Mechanisms of Cardiovascular Calcification and Experimental Models: Impact of Vitamin K Antagonists.

Cardiovascular calcification is a multifactorial and complex process involving an array of molecular mechanisms eventually leading to calcium deposition within the arterial walls. This process increases arterial stiffness, decreases elasticity, influences shear stress events and is related to an increased risk of morbidity and mortality associated with cardiovascular disease. In numerous in vivo and in vitro models, warfarin therapy has been shown to cause vascular calcification in the arterial wall. However, the exact mechanisms of calcification formation with warfarin remain largely unknown, although several molecular pathways have been identified. Circulating miRNA have been evaluated as biomarkers for a wide range of cardiovascular diseases, but their exact role in cardiovascular calcification is limited. This review aims to describe the current state-of-the-art research on the impact of warfarin treatment on the development of vascular calcification and to highlight potential molecular targets, including microRNA, within the implicated pathways.

Surgical limits, pitfalls, and potential solutions in kyphectomy in myelomeningocele: three cases and systematic review of the literature.

OBJECTIVES: To describe surgical treatment of 3 cases of severe and progressive thoracolumbar kyphosis in myelomeningocele and provide a systematic review of the available literature on the topic. METHODS: Medical records and pre- and post-operative imaging of 3 patients with thoracolumbar kyphosis and myelomeningocele were reviewed. A database search was performed for all manuscripts published on kyphectomy and/or surgical treatment of kyphosis in myelomeningocele. Patients' information, preoperative kyphosis angle, type of surgery, levels of surgery degrees of correction after surgery and at follow-up, and complications were reviewed for the included studies. RESULTS: Three cases underwent posterior vertebral column resection (pVCR) of 2-4 segments at the apex of the kyphosis (kyphectomy). Long instrumentation was performed with all pedicle screws constructed from the thoracic spine to the pelvis using iliac screws. According to literature review, a total of 586 children were treated for vertebral kyphosis related to myelomeningocele. At least one vertebra was excised to gain some degree of correction of the deformity. Different types of instrumentation were used over time and none of them demonstrated to be superior over the other. CONCLUSION: Surgical treatment of progressive kyphosis in myelomeningocele has evolved over the years incorporating all major advances in spinal instrumentation techniques. Certainly, the best results in terms of preservation of correction after surgery and less revision rates were obtained with long construct and screws. However, complication rate remains high with skin problems being the most common complication. The use of low-profile instrumentation remains critical for treatment of these patients.

Echocardiographic Normal Reference Ranges for Non-invasive Myocardial Work Parameters in Pediatric Age: Results From an International Multi-Center Study.

Aims: This international multi-center study aimed to demonstrate the feasibility and reliability of non-invasive myocardial work (MW) parameters in the pediatric population, and to provide normal reference ranges for this useful echocardiographic tool in this specific subset of patients. Methods and Results: In this retrospective multi-center study involving three pediatric laboratories, 150 healthy children and adolescents (mean age of 10.6 ± 4.5, 91 males) were enrolled. A complete echocardiographic examination has been performed, including global longitudinal strain (GLS) assessment. The following parameters of non-invasive MW have been obtained through a dedicated software: global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE), using left ventricular (LV) strain loops and non-invasive brachial artery cuff pressure values. The lowest expected values were for GWI 1,723 mmHg% in males and 1,682 mmHg% in females, for GCW 2,089 and 2,106 mmHg%, for GWE 95.9 and 95.5% whereas the highest expected value for GWW was 78 mmHg% in men and 90 mmHg% in women. The univariable and multivariable analysis showed significant associations between either GWI or GCW with SBP (ß coefficient = 0.446, p < 0.001; ß coefficient = 0.456, p < 0.001, respectively) and LV GLS (ß coefficient = -0.268, p = 0.001; ß coefficient = -0.233, p = 0.003, respectively). Inter- and intra-observer variability showed good reproducibility of non-invasive MW parameters. Conclusion: Non-invasive MW parameters were feasible and reliable in the pediatric population. This study provided normal reference ranges of these useful echocardiographic indices.

Marinobufagenin, left ventricular geometry and cardiac dysfunction in end-stage kidney disease patients.

PURPOSE: Left ventricular hypertrophy (LVH) is remarkably prevalent among end-stage kidney disease (ESKD) on chronic dialysis and has a strong prognostic value for adverse outcomes. In experimental models, the endogenous cardiotonic steroid Marinobufagenin (MBG) promotes cardiac hypertrophy and accelerates uremic cardiomyopathy. In this study, we investigated the possible relationships between MBG, LV geometry and cardiac dysfunction in a clinical setting of ESKD. METHODS: Plasmatic MBG was measured in 46 prevalent ESKD patients (n = 30 HD, n = 16 PD) together with a thorough laboratory, clinical, bioimpedance and echocardiography assessment. Different patterns of LV geometry were defined by left ventricular mass index (LVMi) and ventricular morphology. Diastolic dysfunction was diagnosed by the ASE/EACVI criteria. RESULTS: MBG levels were significantly higher in ESKD patients than in healthy controls (p = 0.001) and more elevated in PD than in HD (p = 0.02). At multivariate analyses, E/e' (ß = 0.38; p = 0.009) and LVMi (ß = 0.42; p = 0.02) remained the sole independent predictors of MBG. A statistically significant trend in MBG levels (p = 0.01) was noticed across different patterns of LV geometry, with the highest values found in eccentric LVH. MBG levels were higher in the presence of diastolic dysfunction (p = 0.01) and this substance displayed a remarkable diagnostic capacity in distinguish patients with normal LV geometry, LV hypertrophy and, particularly, eccentric LVH (AUC 0.888; p < 0.0001) and diastolic dysfunction (AUC 0.79; p = 0.001). CONCLUSIONS: Deranged plasma MBG levels in ESKD patients on chronic dialysis reflect alterations in LV structure and function. MBG may, thus, candidate as a novel biomarker for improving cardiac assessment in this high-risk population.

Non-Invasive Myocardial Work in Patients with Severe Aortic Stenosis.

Changes in cardiac mechanics after correction of severe Aortic Stenosis (AS) are under-investigated. Myocardial Work (MW) is emerging as a useful non-invasive correlate of invasively measured myocardial performance and oxygen consumption. The aim of this study was to assess the usefulness of MW in the clinical management of patients with AS undergoing transcatheter aortic valve implantation (TAVI). Consecutive patients referred for TAVI were included in this observational study. Echocardiograms were performed before and after TAVI to measure Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), and Global Work Efficiency (GWE). Mean transvalvular gradient was significantly improved (p < 0.05), without significant changes in left ventricular ejection fraction, nor in global longitudinal strain (GLS). GWI (p < 0.001) and GCW (p < 0.001), but not GWW (p = 0.241) nor GWE (p = 0.854) were significantly reduced after TAVI. Patients with a low flow low gradient (LF-LG) AS had lower left ventricular ejection fraction (LVEF) (p < 0.001), worse global longitudinal strain (GLS) (p < 0.001), and lower baseline GWI (p < 0.001), GCW (p < 0.001) and GWE (p = 0.003). The improvement in GWI and GCW observed after TAVI in the general study population were abolished among LF-LG patients. In conclusion, non-invasive MW might be useful to further classify patients with AS and to predict non responders.

Altered circulating marinobufagenin levels and recurrent intradialytic hypotensive episodes in chronic hemodialysis patients: a pilot, prospective study.

Intradialytic hypotension (IDH) is a sudden and often serious complication of chronic hemodialysis (HD). In this prospective study, we aimed at evaluating the clinical predictors of IDH in a homogeneous cohort of chronic HD patients, with a particular focus on marinobufagenin (MBG), an endogenous cardiotonic steroid which alterations have previously been involved in various cardiovascular disorders. MBG levels in HD patients were significantly higher than in controls (p = 0.03), remained unchanged throughout a single HD session and were not correlated with the absolute or partial fluid loss achieved. During a 30-day follow-up, 19 patients (65.5%) experienced at least one IDH (73 total episodes). An inverse correlation was found between baseline MBG and the number of IDH (R = -0.55; p = 0.001). HD patients experiencing IDH presented remarkably lower baseline MBG as compared to others (p = 0.008) with a statistically significant trend during HD (p = 0.02). At Kaplan-Meier analyses, HD patients with lower MBG manifested a four-to-six fold increased risk of IDH during follow-up (crude Hazard Ratio ranging from 4.37 to 6.68). At Cox regression analyses, MBG measurement at different time points resulted the strongest time-dependent predictors of IDH among all the variables considered (HR ranging from 0.068 to 0.155; p: 0.002 to <0.0001). Findings obtained suggest that differently altered MBG in chronic HD patients may reflect a diverse vascular and hemodynamic tolerance to HD stress, eventually leading to recurrent IDH episodes. Further studies are needed to confirm the prognostic capacity of MBG for identifying HD patients at high risk of IDH, particularly those with apparently optimal fluid status.

Prediction of Significant Coronary Artery Disease Through Advanced Echocardiography: Role of Non-invasive Myocardial Work.

Background: Non-invasive prediction of critical coronary artery stenosis (CAST) in patients with coronary artery disease (CAD) is challenging. Strain parameters can often capture an impairment of regional longitudinal function; however, they are load dependent. A novel non-invasive method to estimate Myocardial Work (MW) has been recently proposed, showing a strong correlation with invasive work measurements. Our aim was to investigate the ability of non-invasive MW to predict the ischaemic risk area underlying a CAST. Methods and Results: The study population comprises 80 individuals: 50 patients with CAST and 30 controls (CTRL). Echocardiography recordings were obtained before coronary angiography to measure global longitudinal strain (GLS), Myocardial Work Index (MWI), Myocardial Constructive Work (MCW), Myocardial Wasted work (MWW), Myocardial Work Efficiency (MWE). Global MWI (p = 0.048), MWE (p < 0.001), and MCW (p = 0.048) at baseline were significantly reduced in patients with CAST compared to controls (p < 0.05). Regional MWE within the myocardial segments underlying the CAST, but not LS, was significantly reduced compared to non-target segments (p < 0.001). At ROC analysis, the diagnostic performance to predict CAST for regional MWE (AUC = 0.920, p < 0.001) was higher compared to both regional post-systolic shortening index (PSI) (AUC = 0.600, p = 0.129) and regional LS (AUC = 0.546, p = 0.469). Conclusions: Non-invasive estimation of MW work indices is able to predict a CAST before invasive angiography.

Early reduction of left atrial function predicts adverse clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

AIMS: To investigate the changes in left atrial strain (LAS) after correction of severe aortic stenosis (AS) with transcatheter aortic valve replacement (TAVR) and assess its prognostic impact. METHODS AND RESULTS: One hundred consecutive patients with severe symptomatic AS who underwent TAVR at the Magna Graecia University of Catanzaro underwent echocardiographic examination including assessment of LAS before and after TAVR. Independent investigators collected outcome data and information. The primary study outcome was the difference in ΔLAS (postTAVR-preTAVR) between patients those met the main clinical endpoint (a composite of cardiovascular mortality and heart failure hospitalisation) and those not meeting the endpoint.During a median follow-up of 31 months, 35 patients (35%) met the combined clinical endpoint. The difference between LAS post-TAVR and LAS pre-TAVR (ΔLAS) was significantly larger in patients who met the combined endpoint (HR=0.76 (0.67-0.86); p<0.001). Multivariate logistic regression analysis including ΔLAS, EuroSCORE II and left ventricular ejection fraction showed that ΔLAS (HR=0.80, p<0.001) was the only independent predictor of the combined clinical endpoint. Finally, a Kaplan-Maier analysis showed that patients with a ΔLAS above its median value had a significantly better event-free survival compared with those below the median (p<0.001). CONCLUSIONS: A lower reduction in ΔLAS after TAVR was an independent predictor of the primary composite outcome of cardiovascular death and hospitalisation for heart failure.

Effects of the COVID-19 pandemic on the formation of fellows in training in cardiology.

CoronaVIrus Disease-19 (COVID-19) had a huge impact on human health and economy. However, to this date, the effects of the pandemic on the training of young cardiologists are only partially known. To assess the consequences of the pandemic on the education of the cardiologists in training, we performed a 23-item national survey that has been delivered to 1443 Italian cardiologists in training, registered in the database of the Italian Society of Cardiology (SIC). Six hundred and thirty-three cardiologists in training participated in the survey. Ninety-five percent of the respondents affirmed that the training programme has been somewhat stopped or greatly jeopardized by the pandemic. For 61% of the fellows in training (FITs), the pandemic had a negative effect on their education. Moreover, 59% of the respondents believe that they would not be able to fill the gap gained during that period over the rest of their training. A negative impact on the psycho-physical well being has been reported by 86% of the FITs. The COVID-19 pandemic had an unparalleled impact on the education, formation and mental state of the cardiologists in training. Regulatory agencies, universities and politicians should make a great effort in the organization and reorganization of the teaching programs of the cardiologists of tomorrow.

Transcoronary concentration gradients of circulating microRNAs in heart failure.

AIMS: Circulating levels of microRNAs (miRNAs) are emergent promising biomarkers for cardiovascular disease. Altered expression of miRNAs has been related to heart failure (HF) and cardiac remodelling. We measured the concentration gradients across the coronary circulation to assess their usefulness to diagnose HF of different aetiologies. METHODS AND RESULTS: Circulating miRNAs were measured in plasma samples simultaneously obtained from the aorta and the coronary venous sinus in patients with non-ischaemic HF (NICM-HF, n = 23) ischaemic HF (ICM-HF, n = 41), and in control patients (n = 11). A differential modulation of circulating levels of miR-423, -34a, -21-3p, -126, -199 and -30a was found across the aetiology groups. Interestingly, a positive transcoronary gradient was found for miR-423 (P < 0.001) and miR-34a (P < 0.001) only in the ICM-HF group. On the contrary, a positive gradient was found for miR-21-3p (P < 0.001) and miR-30a (P = 0.030) only in the NICM-HF group. Finally, no significant variations were observed in the transcoronary gradient of miR-126 or miR-199. CONCLUSIONS: The present findings suggest that circulating levels of miRNAs are differentially expressed in patients with HF of different aetiologies. The presence of a transcoronary concentration gradient suggests a selective release of miRNAs by the failing heart into the coronary circulation. The presence of aetiology-specific transcoronary concentration gradients in HF patients might provide important information to better understand their role in HF, and suggests they could be useful biomarkers to distinguish HF of different aetiologies.

Modulation of Circulating MicroRNAs Levels during the Switch from Clopidogrel to Ticagrelor.

Background. Circulating microRNAs are appealing biomarkers to monitor several processes underlying cardiovascular diseases. Platelets are a major source for circulating microRNAs. Interestingly, the levels of specific microRNAs were reported to correlate with the level of platelet activation. The aim of the present study was to test whether the treatment with the novel antiplatelet agent, ticagrelor, is associated with modulation in the levels of key platelet-derived microRNAs. Methods and Results. Patients were randomly selected from those participating in the SHIFT-OVER study, in which we had previously evaluated the effect of the therapeutic switch from clopidogrel to ticagrelor on platelet aggregation. Circulating levels of selected microRNAs were measured before and after the therapeutic switch from a dual antiplatelet therapy including acetylsalicylic acid (ASA) and clopidogrel to the more potent ticagrelor. Interestingly, the circulating levels of miR-126 (p = 0.030), miR-223 (p = 0.044), and miR-150 (p = 0.048) were significantly reduced, while the levels of miR-96 were increased (p = 0.038). No substantial differences were observed for the remaining microRNAs. Conclusions. Switching from a dual antiplatelet treatment with clopidogrel to ticagrelor is associated with significant modulation in the circulating levels of specific microRNAs. If confirmed in larger, independent cohorts, our results pave the way for the use of circulating microRNAs as biomarkers of platelets activity in response to specific pharmacological treatments.

The impact of immediately placed and restored single-tooth implants on hard and soft tissues in the anterior maxilla.

AIM: The purpose of this literature review is to systematically evaluate the impact of immediate implant placement and restoration (IIPR) on hard and soft tissues and to identify clinical parameters which influence the outcome. MATERIALS AND METHODS: An electronic search of the PubMed database was performed from January 2000 to September 2015. A further hand search was conducted in selected journals and only abstracts published in English were considered for review. Human clinical trials with at least 10 participants and which reported hard and soft tissue outcomes were assessed. Randomised controlled trials (RCT), prospective, prospective comparative and retrospective studies were considered. The effects of the following clinical parameters on hard and soft tissue outcomes were analysed: type of implant, primary stability, gingival biotype, flapless surgery, tooth extraction, spatial arrangement of the implant, socket grafting, the gap between implant surface and alveolar wall and the loading protocol. RESULTS: 17 studies (four RCT, six prospective, two comparative prospective, three controlled cohort and two retrospective studies) were included with 626 censored IIPR in 609 patients. A total of 411(65.56 %) implants were placed flapless vs 215 implants after raising a mucoperiosteal flap. Five studies defined raising a mucoperiostal flap as a mandatory part of the surgical protocol. The mean of the remaining gap in between the implant surface and the alveolar wall, the so-called "jump space", was reported for 170 implants ranging from 1.38 mm to 2.25 mm. Two hundred and one implant sites were not grafted, 405 were grafted, mostly with bone substitutes; for 20 no information was available. For 419 implants, a minimum insertion torque of ≥ 32 Ncm or an ISQ value of ≥ 60 was reached; for 53 implants an insertion torque of 25 Ncm was accepted. The implants were mostly placed palatinally of the jaw bone. The vertical position of the platform was reported either to be 0.5 to 1.0 mm below the vestibular bone crest or 3 to 4 mm apical to the adjacent cementoenamel junction of the neighbouring tooth. Post-insertion healing with a non-functional occlusion occurred for 97.8% of the implants. The final single crowns were inserted 3 to 6 months after implant placement. The IIPR resulted in a high success (97.96 %) and survival rate (98.25%) after a mean followup period of 31.2 months. The soft-tissue biotype was evaluated in 379 (60.5%) sites as thick. The mean crestal bone and the mean interproximal mucosa level changes were less than 1 mm compared to the baseline. The midfacial periimplant mucosal level change was less than 0.95 mm. This level was reached for both thin and thick soft-tissue biotypes, without a significant difference. Only in one study did the thin biotypes show a significantly higher recession. CONCLUSION: The systematic review revealed promising results for immediately placed and immediately restored implants (IIPR) in the anterior maxilla. The possible options of flapless surgery and absence of grafting of the socket allows a minimal surgical intervention. However, a strict patient selection seemed mandatory for all included clinical trials.