseases. This study aimed to describe sex-based differences in clinical characteristics and outcomes among hospitalized patients affected by PAD. This was a retrospective study evaluating all patients with a diagnosis of PAD admitted to the Emergency Department from 1 December 2013 to 31 December 2021. The primary endpoint of the study was the difference between male and female PAD patients in cumulative occurrence of Major Adverse Cardiovascular Events (MACEs) and Major Adverse Limb Events. A total of 1640 patients were enrolled. Among them, 1103 (67.3%) were males while females were significantly older (median age of 75 years vs. 71 years; p =< 0.001). Females underwent more angioplasty treatments for revascularization than men (29.8% vs. 25.6%; p = 0.04); males were treated with more amputations (19.9% vs. 15.3%; p = 0.012). A trend toward more MALEs and MACEs reported in the male group did not reach statistical significance (OR 1.27 [0.99-1.64]; p = 0.059) (OR 0.75 [0.50-1.11]; p = 0.153). However, despite lower extremity PAD severity seeming similar between the two sexes, among these patients males had a higher probability of undergoing lower limb amputations, of cardiovascular death and of myocardial infarction. Among hospitalized patients affected by PAD, even if there was not a sex-based significant difference in the incidence of MALEs and MACEs, adverse clinical outcomes were more common in males.

Development of a biomarker panel for assessing cardiovascular risk in diabetic patients with chronic limb-threatening ischemia (CLTI): a prospective study.

BACKGROUND: Lower-extremity endovascular revascularization (LER) is often required for diabetic patients with chronic limb threatening ischemia (CLTI). During the post-revascularization period patients may unpredictably experience major adverse cardiac events (MACE) and major adverse limb events (MALE). Several families of cytokines are involved in the inflammatory process that underlies the progression of atherosclerosis. According to current evidence, we have identified a panel of possible biomarkers related with the risk of developing MACE and MALE after LER. The aim was to study the relationship between a panel of biomarkers - Interleukin-1 (IL-1) and 6 (IL-6), C-Reactive Protein (CRP), Tumor Necrosis Factor-α (TNF-α), High-Mobility Group Box-1 (HMGB-1), Osteoprotegerin (OPG), Sortilin and Omentin-1- at baseline, with cardiovascular outcomes (MACE and MALE) after LER in diabetic patients with CLTI. METHODS: In this prospective non-randomized study, 264 diabetic patients with CLTI undergoing endovascular revascularization were enrolled. Serum levels of each biomarker were collected before revascularization and outcomes' incidence was evaluated after 1, 3, 6 and 12 months. RESULTS: During the follow-up period, 42 cases of MACE and 81 cases of MALE occurred. There was a linear association for each biomarker at baseline and incident MACE and MALE, except Omentin-1 levels that were inversely related to the presence of MACE or MALE. After adjusting for traditional cardiovascular risk factors, the association between each biomarker baseline level and outcomes remained significant in multivariable analysis. Receiver operating characteristics (ROC) models were constructed using traditional clinical and laboratory risk factors and the inclusion of biomarkers significantly improved the prediction of incident events. CONCLUSIONS: Elevated IL-1, IL-6, CRP, TNF-α, HMGB-1, OPG and Sortilin levels and low Omentin-1 levels at baseline correlate with worse vascular outcomes in diabetic patients with CLTI undergoing LER. Assessment of the inflammatory state with this panel of biomarkers may support physicians to identify a subset of patients more susceptible to the procedure failure and to develop cardiovascular adverse events after LER.

The role of Klotho and FGF23 in cardiovascular outcomes of diabetic patients with chronic limb threatening ischemia: a prospective study.

Cardiovascular complications after lower extremity revascularization (LER) are common in diabetic patients with peripheral arterial disease (PAD) and chronic limb threatening ischemia (CLTI). The Klotho-fibroblast growth factor 23 (FGF23) axis is associated with endothelial injury and cardiovascular risk. We aimed to analyze the relationship between Klotho and FGF23 serum levels and the incidence of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after LER in diabetic patients with PAD and CLTI. Baseline levels of Klotho and FGF23, and their association with subsequent incidence of MACE and MALE were analyzed in a prospective, non-randomized study in a population of diabetic patients with PAD and CLTI requiring LER. A total of 220 patients were followed for 12 months after LER. Sixty-three MACE and 122 MALE were recorded during follow-up period. Baseline lower Klotho serum levels (295.3 ± 151.3 pg/mL vs. 446.4 ± 171.7 pg/mL, p < 0.01), whereas increased serum levels FGF23 (75.0 ± 11.8 pg/mL vs. 53.2 ± 15.4 pg/mL, p < 0.01) were significantly associated with the development of MACE. Receiver operating characteristic (ROC) analysis confirmed the predictive power of Klotho and FGF23 baseline levels. Furthermore, decreased Klotho levels were associated with the occurrence of MALE after LER (329.1 ± 136.8 pg/mL vs 495.4 ± 183.9 pg/mL, p < 0.01). We found that Klotho and FGF23 baseline levels are a potential biomarker for increased cardiovascular risk after LER in diabetic patients with PAD and CLTI.

Serum high mobility group box-1 levels associated with cardiovascular events after lower extremity revascularization: a prospective study of a diabetic population.

BACKGROUND: Peripheral arterial disease (PAD) is one of the most disabling cardiovascular complications of type 2 diabetes mellitus and is indeed associated with a high risk of cardiovascular and limb adverse events. High mobility group box-1 (HMGB-1) is a nuclear protein involved in the inflammatory response that acts as a pro-inflammatory cytokine when released into the extracellular space. HMBG-1 is associated with PAD in diabetic patients. The aim of this study was to evaluate the association between serum HMGB-1 levels and major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after lower-extremity endovascular revascularization (LER) in a group of diabetic patients with chronic limb-threatening ischemia (CLTI). METHODS: We conducted a prospective observational study of 201 diabetic patients with PAD and CLTI requiring LER. Baseline serum HMGB-1 levels were determined before endovascular procedure. Data on cardiovascular and limb outcomes were collected in a 12-month follow-up. RESULTS: During the follow-up period, 81 cases of MACE and 93 cases of MALE occurred. Patients who subsequently developed MACE and MALE had higher serum HMGB-1 levels. Specifically, 7.5 ng/mL vs 4.9 ng/mL (p < 0.01) for MACE and 7.2 ng/mL vs 4.8 ng/mL (p < 0.01) for MALE. After adjusting for traditional cardiovascular risk factors, the association between serum HMGB-1 levels and cardiovascular outcomes remained significant in multivariable analysis. In our receiver operating characteristic (ROC) curve analysis, serum HMGB-1 levels were a good predictor of MACE incidence (area under the curve [AUC] = 0.78) and MALE incidence (AUC = 0.75). CONCLUSIONS: This study demonstrates that serum HMGB-1 levels are associated with the incidence of MACE and MALE after LER in diabetic populations with PAD and CLTI.

Statins in High Cardiovascular Risk Patients: Do Comorbidities and Characteristics Matter?

Atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality are decreasing in high-income countries, but ASCVD remains the leading cause of morbidity and mortality in high-income countries. Over the past few decades, major risk factors for ASCVD, including LDL cholesterol (LDL-C), have been identified. Statins are the drug of choice for patients at increased risk of ASCVD and remain one of the most commonly used and effective drugs for reducing LDL cholesterol and the risk of mortality and coronary artery disease in high-risk groups. Unfortunately, doctors tend to under-prescribe or under-dose these drugs, mostly out of fear of side effects. The latest guidelines emphasize that treatment intensity should increase with increasing cardiovascular risk and that the decision to initiate intervention remains a matter of individual consideration and shared decision-making. The purpose of this review was to analyze the indications for initiation or continuation of statin therapy in different categories of patient with high cardiovascular risk, considering their complexity and comorbidities in order to personalize treatment.

The Gut in Heart Failure: Current Knowledge and Novel Frontiers.

Heart failure (HF) represents a major health problem affecting millions of people worldwide. In the latest years, many efforts have been made to search for more effective strategies to prevent and modify the course of this disease, but results are still not satisfying. HF represents a complex clinical syndrome involving many other systems, including the gastrointestinal system. Although the relationship between the gut and HF is far from being fully understood, based on recent evidence highlighting the putative role of the gastrointestinal system in different cardiovascular diseases, it is conceivable that the gut-heart link may represent the basis for novel therapeutic approaches in the HF context as well. This intricate interplay involving typical hemodynamic changes and their consequences on gut morphology, permeability, and function, sets the stage for alterations in microbiota composition and is able to impact mechanisms of HF through different routes such as bacterial translocation and metabolic pathways. Thus, the modulation of the gut microbiota through diet, probiotics, and fecal transplantation has been suggested as a potential therapeutic approach. More interestingly, another effect of alteration in microbiota composition reflects in the upregulation of cotransporters (NHE3) with consequent salt and fluid overload and worsening visceral congestion. Therefore, the inhibitors of this cotransporter may also represent a novel therapeutic frontier. By review of recent data on this topic, we describe the current state of the complex interplay between the gastrointestinal and cardiac systems in HF, and the relevance of this knowledge in seeking new therapeutic strategies.

Corrigendum to "Anabolic Hormone Deficiencies in Heart Failure with Reduced or Preserved Ejection Fraction and Correlation with Plasma Total Antioxidant Capacity".

[This corrects the article DOI: 10.1155/2020/5798146.].

Anabolic Hormones Deficiencies in Heart Failure With Preserved Ejection Fraction: Prevalence and Impact on Antioxidants Levels and Myocardial Dysfunction.

Purpose: In heart failure with reduced ejection fraction, catabolic mechanisms have a strong negative impact on mortality and morbidity. The relationship between anabolic hormonal deficiency and heart failure with preserved ejection fraction (HFpEF) has still been poorly investigated. On the other hand, oxidative stress is recognized as a player in the pathogenesis of HFpEF. Therefore, we performed a cohort study in HFpEF aimed to (1) define the multi-hormonal deficiency prevalence in HFpEF patients; (2) investigate the relationships between hormonal deficiencies and echocardiographic indexes; (3) explore the modulatory activity of anabolic hormones on antioxidant systems. Methods: 84 patients with diagnosis of HFpEF were enrolled in the study. Plasma levels of N-terminal pro-brain natriuretic peptide, fasting glucose, insulin, lipid pattern, insulin-like growth factor-1, dehydroepiandrosterone-sulfate (DHEA-S), total testosterone (T, only in male subjects) were evaluated. Hormonal deficiencies were defined according to T.O.S.C.A. multi-centric study, as previously published. An echocardiographic evaluation was performed. Plasma total antioxidant capacity (TAC) was measured using the system metmyoglobin -H2O2 and the chromogen ABTS, whose radical form is spectroscopically revealed; latency time (LAG) in the appearance of ABTS• is proportional to antioxidants in sample. Results: Multiple deficiencies were discovered. DHEA-S deficiency in 87% of patients, IGF-1 in 67% of patients, T in 42%. Patients with DHEA-S deficiency showed lower levels of TAC expressed by LAG (mean ± SEM 91.25 ± 9.34 vs. 75.22 ± 4.38 s; p < 0.05). No differences between TAC in patients with or without IGF-1 deficiency were found. A trend toward high level of TAC in patients without hormonal deficiencies compared with patients with one or multiple deficiencies was found. Regarding echocardiographic parameters, Left Atrial and Left Atrial Volume Index were significantly higher in patients with low IGF-1 values (mean ± SD 90.84 ± 3.86 vs. 72.83 ± 3.78 mL; 51.03 ± 2.33 vs. 40.56 ± 2.46 mL/m2, respectively; p < 0.05). Conclusions: Our study showed high prevalence of anabolic deficiencies in HFpEF. DHEA-S seems to influence antioxidant levels; IGF-1 deficiency was associated with alteration in parameters of myocardial structure and dysfunction. These data suggest a role of anabolic hormones in the complex pathophysiological mechanisms of HFpEF and could represent the basis for longitudinal studies and investigations on possible benefits of replacement therapy.

Anabolic Hormone Deficiencies in Heart Failure with Reduced or Preserved Ejection Fraction and Correlation with Plasma Total Antioxidant Capacity.

BACKGROUND: While anabolic hormone deficit is a common finding in heart failure with reduced ejection fraction (HFrEF), few data are available in heart failure with preserved ejection fraction (HFpEF). METHODS: Blood samples were collected for metabolic (total cholesterol, HDL cholesterol, LDL cholesterol, creatinine, and glucose) and hormonal (IGF-1, DHEA-S, TSH, fT3, fT4, and T) determination, comparing 30 patients with HFpEF and 20 patients with HFrEF. Total antioxidant capacity was evaluated by using the spectrophotometric method using the latency time in the appearance of the radical species of a chromogen (LAG, sec) as a parameter proportional to antioxidant content of the sample. Echocardiographic parameters were also assessed in the two groups. RESULTS: A high prevalence of testosterone (32% in HFrEF and 72% in HFpEF, p < 0.05) and DHEA-S deficiencies was observed in HFpEF patients. Echocardiographic parameters did not correlate with hormone values. A significant direct correlation between T (r 2 = 0.25, p < 0.05) and DHEA-S (r 2 = 0.19, p < 0.05) with LAG was observed only in HFpEF. CONCLUSION: Anabolic hormone deficiency is clearly shown in HFpEF, as already known in HFrEF. Although longitudinal studies are required to confirm the prognostic value of this observation, our data suggest different mechanisms in modulating antioxidants in the two conditions, with possible therapeutic implications.

The strange case of congenital mitral stenosis in an adult man with cor triatriatum.

We report the case of a 74-year-old male, with a medical history of cor triatriatum, admitted with a 10-day history of intermittent fever. Three sets of blood cultures were positive for Providencia rettgeri. Transthoracic and transesophageal echocardiogram excluded infective endocarditis, but revealed a congenital accessory tissue adhering to the mitral valve, causing supravalvular mitral stenosis. Cor triatriatum sinistrum is a rare congenital cardiac anomaly, even more uncommon in adults, and quite exceptional when associated with mitral valve disease. Because the patient had no symptoms related to the heart valve disease, no surgical indication was given and he was managed conservatively.

Acute intramucosal dissection in eosinophilic esophagitis.

Acute intramucosal dissection of the esophagus (IED) is a rare complication of eosinophilic esophagitis (EoE). Only few of such IED cases have been described in the literature. We report the case of a 32-year-old man with a 4-months diagnosis of EoE who was referred to the Emergency Department complaining of dysphagia, epigastric pain and fever and who was diagnosed, after an urgent endoscopy, an IED. After careful evaluation and multidisciplinary assessment the patient was managed conservatively, with specific medical therapy-high-dose proton pump inhibitors, swallowed steroid, broad-spectrum antibiotic-and, after a period of absolute fasting, a diet regimen based on "six food elimination diet" with a stepwise increase of food consistency. The patient experienced a rapid and complete relief of symptoms, paralleled by a progressive healing of IED with no recurrence over a 6-month follow-up period. In EoE patients with a high clinical suspicion of an acute IED, we suggest an early execution of chest CT and a contrast esophagography, avoiding potentially dangerous endoscopic procedures in the acute phase that can contribute to enlargement of the dissection, or progression to perforation. Once the diagnosis of IED is confirmed, even in the presence of a contained perforation, a conservative treatment with a multidisciplinary management should always be considered.

Intralobar Pulmonary Sequestration and Increased Serum CA 19-9.

Intralobar pulmonary sequestration is an uncommon congenital lung anomaly which consists of a mass of normal lung tissue not connected to the normal tracheobronchial tree and supplied by an anomalous systemic artery. Carbohydrate antigen 19-9 (CA 19-9) is widely accepted as a tumour marker for biliary, pancreatic and gastrointestinal cancer. However, CA 19-9 may also be increased in patients with benign disease. We describe the case of a 56-year-old woman with intralobar pulmonary sequestration who underwent unnecessary and extensive diagnostic abdominal examinations because of an increase in CA 19-9 serum levels. LEARNING POINTS: Knowledge of pulmonary sequestration causing increased serum CA 19-9 is important for the internist because it can help in the differential diagnosis even with neoplastic disease.Such awareness can also decrease the use of antibiotics.Familiarity with the condition can reduce the number of invasive examinations performed to exclude neoplasms of the gastrointestinal tract.

Cardiovascular Involvement in Erdheim-Chester Disease: A Case Report and Review of the Literature.

Erdheim-Chester disease (ECD) is a rare, multiorgan, non-Langerhans cell histiocytosis of uncertain origin, characterized by systemic xanthogranulomatous infiltration from CD68+CD1a- histiocytes. Skeletal involvement is present in up to 96% of cases with bilateral osteosclerosis of meta-diaphysis of long bones. Furthermore, in more than 50% of cases there is 1 extraskeletal manifestation. In this case report, we describe an interesting case of ECD with an extensive pan-cardiac and vascular involvement, in addition to skeletal, retro-orbital, and retroperitoneum one.A 44-year-old woman with a long history of exophthalmos referred to our hospital for elective surgical orbital decompression. At preoperative examinations a large pericardial effusion was discovered. Echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI) described an inhomogeneous mass involving pericardium and the right heart, abdominal aorta and its main branches and the retroperitoneum, suggestive for a systemic inflammatory disorder. Histological examination on a biopsy sample confirmed the diagnosis of ECD. Radiology showed the pathognomonic long-bone involvement. Surgical orbital decompression was performed and medical therapy with interferon-α (INF-α) was started.Among extraskeletal manifestations of ECD, cardiovascular involvement is often asymptomatic and thus under-diagnosed but linked to poor prognosis. This is why clinician should always look for it when a new case of ECD is diagnosed.

Leukocyte Activation in Obese Patients: Effect of Bariatric Surgery.

The rising prevalence of obesity is a major global health problem. In severe obesity, bariatric surgery (BS) allows to obtain a significant weight loss and comorbidities improvement, among them one of the factors is the thrombotic risk. In this observational study, we measured indices of leukocyte activation in severely obese patients as markers of increased thrombotic risk in relation with serum markers of inflammation before and after BS. Frequency of polymorphonuclear neutrophil-platelet (PLT) and monocyte (MONO)-PLT aggregates as well as of tissue factor (TF) expressing MONOs was measured in the peripheral blood of 58 consecutive obese patients and 30 healthy controls. In 31 of the 58 obese patients, data obtained at the enrollment were compared with those obtained at 3, 6, and 12 months after BS. Compared with healthy controls, obese patients showed a higher frequency of polymorphonuclear leukocyte (PMNL)-PLT aggregates (7.47 ± 2.45 [6.82-8.11]% vs 5.85 ± 1.89 [5.14-6.55]%, P = 0.001), MONO-PLT aggregates (12.31 ± 7.33 [10.38-14.24]% vs 8.14 ± 2.22 [7.31-8.97]%, P < 0.001), and TF expressing MONOs (4.01 ± 2.11 [3.45-4.56]% vs 2.64 ± 1.65 [2.02-3.25]%, P = 0.002). PMNL-PLT and MONO-PLT aggregate frequency was positively correlated with TF expressing MONOs (R2 = 0.260, P = 0.049 and R2 = 0.318, P = 0.015, respectively). BS was performed in 31 patients and induced a significant reduction of the body mass index, and waist and hip circumferences. These effects were associated with a significant decrease of PMNL-PLT aggregates at 12 months (7.58 ± 2.27 [6.75-8.42]% vs 4.47 ± 1.11 [3.93-5.01]%, P < 0.001), and a reduction of TF expressing MONOs at 6 (3.82 ± 2.04 [3.07-4.57]% vs 1.60 ± 1.69 [0.30-2.90]%, P = 0.008) and 12 months (3.82 ± 2.04 [3.07-4.57]% vs 1.71 ± 0.54 [1.45-1.97]%, P = 0.001) after BS.These data suggest that leukocyte-PLT aggregate formation and MONO activation represent an important mechanism underlying the increased thrombotic risk of obese patients. We also show that BS is effective in normalizing these inflammatory indices.

Polycythemia vera: gender-related phenotypic differences.

In polycythemia vera, gender has recently been shown to influence the JAK2(V617F) allele burden, but its effect on the disease phenotype is unknown. This issue was investigated using the database of the European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study. The ECLAP Study recruited 1,638 polycythemic subjects and followed for 2.7 ± 1.3 years. At study entry, men, compared to women, had a higher prevalence of myocardial infarction (11.3 vs. 5.8%; P < 0.0001) and peripheral arterial disease (6.1 vs. 2.9%; P < 0.05) while a history of venous thrombosis was more common in women (11.4 vs. 7.9%, P = 0.016). Among 234 venous thrombosis, there were 39 splanchnic vein thromboses (33 extra-hepatic portal vein thromboses and 6 Budd-Chiari syndromes). Most of these events occurred as an early disease presentation in young female subjects. Women, compared to men, had higher platelet counts (average value 430 ± 213 vs. 375 ± 201 × 10(9)/L; P < 0.0001) and lower hematocrits (0.46 ± 0.06 vs. 0.48 ± 0.06 l/l; P < 0.0001). Cholesterol plasma level, available in 995 subjects (61%), was lower in male patients (180.8 ± 43.1 vs. 196 ± 46.6 mg/dl; P < 0.0001). During follow-up there were 205 major thromboses confirming an high incidence of myocardial infarction in men although not statistically significant (1.2 vs. 0.6 cases per 100 person-years; P > 0.05). These data show several gender-related differences both in the thrombotic diathesis and in the prevalence of vascular risk factors of PV patients.

Polycythemia vera.

The diagnostic approach to a patient with polycythemia has been greatly simplified by the introduction of new genetic testing in addition to traditional tests, such as measurement of red cell mass and serum erythropoietin (Epo) level. Clonal erythrocytosis, which is the diagnostic feature of polycythemia vera (PV), is almost always associated with a JAK2 mutation (JAK2V617F or exon 12). Therefore, in a patient with acquired erythrocytosis, it is reasonable to begin the diagnostic work-up with JAK2 mutation analysis to distinguish PV from secondary erythrocytosis. The clinical course of PV is marked by a high incidence of thrombotic complications that represent the main cause of morbidity and mortality in these patients. Blood hyperviscosity as well as platelet and leukocyte quantitative, and qualitative abnormalities play a major role in the pathogenesis of thrombophilia. Prevention of vascular events and minimizing the risk of disease transition into acute leukaemia are the main targets of the whole PV treatment strategy. This can rely on the use of low-dose aspirin in most patients, while the choice of the optimal cytoreductive strategy is based on the individual vascular risk. Phlebotomy is still the preferred treatment in subjects at low risk, while hydroxyurea or pipobroman is usually administered to most elderly subjects or subjects with a previous vascular history. The use of pegylated interferon, imatinib, and JAK2 inhibitors is currently being evaluated.