Author Correction: Meta-analyses of sulodexide and other drugs in prevention and treatment of post-thrombotic syndrome.

Correction to: Eur Rev Med Pharmacol Sci 2022; 26 (24): 9372-9381. DOI: 10.26355/eurrev_202212_30688-PMID: 36591846-published online on December 21, 2022. After publication, the authors found a typo in the discussion section. The sentence to amend is the following one: ·       In meta-analyses of observational studies, we found a low incidence of PTS, with 9% of patients presenting PTS among patients receiving sulodexide and a 50% reduction in the risk of PTS in patients receiving rivaroxaban. The "9%" in the sentence below should be changed to "15%" (in order to align the Discussion section with the Results section and the Abstract. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30688.

Phantom study of stereotactic radioablation for ventricular tachycardia (STRA-MI-VT) using Cyberknife Synchrony Respiratory Tracking System with a single fiducial marker.

PURPOSE: Within the STRA-MI-VT phase Ib/II trial (NCT04066517), the aim of this phantom study was to explore the feasibility of Cyberknife treatments on cardiac lesions by tracking as a single marker the lead tip of an implantable cardioverter defibrillator. The residual displacement of the lesion during the tracking was studied, planning margins were found and the dosimetric accuracy of the treatment was checked. MATERIALS AND METHODS: A lead was inserted into a phantom (EasyCube phantom, Sun Nuclear Co, USA) and then placed on the translating ExacTrac Gating System (BrainLAB AG, Germany). The phantom was rotated, a virtual lesion was identified and its displacement during the tracking was studied. Two plans were compared, calculated on the unrotated volume and on the envelope of the unrotated and the rotated volumes. The plans were delivered using the Cyberknife System (Accuray Inc, USA) and their dosimetric accuracy verified by gamma analysis with gafchromic films. RESULTS: The residual margin increases enhancing the distance between the lead and the lesion. It is 4 mm for distance 0 cm and 5 mm for distance 5 cm. The coverage is reduced by 3.8% (interquartile range 2.5%-4.7%) when the dose is prescribed on the unrotated volume. All treatment plans are accurate and 3% 3 mm gamma analysis results are greater than 94%. CONCLUSIONS: Results showed that tracking with a single marker is feasible considering adequate residual planning margins. The volumes could be further reduced by using additional markers, for example by placing them on the patient's skin.

Meta-analyses of sulodexide and other drugs in prevention and treatment of post-thrombotic syndrome.

OBJECTIVE: Post-thrombotic syndrome (PTS) is a common chronic complication of deep vein thrombosis. Elastic compression (ECS) is the common pillar for PTS prevention and treatment, while the pharmacological approach for PTS includes direct oral anticoagulants (DOACs) and venoactive drugs (VADs) for prevention and treatment, respectively. Sulodexide can be used both in long-term prevention and in the treatment of PTS. To better understand the efficacy of the main drugs used in the prevention (sulodexide or DOACs) and treatment of PTS (sulodexide or VADs), pairwise meta-analyses of observational studies and RCTs were conducted. MATERIALS AND METHODS: A literature search in MEDLINE, Embase, and Cochrane Library for observational studies and RCTs was performed. Incidence of PTS, reduction in PTS signs or symptoms and proportion of patients with complete venous ulcers healing were the primary outcomes for prevention and treatment of PTS, respectively. Fixed and Random effect model meta-analyses were performed. Heterogeneity and publication bias were assessed. R® software was used for the analysis. RESULTS: 893 articles were identified during the search. 8 observational studies (6 for DOACs and 2 for sulodexide) and 2 RCTs for sulodexide, out of the 11 studies included in the qualitative synthesis, were included for the prevention and treatment of PTS, respectively. Meta-analyses of observational studies showed an overall incidence of PTS of 15% (95% CI, 11-19) for sulodexide, and a 50% reduction of PTS signs and/or symptoms for rivaroxaban compared to warfarin (OR, 0.50; 95% CI, 0.38-0.65). The overall estimate of the two sulodexide RCTs showed a significant improvement in complete ulcer healing, with an OR of 2.32 (95% CI, 1.49-3.63). CONCLUSIONS: In prevention of PTS, sulodexide and rivaroxaban showed a low incidence and reduced risk of PTS respectively, while in PTS treatment, sulodexide was significantly effective in the complete ulcers healing. These results confirm the need to move from the traditional single-pillar approach with elastic compression stockings to a more effective multi-pillar approach, tailoring the treatment to each individual patient.

Systematic literature review and Bayesian network meta-analysis of episodic cluster headache drugs.

OBJECTIVE: The drugs used in Europe to treat episodic cluster headache (eCH) are mainly verapamil and lithium carbonate, even though topiramate and pizotifen can be used. Galcanezumab, a humanized monoclonal antibody was approved by FDA recently for prophylaxis treatment of eCH. In order to evaluate the efficacy of galcanezumab compared to the drugs used for the preventive treatment of eCH, a systematic literature review (SLR) and network meta-analysis (NMA) of only randomized controlled trials (RCTs) was performed. MATERIALS AND METHODS: A literature search in MEDLINE, Embase and Cochrane Library including RCTs and observational studies was conducted. The primary outcomes for the NMA included the main change from baseline in reducing ECH attacks while the percentage of responders was used to pairwise comparisons of the observational studies. The NMA was conducted using a fixed-effect model and a random-effects model with deviance information criterion (DIC) reported for both models. The surface under the cumulative ranking (SUCRA) was shown only for the model with the lower DIC. RESULTS: Three RCTs and six observational studies were included in the SLR. The Bayesian NMA was performed on the two RCTs included in the SLR, specifically galcanezumab and verapamil studies. SUCRA indicated that galcanezumab had the highest probability of being the most effective treatment (probability = 66.33%) compared to verapamil (probability = 31.58%) and placebo (probability = 2.09%). Galcanezumab was also the treatment with the highest overall probability to be the second most effective (probability = 88.79%). CONCLUSIONS: The results suggest that galcanezumab is more effective compared to verapamil as a prophylaxis treatment for reducing eCH attacks in adults. Further, head-to-head RCTs of galcanezumab vs. treatments using in clinical practice are needed to better assess its comparative efficacy and benefit-risk profile.

Sensitive and quantitative method to evaluate DNA methylation of the positive regulatory domains (PRDI, PRDII) and cAMP response element (CRE) in human endothelial nitric oxide synthase promoter.

Nitric oxide plays a prominent role in the cardiovascular system and much attention has been devoted in the last years on deciphering the regulation of human endothelial nitric oxide synthase (eNOS) expression. Epigenetic-based mechanisms have a key role in the eNOS expression and their pathologic perturbations may have profound effects on the steady state RNA levels in the endothelium. The human eNOS promoter lacks a canonical TATA box and it does not contain a proximal CpG island. A differentially DNA methylated region (DMR) in the native eNOS proximal promoter is involved in gene expression regulation. Here we describe a quantitative, sensitive and cost-effective method that, relying on a novel normalization strategy, allows the quantification of DNA methylation status of the positive regulatory domains (PRDI, PRDII) and cAMP response element (CRE) in human eNOS promoter. This technique will enable to explore the functional relevance of DNA methylation perturbations of eNOS promoter both under pathological and physiological conditions.

Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy.

AIM: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder mainly due to mutations in desmosomal genes, characterized by progressive fibro-adipose replacement of the myocardium, arrhythmias, and sudden death. It is still unclear which cell type is responsible for fibro-adipose substitution and which molecular mechanisms lead to this structural change. Cardiac mesenchymal stromal cells (C-MSC) are the most abundant cells in the heart, with propensity to differentiate into several cell types, including adipocytes, and their role in ACM is unknown. The aim of the present study was to investigate whether C-MSC contributed to excess adipocytes in patients with ACM. METHODS AND RESULTS: We found that, in ACM patients' explanted heart sections, cells actively differentiating into adipocytes are of mesenchymal origin. Therefore, we isolated C-MSC from endomyocardial biopsies of ACM and from not affected by arrhythmogenic cardiomyopathy (NON-ACM) (control) patients. We found that both ACM and control C-MSC express desmosomal genes, with ACM C-MSC showing lower expression of plakophilin (PKP2) protein vs. CONTROLS: Arrhythmogenic cardiomyopathy C-MSC cultured in adipogenic medium accumulated more lipid droplets than controls. Accordingly, the expression of adipogenic genes was higher in ACM vs. NON-ACM C-MSC, while expression of cell cycle and anti-adipogenic genes was lower. Both lipid accumulation and transcription reprogramming were dependent on PKP2 deficiency. CONCLUSIONS: Cardiac mesenchymal stromal cells contribute to the adipogenic substitution observed in ACM patients' hearts. Moreover, C-MSC from ACM patients recapitulate the features of ACM adipogenesis, representing a novel, scalable, patient-specific in vitro tool for future mechanistic studies.

Cyclophilin A: a key player for human disease.

Cyclophilin A (CyPA) is a ubiquitously distributed protein belonging to the immunophilin family. CyPA has peptidyl prolyl cis-trans isomerase (PPIase) activity, which regulates protein folding and trafficking. Although CyPA was initially believed to function primarily as an intracellular protein, recent studies have revealed that it can be secreted by cells in response to inflammatory stimuli. Current research in animal models and humans has provided compelling evidences supporting the critical function of CyPA in several human diseases. This review discusses recently available data about CyPA in cardiovascular diseases, viral infections, neurodegeneration, cancer, rheumatoid arthritis, sepsis, asthma, periodontitis and aging. It is believed that further elucidations of the role of CyPA will provide a better understanding of the molecular mechanisms underlying these diseases and will help develop novel pharmacological therapies.

Direct minimally invasive intramyocardial injection of bone marrow-derived AC133+ stem cells in patients with refractory ischemia: preliminary results.

BACKGROUND: Bone marrow-derived stem cells (BMSC) may represent a viable option for patients with myocardial ischemia refractory to conventional treatments. MATERIAL AND METHODS: In 5 patients (4 males and 1 female, mean age 64 +/- 8 years) with untreatable angina pectoris (Canadian Cardiovascular Society Class III/IV), myocardial segments with stress-induced ischemia as assessed by gated single-photon emission computed tomography were injected with 4 to 12 million CD133+ BMSC. Cells were injected into the myocardium (2 anterior, 2 lateral, 1 inferior wall) through minimally invasive approaches (left minithoracotomy [n = 4] and subdiaphragmatic approach [n = 1]). At baseline, at 6 months and at 1 year of follow-up, an exercise test, gated single-photon emission computed tomography (SPECT), 2-D echocardiography and coronary angiography were performed to assess exercise capacity, myocardial perfusion, LV function and coronary anatomy. RESULTS: Intramyocardial injection of autologous CD133+ BMSC cells was safe. No early or long-term complications were observed. After an average of 3.8 weeks from cell inoculation, all patients experienced a significant improvement of CCS class (from 3.8 to 1.8 at 6 months) and serial SPECT documented improvements of rest and stress perfusion in the injected territories at 6 months from operation. In 3 cases, coronary angiography showed an increase in the collateral score of the target areas. Clinical improvements still persist unchanged in 4 out of 5 cases at a mean of 36.5 months postoperatively. CONCLUSIONS: After stand-alone BMSC transplantation for refractory myocardial ischemia, we observed long-term clinical and perfusion improvements in the absence of adverse events.

Determinants of late outcome after minimally invasive direct coronary artery bypass.

AIM: Minimally invasive direct coronary artery bypass (MIDCAB) is a reliable method to revascularize the left anterior descending (LAD) coronary artery. However, a more consistent body of knowledge is needed to assess factors influencing long-term outcome. With this study, we retrospectively investigated the long-term determinants of survival and freedom from cardiac morbidity and revascularization in patients who underwent MIDCAB. METHODS: From 1997 to 2005, 109 patients underwent MIDCAB. Seventy-five (68.8%) presented isolated LAD disease and 34 (31.2%) multivessel disease. The first 57 patients (53.2%) in the series underwent early postoperative angiographic reinvestigation. All 109 patients were subsequently followed-up at our outpatient clinic. Follow-up (mean 50.7 months, range 3-93) was completed in 100% of cases. RESULTS: No in-hospital deaths occurred; 2 patients (1.8%) experienced perioperative myocardial infarction. At early postoperative angiographic reinvestigation, the anastomotic perfect patency rate was 54/57 (94.7%); survival was 100% and 95.8% at 1 and 5 years, respectively. Overall freedom from repeated revascularization was 95.3% and 88.3% at 1 and 5 years respectively; freedom from LAD revascularization was 95.3% and 91.6% at 1 and 5 years, respectively; cardiac event-free survival was 95.3% and 80.8% at 1 and 5 years respectively. At multivariable analysis (Cox regression), women were found to have a higher risk of repeated LAD revascularization (hazard ratio [HR] 30.24; P<0.001); female sex and left ventricular dysfunction were the only predictors affecting long-term cardiac outcome (hazard ratio 29.35; P<0.001 and 5.1; P<0.001), respectively. CONCLUSIONS: A key factor in the long-term success of MIDCAB seems to be appropriate patient selection. Special attention should be reserved for female patients, as they appear to have a worse cardiac outcome and a higher probability of repeated revascularization on LAD. MIDCAB may represent a viable option for treating multivessel disease when complete revascularization is unfeasible or a hybrid procedure is envisaged.

Abdominal aortic aneurysm repair in octogenarians: outcomes and predictors.

OBJECTIVES: This study was undertaken to evaluate predictors and outcomes of octogenarians who underwent abdominal aortic aneurysm repair. DESIGN: A prospective observational study. MATERIALS AND METHODS: Between January 1st, 1997 and April 15th, 2005, 31 octogenarians were admitted to our Department with the diagnosis of abdominal aortic aneurysm. Mean follow-up time was 53.7+/-27.2 months. All patients were in good clinical condition and represented a selected healthy group of octogenarians. RESULTS: The overall perioperative (30-days) mortality rate was 3.1%. The total in-hospital morbidity rate was 22.6%. Overall survival estimates at 48 and 96 months were 81+/-8% and 46+/-21%, respectively. The actuarial freedom from aneurysm-related death at 48 and 96 months was 96+/-4% and 96+/-4%, respectively. The actuarial freedom from aneurysm-unrelated death at 48 and 96 months was 84+/-7% and 48+/-21%. Only coronary artery disease was a significant predictor of survival using multivariate stepwise logistic regression analysis. CONCLUSIONS: In this series, AAA surgery was carried out in selected octogenarians without affecting long-term survival.

Long-lasting improvement of myocardial perfusion and chronic refractory angina after autologous intramyocardial PBSC transplantation.

We report the case of a 60-year-old man with patent coronary by-pass grafts on the left anterior descending and circumflex coronary arteries, who experienced recurrent Canadian class IV angina refractory to medical and interventional treatments for a dominant right coronary artery occlusion. He underwent autologous PBSC transplant into the inferior ventricular wall through a minimally invasive approach as a stand-alone therapy, in an attempt to induce therapeutic angiogenesis. Six months after the operation, angina significantly ameliorated; scintigraphy and coronary angiography showed a marked improvement in perfusion of the target injection area. These benefits had persisted at 25 months after stem cell transplant.

Off-pump redo coronary artery bypass grafting: technical aspects and early results.

BACKGROUND: Redo coronary artery bypass grafting (CABG) represents an high-risk surgical procedure, because of an increased incidence of perioperative death, myocardial infarction and stroke. Theoretically, the avoidance of cardiopulmonary bypass may reduce surgical traumatism and ameliorate early results. MATERIALS AND METHODS: From January 1995 to May 2001, we performed 123 redo CABGs, of which 53 (44%) off-pump. Off-pump procedure represented respectively 90% of redo CABG in the period 2000-2001 versus 30% in the 1995-1999 period. The mean age was 66.4 years, males were 39 (73%). The mean 2D-echo ejection fraction was 56% and in 9 cases (17%) was less than 40%. Three operations (5.6%) were performed on an urgent base. The access was median sternotomy in all cases. The mean number of grafts per patient was 1.9 (1.7 in the period 1995-99 vs. 2.3 in the period 2000-01, p=0.01). In 20 cases (38%) we grafted the circumflex artery branches (19% in the period 1995-99 vs. 55.5% in the period 2000-01, p=0.015). Improvements in surgical techniques were achieved over time. The current operative strategy includes the use of deep traction stitches in the posterior pericardium and wall stabilizers to expose target vessels, coronary intraluminal shunts during construction of the anastomoses and continuous trans-esophageal echocardiographic monitoring. Urgent conversion to on-pump procedure was not required in any case. RESULTS: We recorded no in-hospital death, one perioperative myocardial infarction (1.9%), one fifth postoperative day-stroke (1.9%) and 9 atrial fibrillations (17%). Mediastinal re-exploration for bleeding was performed in no one patient; 13 patients (24.5%) required postoperative blood transfusion. The mean length of postoperative stay was 7.5 days, ranging from 6 to 18 days. CONCLUSIONS: In our experience off-pump redo CABG is a safe and effective alternative to on-pump procedure and now off-pump is our first choice-technique in redo CABG. A complete revascularization is technically feasible with a low incidence of perioperative complications.

Comparison of endothelium-dependent vasoactivity of internal mammary arteries from hypertensive, hypercholesterolemic, and diabetic patients.

BACKGROUND: Endothelium-dependent relaxation is abnormal in a variety of diseased states. Despite the widespread use of the internal mammary artery (IMA) in coronary artery bypass grafting, there is a lack of comparative studies on IMA endothelial-dependent function in patients with major cardiovascular risk factors. METHODS: An IMA segment from 48 selected patients undergoing coronary artery bypass grafting was harvested intraoperatively and assigned to one of four groups (n = 12): diabetics requiring therapy, hypertensives, hypercholesterolemic, and nondiabetic-normotensive-normocholesterolemic patients. Internal mammary artery specimens were cut into rings and suspended in organ bath chambers, and the isometric tension of vascular tissues was recorded. The IMA rings were (1) precontracted with norepinephrine, and the endothelium-derived relaxation was evaluated by cumulative addition of acetylcholine, (2) contracted with cumulative concentrations of endothelin-1, and (3) contracted with the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine. Furthermore, the release of prostacyclin by the IMA rings was directly measured during basal tone conditions and at the end of the various pharmacologic interventions. Histology of IMA rings was randomly performed. RESULTS: The results obtained in these experiments showed that IMA rings harvested from hypertensive patients have the greatest impairment of endothelium-dependent response to relaxant and contracting stimuli (p < 0.01 versus nondiabetic-normotensive-normocholesterolemic tissues; p < 0.05 versus hypercholesterolemic and diabetic tissues) and prostacyclin release in normal and stimulated conditions. To a lesser extent, hypercholesterolemic and diabetic tissues show similar depression (diabetic > hypercholesterolemic) both of relaxation and prostacyclin production, with respect to nondiabetic-normotensive-normocholesterolemic specimens (p < 0.05). Histology findings (scanning electron microscopy) did not differ in multiple sections from vessel studies. CONCLUSIONS: Major cardiovascular risk factors affect the endothelium-dependent vasoactive homeostasis of human IMA differently. Depression of relaxation is highest in patients with a history of hypertension. These findings may be pertinent to early and long-term treatment of patients undergoing coronary artery bypass grafting.

[Banks of vascular homografts]. / Banking degli omoinnesti vascolari.

We define as Banking of the tissues all the procedures that include the finding, preparation, conservation and distribution of the homograft. The vascular homografts are taken and put into a solution of transportation at +4 degrees C and kept at this temperature till their arrival at the Bank. The following step is the dissection of the homograft which will have to be performed as quickly as possible at most 24 hours after the taking in conditions of maximum sterility. At the Italian Homograft Bank at Centro Cardiologico, the vascular homografts are kept at +4 degrees C for 96 hours on average with antibiotics. After a phase of sterilization at +4 degrees C the tissue is frozen according to a homogeneous and controlled thermic decrease and stored at -150 degrees C/-180 degrees C in fumes of liquid nitrogen till the moment of their employment allowing a long term conservation. The aim of all these procedures of cryopreservation is to keep the structural and functional integrity of cells and tissues. The thermic decrease of the tissues must occur so that to avoid all the damages of the cellular vitality and functionality and especially of the tissue structure in toto. In order to limitate these events some cryoprotector agents are employed because they reduce the concentration of the solutes, the cellular dehydration, the formation of micro-macro crystals. Another step to establish if the homograft is proper is the study of bacteriological and viral aspects. The viral screenings are performed on the donor's blood and the bacteriological tests are performed on the tissue and on the liquids. For each phase of the banking a series of information about the donor and about the tissues are recorded and filed both on paper and database so that to grant always a right conduct of the material.

[Myocarcial revascularisation without extracorporeal circulation: current indications, surgical technique and results]. / La rivascolarizzazione coronarica senza circolazione extracorporea. Indicazioni attuali, tecnica chirurgica e risultati.

BACKGROUND: This study was undertaken to assess our experience of the evolution, over time, of beating heart surgery in the Cardiologic Center Foundation Monzino. METHODS: From March 1995 to June 2000, 506 patients underwent myocardial revascularization on beating heart: 313 until May 1999, and 193 between June 1999 and June 2000, after the advent of coronary artery stabilizers and shunts, to keep the surgical field bloodless, with minimal motion and continuous myocardial perfusion. Surgical accesss was via a median sternotomy for 408 cases and via a left anterior thoracotomy for 98 cases. RESULTS: The indications by choice increased, from I to II period, from 61% to 83% with special situations in which patients had three-vessel coronary artery disease raised from 33% to 50%, concerning also bypass grafts performed on circumflex artery and right coronary increased. Postoperative mortality in hospital decreased from 1.3% to 0.5% and perioperative IMA (acute myocardial infarction) from 3.8% to 0.5% in patients undertaken to median thoracotomy. Hospital stay decreased from 8 to 7 days about [no significant differences with patients who underwent CPB (cardiopulmonary bypass)]; in patients who underwent to MTS (left anterior minithoracotomy) there was no deaths, IMA decreased from 3.9% to 0% and hospital stay from 6 to 5 days. Grafts patency increased from 92.3% to 100%. CONCLUSIONS: To perform completed revascularisations is possible now even on the beating heart, and also to make precise anastomosis as on pump CABG, in a reproducible and easy way. The beating heart procedure, that is also more economical, might be expanded to all patients, not only high risk patients.

A preoperative index of mortality for patients undergoing surgery of type A aortic dissection.

BACKGROUND: The aim of this study was to identify and stratify the most important preoperative factors for in-hospital death after surgery for type A aortic dissection. METHODS: From January 1985 to June 1998, 108 patients underwent surgery for type A aortic dissection. 89.9% of the patients had an acute type A dissection (AD), whereas 11.1% had a chronic dissection (CD). Cardiac tamponade and shock occurred in 22% and 14.8% of the patients, respectively. The location of the primary intimal tear was in the ascending aorta in 71.2% of the cases, in the arch in 16.6% and in the descending aorta in 7.4%. Univariate and multivariate analyses were conducted to identify non-embolic variables independently correlated to in-hospital death. A predictive model of in-hospital mortality was then constructed by means of a mathematical method with the variables selected from logistic regression analysis. RESULTS: The overall in-hospital mortality rate was 20.3% (22/108 patients), being 9% for CD and 21.6% for AD. Emergent procedures had an in-hospital mortality rate of 47.6%, whereas non-emergent operations had an in-hospital mortality rate of 13.7% (p<0.01). Univariate analysis revealed among 39 preoperative and operative variables, age (years), age >70 years, remote myocardial infarction, cerebrovascular dysfunction, diabetes, preoperative renal failure, shock, cardiopulmonary bypass time (minutes), emergency operation as factors associated to in-hospital death (p<0.05). Stepwise logistic regression analysis selected as independent predicting variables (p<0.05), remote myocardial infarction (p=0.006), preoperative renal failure (p=0.032), shock (p=0.001), age >70 years (p=0.007). Finally, a probability table of death risk was obtained with the logistic regression coefficients. The lower death probability (10.6%) was calculated in absence of risk variables; the higher one in presence of all of them (79.7%). Between these extremes, a total of 64 combinations of death risk were obtained. CONCLUSIONS: Increasing age, shock, coronary artery disease and renal failure are variously associated to a high risk of in-hospital death after surgical correction of type A aortic dissection. This predictive model of death probability allows to collocate preoperatively patients with type A aortic dissection at different levels of risk for in-hospital death.