Long-Term Outcomes in Two-Year Follow-Up after Primary Treatment in Patients with a Prior Venous Thromboembolic Event: A Prospective, Observational, Real-Life Study.

BACKGROUND: Patients with acute venous thromboembolism (VTE) need anticoagulation (AC) therapy for at least 3/6 months (primary treatment); after that period, they should receive a decision on the duration of therapy. METHODS: This study examined the complications occurring during two years of follow-up (FU) in patients with a first VTE who were recruited in 20 clinical centers and had discontinued or prolonged AC. They were included in the START2-POST-VTE prospective observational study. RESULTS: A total of 720 patients (53.5% males) who, after the completion of primary treatment, had received the decision to continue (n = 281, 39%; 76.1% with a DOAC) or discontinue (n = 439, 61%) AC were followed up for 2 years (total FU = 1318 years). The decision to prolong or suspend AC was made in similar proportions in patients with unprovoked or provoked index events. Courses of sulodexide treatment or Aspirin (100 mg daily) were prescribed to 20.3% and 4.5%, respectively, of the patients who discontinued AC. The bleeding rate was significantly higher in patients who extended AC (1.6% pt/y) than in those who stopped AC (0.1% pt/y; p = 0.001) and was higher in patients using standard-dose DOACs (3.1% pt/y) than in those using reduced-dose DOACs (0.4% pt/y). The recurrent VTE rates were similar between the two groups (2.2% pt/y during AC vs. 3% pt/y off AC). CONCLUSION: Physicians' decisions about AC duration were independent of the unprovoked/provoked nature of the index event. The bleeding rate was higher in patients who continued AC using standard-dose DOACs. Surprisingly, the rate of thrombotic recurrence was not different between those who continued or discontinued AC. Randomized studies comparing different procedures to decide on the duration of AC after a first VTE are needed.

Role of Endothelium in Cardiovascular Sequelae of Long COVID.

The global action against coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection, shed light on endothelial dysfunction. Although SARS-CoV-2 primarily affects the pulmonary system, multiple studies have documented pan-vascular involvement in COVID-19. The virus is able to penetrate the endothelial barrier, damaging it directly or indirectly and causing endotheliitis and multi-organ injury. Several mechanisms cooperate to development of endothelial dysfunction, including endothelial cell injury and pyroptosis, hyperinflammation and cytokine storm syndrome, oxidative stress and reduced nitric oxide bioavailability, glycocalyx disruption, hypercoagulability, and thrombosis. After acute-phase infection, some patients reported signs and symptoms of a systemic disorder known as long COVID, in which a broad range of cardiovascular (CV) disorders emerged. To date, the exact pathophysiology of long COVID remains unclear: in addition to the persistence of acute-phase infection mechanisms, specific pathways of CV damage have been postulated, such as persistent viral reservoirs in the heart or an autoimmune response to cardiac antigens through molecular mimicry. The aim of this review is to provide an overview of the main molecular patterns of enduring endothelial activation following SARS-CoV-2 infection and to offer the latest summary of CV complications in long COVID.

Gut Microbiota and Cardiovascular Disease: Evidence on the Metabolic and Inflammatory Background of a Complex Relationship.

Several studies in recent years have demonstrated that gut microbiota-host interactions play an important role in human health and disease, including inflammatory and cardiovascular diseases. Dysbiosis has been linked to not only well-known inflammatory diseases, such as inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematous, but also to cardiovascular risk factors, such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. The ways the microbiota is involved in modulating cardiovascular risk are multiple and not only related to inflammatory mechanisms. Indeed, human and the gut microbiome cooperate as a metabolically active superorganism, and this affects host physiology through metabolic pathways. In turn, congestion of the splanchnic circulation associated with heart failure, edema of the intestinal wall, and altered function and permeability of the intestinal barrier result in the translocation of bacteria and their products into the systemic circulation, further enhancing the pro-inflammatory conditions underlying cardiovascular disorders. The aim of the present review is to describe the complex interplay between gut microbiota, its metabolites, and the development and evolution of cardiovascular diseases. We also discuss the possible interventions intended to modulate the gut microbiota to reduce cardiovascular risk.

High prevalence of lower limb atherosclerosis is linked with the gut-liver axis in patients with primary biliary cholangitis.

BACKGROUND AND AIMS: Hypercholesterolemia is frequent in people with primary biliary cholangitis (PBC); however, it does not seem to confer an increased risk of cardiovascular disease. We aimed to evaluate the prevalence of peripheral arterial disease in PBC women and its association with the gut-liver axis and systemic inflammation. METHODS: Thirty patients affected by PBC and hypercholesterolemia were enrolled, with equal-sized groups of women with non-alcoholic fatty liver disease (NAFLD) and healthy controls (CTRL). All patients underwent Doppler ultrasound examination of peripheral arteries, assessment of flow-mediated dilation, quantification of circulating cytokines and vasoactive mediators and characterization of the gut microbiota. RESULTS: PBC patients had a higher prevalence of lower extremity arterial disease (LEAD) defined as atherosclerotic plaques in any of femoral, popliteal and/or tibial arteries compared with both NAFLD and CTRL women (83.3% vs. 53.3% and 50%, respectively; p = .01). Factors associated with LEAD at univariate analysis were VCAM-1 (p = .002), ICAM-1 (p = .003), and TNF-alpha (p = .04) serum levels, but only VCAM-1 (OR 1.1, 95% CI 1.0-1.1; p = .04) and TNF-alpha (OR 1.12, 95% CI 0.99-1.26; p = .04) were confirmed as independent predictors in the multivariate model. Gut microbiota analysis revealed that Acidaminococcus (FDR = 0.0008), Bifidobacterium (FDR = 0.001) and Oscillospira (FDR = 0.03) were differentially expressed among groups. Acidaminococcus, which was increased in PBC, was positively correlated with TNF-alpha serum levels. Down-regulation of metabolic pathways linked to fatty acid and butyrate metabolism, glyoxylate metabolism and branched-chain amino acids degradation was found in the functional gut metagenome of PBC women. CONCLUSIONS: LEAD is common in patients affected by PBC and is associated with inflammatory markers and alterations in the gut-liver axis.

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial.

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.

Depression and Endothelial Dysfunction in Psoriatic Arthritis: Is There Any Possible Relationship?

Background: Cardiovascular events (CVEs) are the first cause of death in patients with psoriatic arthritis (PsA). Depression is a recognized risk factor in cardiovascular events and is frequently associated with PsA. Flow-mediated dilatation (FMD) is a widely used method for assessing endothelial dysfunction, a parameter with strong prognostic implications for CVEs. The study aims to explore the relationship between FMD, depressive symptoms and serum cytokines in a cohort of patients with PsA. Patients and Methods: FMD was assessed in 50 consecutive PsA patients aged between 30 and 75 years without known cerebrovascular and coronary heart disease or diabetes. Depressive symptoms were reported using the related subscale of the Hospital Anxiety and Depression Scale (HDS). Disease features, activity indexes, and adjusted Framingham risk score (aFRS) were calculated. Serum level of IL-6, TNF-α, and IL-17A were also assessed. Results: In PsA patients (age 50.7 ± 10.2 years, male 42%, disease duration 5.9 ± 3.3 years, Disease Activity in PSoriatic Arthritis (DAPSA) score 14.0 ± 9.4) FMD inversely correlated with the severity of depressive symptoms according to HDS (ρ = -0.339, p = 0.016), age (ρ = -0.507, p = 0.001), aFRS (rs = -0.453, p < 0.001), duration of PsA (ρ = -0.507, p = 0.001), intensity of pain (ρ = -0.507, p = 0.001), and DAPSA (ρ = -0.507, p = 0.001). No statistically significant correlation was found between FMD or HDS and serum cytokines concentrations. HDS predicted FMD in a model adjusted for age, aFRS, PsA duration, and pain intensity (ß = -0.271, p = 0.008), with depressive symptoms contributing directly to 6.4% of the variance. Conclusions: Depressive symptoms correlate with endothelial dysfunction with an exposure-response pattern in our cohort of PsA patients.

Treatment Decision-Making of Secondary Prevention After Venous Thromboembolism: Data From the Real-Life START2-POST-VTE Register.

Patients with venous thromboembolism (VTE) should receive a decision on the duration of anticoagulant treatment (AT) that is often not easy to make. Sixteen Italian clinical centers included patients with recent VTE in the START2-POST-VTE register and reported the decisions taken on duration of AT in each patient and the reasons for them. At the moment of this report, 472 (66.9%) of the 705 patients included in the registry were told to stop AT in 59.3% and to extend it in 40.7% of patients. Anticoagulant treatment lasted ≥3 months in >90% of patients and was extended in patients with proximal deep vein thrombosis because considered at high risk of recurrence or had thrombophilic abnormalities. d-dimer testing, assessment of residual thrombus, and patient preference were also indicated among the criteria influencing the decision. In conclusion, Italian doctors stuck to the minimum 3 months AT after VTE, while the secondary or unprovoked nature of the event was not seen as the prevalent factor influencing AT duration which instead was the result of a complex and multifactorial evaluation of each patient.

Ultrasonography involvement of carotid, upper and lower limb arteries in a large cohort of systemic sclerosis patients.

OBJECTIVES: Data on macrovascular involvement in systemic sclerosis (SSc) are still debatable. The aim of this study was to estimate its prevalence and possible determinants in a large cohort. METHODS: One hundred and fifty-five outpatients with SSc were enrolled. Data about disease characteristics and cardiovascular risk factors were collected and patients underwent ecocolor Doppler ultrasonography of arteries of the neck and lower (LL) and upper (UL) limbs. RESULTS: Mean age was 57.9 ± 14.5 years and most were female (88.4%) with a limited subset (63.2%). Mean disease duration was 11.4 ± 8.1 years. Twenty-three (14.8%) had hypertension, 7 (4.8%) diabetes, 64 (41.3%) hypercholesterolemia and 63 (40.6%) were active/past smokers. Seventy-nine (49%) patients had plaques at carotids, 49 (32.9%) at LL and 7 (4.9%) at UL. In multivariate analysis, patients with carotid plaques had more often a limited pattern (P = .001), patients with distal LL plaques pulmonary arterial hypertension (P = .006) and patients with proximal LL plaques lower diffusing capacity for carbon monoxide adjusted to hemoglobin and its ratio to alveolar volume (P = .004). In patients with UL plaques traditional cardiovascular risk factors were not more common, while forced vital capacity was lower (P = .023). Finally, upper limb and proximal LL plaques were as common in early disease patients as in longstanding ones, although the former were younger. CONCLUSIONS: This study shows that macrovascular involvement is quite common in SSc and that some disease characteristics linked to microvascular involvement are associated with atherosclerotic plaques, which can be present even in early disease. Our study suggests that a complete evaluation of macrocirculation is mandatory for rheumatologists treating SSc patients.

Effects of a New Combination of Medical Food on Endothelial Function and Lipid Profile in Dyslipidemic Subjects: A Pilot Randomized Trial.

Nutritional approaches to improve dyslipidemias have been recently developed, but evidences on different medical foods are often incomplete. The main aim of our study was to evaluate the effects on endothelial function, lipid profile, and glucose metabolism of two different combinations of nutraceuticals, first one containing Bergavit (200 mg Citrus bergamia), Omega-3 (400 mg), Crominex 3+ (10 mcg trivalent chromium), and red yeast rice (100 mg; 5 mg monacolin K) and second one containing red yeast rice (200 mg; 3 mg monacolin K), Berberine (500 mg), Astaxanthin (0.5 mg), folic acid (200 mcg), Coenzyme Q10 (2 mg), and Policosanol (10 mg). Fifty subjects affected by dyslipidemia not requiring statin treatment were enrolled in this randomized, blind, controlled trial and submitted to blood sampling for lipid and glucose profiles and instrumental evaluation of endothelial function before and after 6 weeks of treatment with nutraceuticals. Both nutraceutical combinations improved the lipid profile; the nutraceutical containing 5 mg of monacolin K, 200 mg of the extract Citrus bergamia, 400 mg of Omega-3, and 10 mcg of trivalent chromium entailed a significant improvement of endothelial function with enhanced cholesterol lowering effect. In conclusion, this study confirms the positive effect of functional food on lipid profile and endothelial function in absence of major undesirable effects.

Concept and practice of transradial 5 French percutaneous treatment of coronary bifurcation lesions.

OBJECTIVES: To assess the efficacy and safety of transradial 5 French percutaneous treatment of coronary bifurcations using conventional devices. BACKGROUND: Radial artery is smaller than femoral artery, and its size may potentially limit transradial intervention, especially when coronary anatomy is not known. METHODS: Patients with bifurcations lesions undergoing transradial 5 French ad hoc revascularization were treated according to provisional side branch (SB) stenting followed by the POT-SB dilation-final POT sequence. Only conventional devices were used. RESULTS: Overall, 80 patients (58 men, 65 ± 10 years) were enrolled. True bifurcations accounted for 64% of cases, with the left anterior descending artery/diagonal branch being the most frequent bifurcation site (n = 37, 46%) and left main coronary artery bifurcation being treated in 6 (8%) patients. Angiographic success was achieved in 78 (97.5%) patients through a 5 French guiding catheter whereas in two cases, a 5-6 French guiding catheter upgrade was required to optimize SB treatment after the main bifurcation vessel have been secured. Overall, procedural success was achieved in all but one patient who had periprocedural necrosis following multivessel PCI. Another patient underwent target bifurcation revascularization because of a critical restenosis in a significant SB yielding an acute coronary syndrome five months after the index procedure. CONCLUSIONS: This study demonstrates the feasibility of transradial 5 French bifurcation intervention with nondedicated devices and preliminary supports its efficacy and safety over a wide range of bifurcation anatomy and complexity.

Anatomic Basis and Physiological Rationale of Distal Radial Artery Access for Percutaneous Coronary and Endovascular Procedures.

Transradial access offers important advantages over transfemoral access, including overall increased procedure comfort and better outcomes. Still, complications of transradial access exist, with radial artery occlusion being the most clinically relevant one. Puncture sites in the hand allowing distal radial artery access have initially been described for anterograde angioplasty of occluded radial arteries and could represent a valuable alternative to traditional wrist puncture for radial artery catheterization. What may at first appear as a "radialist eccentricity" definitely has a sound rationale, which the authors review. Knowledge of the anatomic and physiological principles at the basis of distal radial artery access is essential to promote rigorous understanding and practice of this new opportunity for both patients and interventional specialists.

Identifying a better strategy for ad hoc percutaneous coronary intervention in patients with anticipated unfavorable radial access: the Little Women study.

BACKGROUND: Transradial percutaneous coronary intervention (PCI) offers important advantages over transfemoral PCI, including better outcomes. However, when there is indication to ad hoc PCI, a 6 French workflow is a common default strategy, hence potentially influencing vascular access selection in patients with anticipated small size radial artery. METHODS: A multidimensional evaluation was performed to compare two ad hoc interventional strategies in women <160cm: a full 6 French workflow (namely 6 French introducer sheath, diagnostic catheters and guiding catheter) with a modified workflow consisting in the use of 5 French diagnostic catheters preceded by the placement of a 6 French sheath introducer and followed by a 6 French guiding catheter use for PCI. RESULTS: Overall 120 women (68±11years) were enrolled in the study. Coronary angiography has been performed using 5 French or 6 French diagnostic catheters in 57 (47.5%) and 63 (52.5%) cases, respectively. Radial spasm and switch to another access occurred more frequently among women who underwent coronary angiography with 6 French rather than 5 French diagnostic catheters (43% vs. 25%, p=0.03 and 2% vs. 11%, p=0.04, respectively). Total time to guidewire lesion crossing was also significantly higher when PCI has been preceded by 6 French rather than 5 French coronary angiography (23±11min vs 16±7min, p=0.013). CONCLUSIONS: In patients with anticipated unfavorable radial access, a workflow consisting in 6 French introducer sheath placement, 5 French coronary angiography, and 6 French coronary intervention is on multiple parameters the most straightforward and effective strategy.

Exercise and Protein Intake: A Synergistic Approach against Sarcopenia.

Sarcopenia, the age-dependent loss of muscle mass and function/strength, is increasingly recognized as a major risk factor for adverse outcomes in frail older people. As such, the skeletal muscle is a relevant target for interventions aimed at preventing or postponing the occurrence of negative health-related events in late life. The association among physical inactivity, insufficient intake of energy and protein, and poor muscle health in older adults suggests that physical exercise and targeted nutritional supplementation may offer substantial therapeutic gain against sarcopenia and its negative correlates. This view is supported by observational studies as well as by small-scale clinical trials. In this review, we summarize the available evidence on the beneficial effects of behavioral interventions on sarcopenia. We also briefly describe how the knowledge gathered so far has been used to design the "Sarcopenia and Physical fRailty IN older people: multicomponenT Treatment strategies" (SPRINTT) project. The randomized clinical trial conducted within SPRINTT will provide robust evidence on the effectiveness of exercise and nutrition at preventing negative outcomes associated with sarcopenia and physical frailty.

New semiquantitative ultrasonographic score for peripheral arterial disease assessment and its association with cardiovascular risk factors.

The data concerning the distribution, extent and progression of peripheral arterial disease (PAD), as well as its association with traditional cardiovascular (CV) risk factors, have generally been obtained from studies of patients in advanced stages of the disease undergoing surgical or endovascular treatment. In this study, we have introduced a new semiquantitative ultrasonographic score (ultrasonographic lower limb atherosclerosis (ULLA) score) that is able to categorize lower limb atherosclerotic lesions at all stages of PAD. We then associated these ultrasonographic categories with a CV risk profile. We enrolled 320 consecutive subjects with symptoms suggestive of PAD or with known CV risk factors referring to our angiology unit between 1 July 2014 and 30 June 2015 for ultrasonographic evaluation of the lower limb arteries. Femoropopliteal and run-off segments were categorized together and separately based on their ultrasonographic characteristics. In univariate and multivariate analyses, the ULLA scores were significantly associated with the main CV risk factors, that is, age, male gender, cigarette smoking, arterial hypertension, diabetes, dyslipidemia, sedentary lifestyle, previous CV events and family history of CV disease, and also confirming the specific association of single risk factors with different segments of lower limb arteries. The proposed ULLA score enables a complete evaluation of the entire lower limb atherosclerotic burden, extending the results concerning the association of PAD with CV risk factors to all stages of the disease, including the early stages. It can be feasible that this new score will facilitate better evaluation of the progression of PAD and its prospective role in CV risk stratification.