Clinical impact of high platelet reactivity in patients with atrial fibrillation and concomitant percutaneous coronary intervention on dual or triple antithrombotic therapy.

High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y12 inhibitor. In the present study all consecutive patients with history of AF discharged from our cardiology ward with dual (DAT) or triple (TAT) antithrombotic therapy after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y12 inhibitor. P2Y12 dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p = 0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p = 0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p = 0.045). In conclusion, in a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y12 inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario. The present analysis was performed in patients with AF undergoing PCI on dual or triple antithrombotic therapy. At 1 year follow-up MACCE incidence was consistent, and it was not different in different antithrombotic pattern groups. P2Y12 dependent HPR was a potent independent predictor of MACCE both at 3- and 12-months follow-up. In the first 3 months after stenting the carriage of CYP2C19*2 allele was similarly associated with MACCE. Abbreviation: DAT, dual antithrombotic therapy; HPR, high platelet reactivity; MACCE, major adverse cardiac and cerebrovascular events; PRU, P2Y12 reactive unit; TAT, triple antithrombotic therapy. Created with BioRender.com.

Case report: Dupilumab treatment improved type 2 disorders in a patient with IPEX syndrome diagnosis.

We described a case of IPEX syndrome successfully controlled with dupilumab, an anti-IL4 receptor alpha subunit inhibitor. IPEX syndrome is a rare and generally fatal genetic disorder characterized by immune dysregulation, polyendocrinopathy and enteropathy, mostly diagnosed in early childhood. Nonetheless, cases reported in the last 20 years demonstrated that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features. A 21-year-old caucasian man presented with immune dysregulation (hypereosinophilia and elevated IgE), protein-losing enteropathy, polyendocrinopathy (thyroiditis, osteoporosis, delayed puberty), weight loss, eczema manifestations and celiac disease. IPEX syndrome was diagnosed because of the presence of a hemizygous mutation in FOXP3 gene (c.543C>T (p.S181S) in the exon 5). During the course of the disease, the patient developed erosive proctitis, pyoderma gangrenosum, and erythema nodosum. Symptoms improved only after enteral and parenteral corticosteroid therapy and the patient soon developed steroid-dependence. Notwithstanding various therapies including azathioprine, sirolimus, tacrolimus, adalimumab, vedolizumab, the patient failed to achieve a good control of symptoms without steroids. Almost exclusive enteral nutrition with a hypoallergenic, milk-protein free, amino acid-based food for special medical purposes. He continued to lose weight (BMI 14.5 kg/m2) with a consequent high limitation of physical activity and a progressive worsening of the quality of life. In consideration of the poor response to conventional immunosuppressants and the presence of type 2 inflammatory manifestations, treatment with dupilumab at an initial dose of 600 mg, followed by a maintenance dose of 300 mg every other week, according to atopic dermatitis labeled dose, was started and combined to oral budesonide 6 mg/day and 6-mercaptopurine 75 mg/day. The patient experienced a rapid improvement in bowel and skin symptoms, leading to a progressive tapering of steroids. By our knowledge, this is the first report of IPEX syndrome successfully treated by antiIL-4/IL-13 therapy. In this case dupilumab demonstrated to be an effective, safe and steroid-sparing option.

Tenosynovial complications identify TTR cardiac amyloidosis among patients with hypertrophic cardiomyopathy phenotype.

Recent evidence suggests that carpal tunnel syndrome (CTS) and brachial biceps tendon rupture (BBTR) represent red flags for ATTR cardiac amyloidosis (ATTR-CA). The prevalence of upper limb tenosynovial complications in conditions entering differential diagnosis with CA, such as HCM or Anderson-Fabry disease (AFD), and hence their predictive accuracy in this setting, still remains unresolved. OBJECTIVE: To investigate the prevalence of CTS and BBTR in a consecutive cohort of ATTR-CA patients, compared with patients with HCM or AFD and with individuals without cardiac disease history. PARTICIPANTS: Consecutive patients with a diagnosis of ATTR-CA, HCM and AFD were evaluated. A control group of consecutive patients was recruited among subjects hospitalized for noncardiac reasons and no cardiac disease history. The presence of BBTR, CTS or prior surgery related to these conditions was ascertained. RESULTS: 342 patients were prospectively enrolled, including 168 ATTR-CA (141 ATTRwt, 27 ATTRm), 81 with HCM/AFD (N = 72 and 9, respectively) and 93 controls. CTS was present in 75% ATTR-CA patients, compared with 13% and 10% of HCM/AFD and controls (P = 0.0001 for both comparisons). Bilateral CTS was present in 60% of ATTR-CA patients, while it was rare (2%) in the other groups. BBTR was present in 44% of ATTR-CA patients, 8% of controls and 1% in HCM/AFD. CONCLUSIONS: CTS and BBTR are fivefold more prevalent in ATTR-CA patients compared with cardiac patients with other hypertrophic phenotypes. Positive predictive accuracy for ATTR-CA is highest when involvement is bilateral. Upper limb assessment of patients with HCM phenotypes is a simple and effective way to raise suspicion of ATTR-CA.

Severe eosinophilic asthma and aspirin-exacerbated respiratory disease associated to eosinophilic gastroenteritis treated with mepolizumab: a case report.

BACKGROUND: Mepolizumab (MEP) is the first anti Interleukin (IL)-5 add-on therapy approved for the treatment of severe refractory eosinophilic asthma. CASE PRESENTATION: We describe here the case of a 49 years-old woman with Aspirin-exacerbated respiratory disease (AERD), chronic rhinosinusitis, nasal polyposis and eosinophilic gastroenteritis successfully treated with MEP. Several laboratory and clinical items improved during therapy; moreover MEP showed to be useful as steroid sparing agent. CONCLUSIONS: This case supports that the use of mepolizumab can be effective also in other eosinophilic conditions different from asthma and this opens to new therapeutic perspectives.

Interleukin-6 and IgA-rheumatoid factor are crucial for baseline erosiveness, and anti-citrullinated peptide antibodies for radiographic progression in early rheumatoid arthritis treated according to a treat-to-target strategy.

OBJECTIVES: To define baseline clinical and immunological characteristics [anti-citrullinated peptide antibodies (ACPAs), immunoglobulin M (IgM)- and IgA-rheumatoid factor (RF), and interleukin-6 (IL-6) levels] involved in determining baseline erosiveness, outcome, and radiographic progression among seropositive and seronegative early rheumatoid arthritis (ERA) patients. METHOD: The 408 ERA patients enrolled in the study were monitored every 3 months according to the treat-to-target strategy. At baseline and after 12 months, hand and foot radiographs were evaluated using the Sharp/van der Heijde erosion score. RESULTS: At diagnosis, seronegative patients were older and had higher Disease Activity Scores (DASs) than seropositive patients. A higher risk of erosiveness at baseline was conferred by IgA-RF positivity and IL-6 plasma levels ≥7.6 pg/mL, particularly when simultaneously present. In multivariate analysis, disease duration and IL-6 plasma levels ≥7.6 pg/mL arose as independent variables associated with presence of erosions at onset. Radiographic progression at 1 year follow-up, which occurred in 11.1% of ERA patients, was predicted by ACPA positivity, together with higher age at diagnosis. Despite similar percentages of good European League Against Rheumatism response, DAS and Boolean remission being observed over time among seropositive and seronegative patients and between erosive and non-erosive subjects, ERA patients who were erosive at onset, IgA-RF seropositive, and simultaneously having high baseline IL-6 plasma levels (≥7.6 pg/mL) were treated to a greater extent with tumour necrosis factor blockers after 12 months. CONCLUSION: IgA-RF positivity and IL-6 plasma levels are crucial for baseline erosiveness, while ACPA positivity represents the strongest risk factor for developing radiographic progression in ERA.

Psychological impairments burden and spirituality in caregivers of terminally ill cancer patients.

The role of spirituality on the psychological health was mostly investigated through studies conducted in terminally ill patients. However, there are not studies investigating the role of religious and spiritual beliefs on psychological state and on burden dimensions in caregivers. The purpose of this study was to investigate the association between spirituality, burden, and psychological state in caregivers of terminally ill cancer patients. Two hundred caregivers of terminally ill patients with cancer were interviewed using Prolonged Grief Disorder 12 (PG-12), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Caregiver Burden Inventory (CBI) and System of Belief Inventory (SBI-15R). The caregiver burden was positively correlated with anxiety, depression and PG-12 scores. The intrinsic spirituality was a significant predictor of the time-dependence burden (positively associated); and of the emotional burden (negatively associated). In caregivers of terminally ill cancer patients, higher levels of intrinsic spirituality predicted a higher amount of time devote to caregiving, and also protected against the emotional distress linked to providing assistance.

Predictors of paravalvular aortic regurgitation following self-expanding Medtronic CoreValve implantation: the role of annulus size, degree of calcification, and balloon size during pre-implantation valvuloplasty and implant depth.

OBJECTIVES: We sought to investigate the role of balloon size during pre-implantation valvuloplasty in predicting AR and optimal Medtronic CoreValve (MCS) implantation depth. BACKGROUND: Paravalvular aortic regurgitation (AR) is common following MCS implantation. A number of anatomical and procedural variables have been proposed as determinants of AR including degree of valve calcification, valve undersizing and implantation depth. METHODS: We conducted a multicenter retrospective analysis of 282 patients who had undergone MCS implantation with prior cardiac CT annular sizing between 2007 and 2011. Native valve minimum (Dmin), maximum (Dmax) and arithmetic mean (Dmean) annulus diameters as well as agatston calcium score were recorded. Nominal and achieved balloon size was also recorded. AR was assessed using contrast angiography at the end of each procedure. Implant depth was measured as the mean distance from the nadir of the non- and left coronary sinuses to the distal valve frame angiographically. RESULTS: 29 mm and 26 mm MCS were implanted in 60% and 39% of patients respectively. The majority of patients (N=165) developed AR <2 following MCS implantation. AR ≥3 was observed in 16% of the study population. High agatston calcium score and Dmean were found to be independent predictors of AR ≥3 in multivariate analysis (P<0.0001). Nominal balloon diameter and the number of balloon inflations did not influence AR. However a small achieved balloon diameter-to-Dmean ratio (≤0.85) showed modest correlation with AR ≥3 (P=0.04). This observation was made irrespective of the degree of valve calcification. A small MCS size-to-Dmean ratio is also associated with AR ≥3 (P=0.001). A mean implantation depth of ≥8+2mm was also associated with AR ≥3. Implantation depth of ≥12 mm was associated with small MCS diameter-to-Dmean ratio and increased 30-day mortality. CONCLUSION: CT measured aortic annulus diameter and agatston calcium score remain important predictors of significant AR. Other procedural predictors include valve undersizing and low implantation depth. A small achieved balloon diameter-to-Dmean ratio might also predict AR ≥3. Our findings confirm that a small achieved balloon size during pre-implantation valvuloplasty predicts moderate-severe AR in addition to previously documented factors.

Optical coherence tomography in bioabsorbable stents: mechanism of vascular response and guidance of stent implantation.

Fully biodegradable L-polylactic acid stents (biodegradable vascular scaffold, BVS), the latest breakthrough in the area of coronary implants, entered clinical trials in 2005 and became commercially available in 2011. Optical coherence tomography (OCT) was used from the first implants to study the vessel wall response and the timing of the resorption process in man. Analysis of BVS with OCT has several advantages over that of metallic stents. BVS polymeric struts are transparent to the light so that scaffold integrity, apposition to the underlying wall, presence of thrombus and hyperplasia, and changes in the strut characteristics over time can be easily studied. We present a comprehensive review of the findings OCT provided when used as a research tool in serial examination up to five years for investigation of the mechanism of resorption, neointimal coverage, shrinkage and late lumen enlargement. We also report our experience with OCT in 47 lesions of various complexity as a practical means of percutaneous coronary intervention guidance during BVS implantation.

How to optimize the percutaneous treatment of bifurcated lesions: dedicated stents vs. provisional stenting.

Although provisional T-stenting with stenting of the main branch and optional side branch stenting is nowadays the default strategy generally preferred for simple bifurcation lesions, percutaneous coronary intervention (PCI) of complex true bifurcation lesions remains a difficult task to achieve also with modern second generation drug eluting stents. Treatment of complex bifurcational lesions is not only more time consuming but can lead to significantly higher rate of periprocedural myocardial infarction and late estenosis, stent thrombosis and target lesion revascularization. These clinical complications may be at least in part be due to the fact that current bifurcation techniques often fail to ensure continuous stent coverage of the SB ostium and the bifurcation branches and often leave a significant number of malapposed struts. Struts left unapposed in the lumen are not efficient for drug delivery to the vessel wall, disturb blood flow and may increase the risk of restenosis and stent thrombosis. This article summarises the various techniques of bifurcation stenting, highlighting their relative merits and disadvantages. In addition, the role of newer dedicated bifurcation stent devices, as well as the role of imaging in guiding optimal stent deployment will be discussed.

Location of side branch access critically affects results in bifurcation stenting: Insights from bench modeling and computational flow simulation.

BACKGROUND: The aim of this study was to evaluate the impact of stent design and side branch access on final strut apposition during bifurcation stenting. METHODS AND RESULTS: A series of 6 different commercially available Drug Eluting Stents (DES) (n=42) were deployed in an identical model of a coronary bifurcation. Kissing Balloon (KB) optimization was performed after either proximal or distal recrossing of the guidewire and results were analyzed by micro-Computed-Tomography. Stent design only had a minor impact on side branch lumen area free of stent struts. Similar rate of strut malapposition was observed within the bifurcation when a consistent KB optimization protocol and an optimal distal recrossing of the wire to reaccess the side branch (SB) are followed. Conversely, proximal instead of distal cell recrossing toward the side branch produced a significant lower area of the side branch lumen free of struts than an optimal distal recrossing (60.3±7.1% versus 81.1±8.0%, p<0.0001), as well as a higher rate of strut malapposed toward the SB ostium (40.6±6.0% versus 26.0±5.7%, p=0.0005). CONCLUSIONS: Optimal cell recrossing of the guidewire may be critical to ensure successful stent optimization in bifurcation PCI.

Stent flexibility versus concertina effect: mechanism of an unpleasant trade-off in stent design and its implications for stent selection in the cath-lab.

The "concertina effect", longitudinal deformation of the proximal segments of a deployed stent when force is applied from a guide catheter or other equipment, is a recently recognised problem which seems to particularly affect more recent stent designs. Until now, flexibility and deliverability have been paramount aims in stent design. Developments have focussed on optimising these features which are commonly evaluated by clinicians and demanded by regulatory bodies. Contemporary stent designs now provide high flexibility by reducing the number of connecting links between stent segments and by allowing the connecting links to easily change their length. These design evolutions may, however, simultaneously reduce longitudinal strength and have the unintended effect of inducing some risk of longitudinal compression of the stent (the "concertina effect") during difficult clinical cases. Progress in stent design and elimination of restenosis by drug coating has improved PCI outcome and enabled new applications. Here we discuss design trade-offs that shaped evolution and improvement in stent design, from early bare metal designs to the latest generation of drug eluting stent (DES) platforms. Longitudinal strength was not recognised as a critical parameter by clinicians or regulators until recently. Measurements, only now becoming publically available, seem to confirm vulnerability of some modern designs to longitudinal deformation. Clinicians could be more guarded in their assumption that changes in technology are beneficial in all clinical situations. Sometimes a silent trade-off may have taken place, adopting choices that are favourable for the vast majority of patients but exposing a few patients to unintended hazard.

Uric acid does not affect the prevalence and extent of coronary artery disease. Results from a prospective study.

BACKGROUND: Hyperuricemia may be involved in the atherosclerotic process due to endothelial dysfunction and facilitation of smooth muscle cell proliferation. However, debates still exist on the independent role of hyperuricemia, due to its association with several cardiovascular risk factors, such as hypertension, hyperlipidemia, obesity and insulin resistance. Thus, the aim of the current study was to investigate in a consecutive cohort of patients undergoing coronary angiography whether hyperuricemia is associated with the extent of coronary artery disease. METHODS AND RESULTS: Our population is represented by a total of 1901 consecutive patients undergoing coronary angiography between May 2007 and January 2010 at the Azienda Ospedaliera "Maggiore della Carità", Novara, Italy. We additionally evaluated platelet aggregation by PFA-100 (Collagen/Epinefrine) and Multiplate. Quantitative coronary angiography and analysis of IMT were performed by experienced cardiologists who had no knowledge of the patients' clinical information. Higher uric acid was associated with advanced age, larger prevalence of male gender, diabetes, renal insufficiency, hypertension, previous CABG and MI, but with a lower prevalence of family history of CAD. Patients with high uric acid were more often on calcium antagonists, ace-inhibitors, angiotensin receptor antagonists, and, as expected, on diuretics. A significant relationship was observed between uric acid and the prevalence (OR [95% CI] = 1.18 [1.04-1.32], p = 0.01) and severity of CAD (OR [95% CI] = 1.17 [1.03-1.33], p = 0.014). However, the relationship disappeared after correction for baseline confounding factors for both prevalence (OR [95% CI] = 1.06 [0.93-1.21], p = 0.35) and extent of CAD (OR [95% CI] = 1.0 [0.87-1.15], p = 0.96). No relationship was observed between acid uric and IMT (p = 0.73) analyzed in 359 consecutive patients. Finally, there was no relationship between uric acid and platelet aggregation in patients with or without aspirin therapy, as measured by PFA-100 and Multiplate. CONCLUSIONS: Our study showed that uric acid is not associated with platelet aggregation, the extent of coronary artery disease and IMT. Thus, waiting for the results of additional large studies, uric acid may not be considered as a risk factor for coronary artery disease, and its reduction by specific therapies may not be recommended to prevent coronary artery disease and atherosclerosis.

New strategies in the treatment of coronary bifurcations.

Despite major improvements in stent technology (i.e., drug-eluting stents, DES), treatment of coronary bifurcations is an ever occurring problem of the interventional cardiology. While stenting the main branch with provisional side branch stenting seems to be the prevailing approach, in the era of DES various two-stent techniques emerged (crush) or were re-introduced (V or simultaneous kissing stents, crush, T, culottes, etc.) to allow stenting in the side branch when needed. New techniques in imaging like optical coherence tomography help in better understanding bifurcation anatomy and, thus, have the potential to help us better treat this challenging subset of lesions. In addition, new dedicated bifurcation stents have been proposed in an attempt to overcome limitations associated with current approaches, and they showed promising results in early studies; however, the safety and the efficacy of these devices remain to be seen in the ongoing and upcoming trials. This review focuses on the current approaches and the development of new techniques employed for the treatment of bifurcation disease.

Darwin and the survival of the fittest in modern interventional cardiology.

The diabetic patient requires a full armamentarium of proven and developing treatments in order to minimise periprocedural risk as well as improve long term outcome.

Thrombectomy and distal protection devices.

Visible distal embolization is a relatively rare complication during percutaneous coronary interventions but it may occur in 15-20% of angioplasties in saphenous vein grafts (SVG) and in thrombus containing lesions of native coronary arteries, especially in the setting of acute myocardial infarction (AMI). Mechanical thrombectomy devices and distal protection devices have been introduced to reduce the incidence of distal embolisation. Angiojet thrombectomy has shown positive outcomes in thrombus containing lesions when compared with intracoronary thrombolysis but a randomised trial failed to show benefit in the context of AMI. The X-Sizer, Excimer LASER and various simple aspiration thrombectomy catheters show promise in treatment of AMI with improvement shown in surrogate end-points such as resolution of ST-elevation but there have been no randomised trials large enough to demonstrate changes in hard clinical end-points. Distal protection devices have come to be routinely used during SVG treatment and, after the results of the SAFER and FIRE trials; they became a treatment recommendation in the recently issued European Society of Cardiology (ESC) guidelines. For AMI, these devices showed great promise in early single-centre studies which have been offset by the lack of clinical benefit in the multi-centre EMERALD trial. Proximal occlusion devices may further decrease the incidence of distal embolisation, especially in the treatment of totally occluded SVGs or native arteries, by reversing the blood flow and offering protection at a very early stage of the procedure before wire passage. Despite continuous technical improvement and a growing number of miniaturised thrombectomy devices and filters, because of the paucity of controlled large studies, it remains unclear whether these devices will remain limited to niche' applications or will become a regular companion to balloons and stents in mainstream angioplasty procedures.