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Background: Raphe-type bicuspid aortic valve (BAV) is a potential hostile scenario in trans-catheter aortic valve replacement (TAVR) due to pronounced calcium burden, possibly associated with tapered valve configuration. Trans-Catheter heart valve (THV) sizing strategy (annular vs. supra-annular) is controversial in this valve subtype., Objectives: To describe the phenotypical characteristics of severe, tapered, raphe-type, BAV stenosis undergoing TAVR and to explore safety and efficacy of modern-generation THVs, analysing the impact of annular and supra-annular sizing strategies on short- and mid-terms outcomes., Methods: This is a retrospective, multicenter registry enrolling consecutive stenotic Sievers type 1 BAV treated with TAVR. Study population was divided into tapered and non-tapered configuration according to MSCT analysis. Matched comparison between annular and supra-annular sizing groups was performed in tapered population., Results: From January 2016 to June 2023, 897 patients were enrolled. Of them, 696 patients displayed a tapered configuration. Of those, 510 received a THV according to annular sizing. After propensity score matching 186 matched pairs were selected. Technical success (96.2 % vs 94.1 %, OR 1.61 [0.61-4.24], p = 0.34), 30-day device success (83.6 % in both groups, OR 1.42 [0.78-2.57], p = 0.25) and 30-day early safety (71.8 % vs 70.5 %, OR 1.07 [0.68-1.68], p = 0.78) were similar between the annular and supra-annular sizing groups; a higher post-TAVR gradient was observed in supra-annular group, although it was only 2 mmHg mean. At mid-term follow-up, the rate of clinical efficacy was 84.7 %., Conclusions: TAVR with modern-generation devices is safe and effective for tapered raphe-type BAV, showing comparable results for annular and supra-annular sizing strategies., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Sodium-glucose cotransporter 2 inhibitors were shown to reduce morbidity and mortality in patients with heart failure., Objectives: This study aims to assess potential effects of dapagliflozin in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with mildly reduced ejection fraction (HFmrEF) on cardiac function assessed by speckle tracking echocardiography (STE)., Methods: This randomized, prospective, single-center, open-label trial compared consecutive nondiabetic outpatients with HFrEF or HFmrEF receiving dapagliflozin with patients treated with optimal medical therapy (OMT) except sodium-glucose cotransporter type 2 inhibitors. Primary endpoint was the presence of a significant modification of left ventricular global longitudinal strain, diastolic function (as peak atrial longitudinal strain) and right ventricular function by STE from baseline to 6 months. Cardiovascular events and parameters of congestion were assessed as safety-exploratory endpoints., Results: Overall, 88 patients (38% HFmrEF) were enrolled and randomized to start dapagliflozin on top of OMT (n = 44) or to continue with OMT (n = 44). All STE values improved in the dapagliflozin group after 6 months, whereas there was a nonsignificant improvement in OMT group. Moreover, when comparing the modification of STE parameters at follow-up in patients with HFrEF and HFmrEF, only the main treatment effect resulted statistically significant in both groups (P < 0.0001), indicating a significant difference between dapagliflozin and OMT., Conclusions: This study provided randomized data on the beneficial effect of dapagliflozin in nondiabetic patients with HFrEF and HFmrEF in terms of myocardial performance measured by the most sensitive echocardiographic technique, ie, STE. This suggests its usefulness for left ventricular reverse remodeling and better quality of life in patients with HFrEF and HFmrEF. (Effects of Dapagliflozin on cardiac deformation and clinical outcomes in heart failure with reduced and mildly reduced ejection fraction [DAPA ECHO trial]; EudraCT number: 2021-005394-66)., Competing Interests: Funding Support and Author Disclosures The study has been supported with an unrestricted grant by AstraZeneca. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Balloon-expandable valves (BEVs) and self-expanding valves (SEVs) have different features that may impact the outcomes of patients with Sievers type 1 bicuspid aortic valve (BAV) stenosis undergoing transcatheter aortic valve replacement., Objectives: This study sought to compare procedural and clinical outcomes of BEVs and SEVs in Sievers type 1 BAV stenosis., Methods: AD-HOC (Characteristics, Sizing, and Outcomes of Stenotic Raphe-Type Bicuspid Aortic Valves Treated With Transcatheter Device Implantation) is an observational registry enrolling patients with Sievers type 1 BAV stenosis undergoing transcatheter aortic valve replacement with current-generation BEVs and SEVs at 24 international centers. A 1:1 propensity score matching analysis was performed to adjust for baseline imbalances. The primary endpoint was midterm major adverse events, defined as a composite of all-cause death, neurologic events, or hospitalization for heart failure., Results: Among 955 eligible patients, propensity score matching resulted in 301 pairs. At a median follow-up of 1.3 years, BEVs and SEVs had a similar risk of major adverse events (BEV vs SEV: HR: 0.75; 95% CI: 0.49-1.16; P = 0.200). Technical success was similar (OR: 1.38; 95% CI: 0.63-3.04; P = 0.421). At 30 days, BEVs were associated with a lower risk of new permanent pacemaker implantation (OR: 0.42; 95% CI: 0.24-0.72; P = 0.002) and moderate or greater paravalvular regurgitation (OR: 0.16; 95% CI: 0.05-0.48; P = 0.001) but a higher risk of severe patient-prosthesis mismatch (OR: 3.03; 95% CI 1.02-8.95; P = 0.045)., Conclusions: Current-generation BEVs and SEVs proved similar technical success and midterm clinical efficacy in Sievers type 1 BAV stenosis. Compared to SEVs, BEVs were associated with less permanent pacemaker implantation and moderate or greater paravalvular regurgitation but with more severe patient-prosthesis mismatch., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve (BAV) stenosis is technically challenging and is burdened by an increased risk of paravalvular regurgitation (PVR)., Objectives: The aim of this study was to identify the incidence, predictors, and clinical outcomes of PVR after TAVR in Sievers type 1 BAV stenosis., Methods: Consecutive patients with Sievers type 1 BAV stenosis undergoing TAVR with current-generation transcatheter heart valves (THVs) in 24 international centers were enrolled. PVR was graded as none/trace, mild, moderate, and severe according to echocardiographic criteria. The endpoint of major adverse events (MAEs), defined as a composite of all-cause death, stroke, or hospitalization for heart failure, was assessed at the last available follow-up., Results: A total of 946 patients were enrolled. PVR occurred in 423 patients (44.7%)-mild, moderate, and severe in 387 (40.9%), 32 (3.4%), and 4 (0.4%) patients, respectively. Independent predictors of moderate or severe PVR were a larger virtual raphe ring perimeter (adjusted OR: 1.07; 95% CI: 1.02-1.13), severe annular or left ventricular outflow tract calcification (adjusted OR: 5.21; 95% CI: 1.45-18.77), a self-expanding valve (adjusted OR: 9.01; 95% CI: 2.09-38.86), and intentional supra-annular THV positioning (adjusted OR: 3.31; 95% CI: 1.04-10.54). At a median follow-up of 1.3 years (Q1-Q3: 0.5-2.4 years), moderate or severe PVR was associated with an increased risk of MAEs (adjusted HR: 2.52; 95% CI: 1.24-5.09)., Conclusions: After TAVR with current-generation THVs in Sievers type 1 BAV stenosis, moderate or severe PVR occurred in about 4% of cases and was associated with an increased risk of MAEs during follow-up., Competing Interests: Funding Support and Author Disclosures Dr Aurigemma has reported speaker fees from Abbott, Medtronic, Abiomed, and Terumo. Dr Trani has been involved in advisory board meetings or received speaker fees from Medtronic, Abbott, Terumo, Daiichi-Sankyo, and Abiomed. Dr Adamo has reported speaker honoraria from Abbott Vascular and Edwards Lifesciences. Dr Burzotta has been involved in advisory board meetings or has received speaker fees from Medtronic, Abbott, Terumo, Daiichi-Sankyo, and Abiomed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Amyloid light-chain amyloidosis is a rare condition characterized by the abnormal production of immunoglobulin light chain that misshape and form amyloid fibrils. Over time, these amyloid deposits can accumulate slowly, causing dysfunction in organs and tissues. Early identification is crucial to ensure optimal treatment. We aim to identify a better marker of cardiac amyloidosis, using advanced echocardiography, to improve diagnosis and the timing of available treatments., Materials and Methods: 108 consecutive hematological patients (32, 30% female and 76, 70% male) with a plasma cell disorder referred to our Cardiological center underwent ECG, first and second-level echocardiography (Speckle Tracking) and complete biochemical profile. The best predictors of ALCA (AUC ≥ 0.8) were included in a further analysis stratified by AL score., Results: At ROC analysis, the best bio-humoral predictors for the diagnosis of ALCA were Nt-pro-BNP (AUC: 0.97; p < 0.01) and Hs-Tn (AUC: 0.87; p < 0.01). Regarding echocardiography, the best diagnostic predictors were left atrial stiffness (LAS) (AUC: 0.83; p < 0.01) for the left atrium; free wall thickness for the right ventricle (AUC: 0.82; <0.01); left ventricular global longitudinal strain (LVGLS) (AUC: 0.92; p < 0.01) and LVMi (AUC 0.80; p < 0.001) for the left ventricle; and AL-score (AUC 0.83 p < 0.01). In patients with AL-SCORE < 1, LAS (AUC 0.86 vs AUC 0.79), LVGLS (AUC 0.92 vs AUC 0.86) and LV mass (AUC 0.91 vs AUC 0.72) had better diagnostic accuracy than patients with higher AL-score (AL SCORE ≥ 1)., Conclusion: Multi-parametric imaging approach with LVGLS and LAS may be helpful for detecting early cardiac involvement in AL amyloidosis., (Copyright © 2023. Published by Elsevier B.V.)

Background: Long-term data on the potential advantages of combining the third-generation subcutaneous implantable cardioverter defibrillator (S-ICD) with modern software upgrade including the "SMART Pass", modern programming strategies and the intermuscular (IM) two-incision implantation technique in arrhythmogenic cardiomyopathy (ACM) with different phenotypic variants are lacking. In this study we evaluated the long-term outcome of patients with ACM who underwent third-generation S-ICD (Emblem, Boston Scientific) and IM two-incision technique., Methods: The study population included 23 consecutive patients [70% male, median age 31 (24-46) years] diagnosed with ACM with different phenotypic variants who received third-generation S-ICD implantation with the IM two-incision technique., Results: During a median follow-up of 45.5 months [16-65], 4 patients (17.4%) received a at least one inappropriate shock (IS), with median annual event rate of 4.5%. Extra-cardiac oversensing (myopotential) during effort represented the only cause of IS. No IS due to T-wave oversensing (TWOS) were recorded. Only one patient (4.3%) experienced device-related complication consisting of premature cell battery depletion requiring device replacement. No device explantation because of need for anti-tachycardia pacing or ineffective therapy occurred. There was no significant difference between patients who did and did not experienced IS with regard to baseline clinical, ECG and technical characteristics. Five patients (21.7%) received appropriate shocks on ventricular arrythmias., Conclusions: According to our findings, although the third-generation S-ICD implanted with the IM two-incision technique appears to be associated with a low risk of complications and IS due to cardiac oversensing, the risk of IS due to myopotential mainly during effort should be considered., Competing Interests: Declaration of Competing Interest All the authors declare that there are no conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The limited available data regarding the prevalence of transthyretin amyloidosis, both for wild-type (ATTRwt) and hereditary form (ATTRv), is inferred from highly selected patients and subsequent extrapolations that limit the comprehension of the clinical disease impact. The Tuscan healthcare system in 2006 developed a web-based rare disease registry, to monitor and profile patients affected by rare diseases. Clinicians belonging to regional validated healthcare data centres can register patients at the diagnosis, with a rigorous approach and distinguishing the types of amyloidosis, i.e., ATTRwt versus ATTRv. Thanks to this data collection method, available from July 2006 and extended with electronic therapy plans related to a diagnosis since May 2017, we analysed prevalence and incidence of ATTR and its subtypes. On November 30th 2022, ATTRwt prevalence in Tuscany is 90.3 per 1,000,000 persons and ATTRv prevalence is 9.5 per 1,000,000 persons, whereas the annual incidence ranges from 14.4 to 26.7 per 1,000,000 persons and from 0.8 to 2.7 per 1,000,000 persons, respectively. The male gender is predominant in both forms. All except one patient showed evidence of cardiomyopathy. This epidemiological data requires attention, not only to increase the effort for the clinical management and earlier diagnosis, but also to underline the need for the disease-specific treatments., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Subclinical atrial fibrillation (SCAF) may represent a cause of embolic stroke of undetermined source (ESUS) and its detection has important implications for secondary prevention with anticoagulation. Indications to implantable cardiac monitors (ICM) include SCAF detection. The aims of this study were to (1) evaluate the frequency of ICM-detected SCAF; (2) determine predictors of SCAF; and (3) identify patients who would benefit most from ICM implantation., Methods: Between February 2017 and November 2020, all consecutive patients referred for ICM implantation after a diagnosis of ESUS and without previous history of atrial fibrillation or atrial flutter were included in this study. SCAF was diagnosed if the ICM electrogram demonstrated an episode of irregularly irregular rhythm without distinct P waves lasting > 2 min., Results: We enrolled 109 patients (age 66, SD = 13 years; 36% females). During a median follow-up of 19.2 (IQR 11.0-27.5) months, SCAF episodes were detected in 36 (33%) patients. Only abnormal P wave terminal force in lead V1, left atrial end-systolic indexed volume > 34 ml/m 2 , and BMI > 25 kg/m 2 were independently associated with an increased risk of SCAF (HR 2.44, 95% CI 1.14-5.21, p = 0.021; HR 2.39, 95% CI 1.11-5.13, p = 0.026; and HR 2.64, 95% CI 1.06-6.49, p = 0.036 respectively). The ROC curve showed that the presence of all three parameters had the best accuracy (74%) to predict SCAF detection (sensitivity 39%, specificity 91%)., Conclusion: A multiparametric evaluation has the best accuracy to predict SCAF in ESUS patients and may help identifying those who would benefit most from ICM., (© 2022. Fondazione Società Italiana di Neurologia.)

The prevalence of cardiac amyloidosis has progressively increased over the last years, being recognized as a significant cause of heart failure. In fact, the management of advanced heart failure is a cornerstone treatment of amyloid cardiomyopathy due to the frequent delay in its diagnosis. Left ventricular assist devices (LVADs) have been gaining importance in the scenario of end-stage heart failure, representing an alternative to heart transplant. However, only few studies have investigated the role of LVAD in restrictive cardiomyopathies such as cardiac amyloidosis, since there are several problems to consider. In fact, both anatomical factors and the restrictive physiology of this condition make LVAD implant a relevant challenge in this subset of patients. Furthermore, due to the systemic involvement of amyloidosis, several factors have to be considered after LVAD implant, such as an increased risk of bleeding and right ventricular failure. This review attempts to summarize the current evidence of LVAD in cardiac amyloidosis, especially focusing on the challenges that this cardiomyopathy imposes both to the implant and to its management thereafter., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The aim of the present study was to evaluate the outcome of patients underwent subcutaneous implantable cardioverter defibrillator (S-ICD) implantation with the intermuscular (IM) two-incision technique during 3-year follow-up., Methods: the study population consisted of 105 consecutive patients (79 male; median 50 [13-77] years) underwent S-ICD implantation with the IM two-incision technique. The composite primary end point of the study consisted of device-related complications and inappropriate shocks (IAS). Secondary end points included the individual components of the primary end point, death from any cause, appropriate therapy, major adverse cardiac events, hospitalization for heart failure, and heart transplantation., Results: According to the PRAETORIAN score, the risk of conversion failure was classified as low in 99 patients (94.3%), intermediate in 6 (5.7%).Ventricular fibrillation was successfully converted at ≤65 J in 97.4% of patients. During a median follow-up of 39 (16-53) months, 10 patients (9.5%) experienced device-related complications, and 9 (8.5%) patients reported IAS. Lead-associated complications were the most common (5 patients, 4.7%), including 2 cases of lead failure (1.9%). Pocket complications were reported in 2 patients (1.9%). Extra-cardiac oversensing (3.8%) represented the leading cause of IAS. No T-wave oversensing episodes were recorded. Twelve patients (11.4%) experienced appropriate shocks. Eight patients (7.6%) died during follow-up. IAS or device-related complications did not impact on mortality., Conclusions: The overall device-related complications and IAS rates over 3 years of follow-up were 9.5% and 8.5%, respectively. According to our findings, the IM two-incision technique allows for optimal positioning of the device achieving a low PRAETORIAN score with a high conversion rate. IM two-incision technique allows low incidence of pocket complications, shifting the type of complications towards lead-related complications, which represent the most common complications. The IM two-incision technique would not seem to impact the occurrence of IAS. Management of complications are safe without impact on the outcome., (© 2023. The Author(s).)

Aim: To investigate the prevalence of amyloid cardiomyopathy (AC) and the diagnostic accuracy of echocardiographic red flags of AC among consecutive adult patients undergoing transthoracic echocardiogram for reason other than AC in 13 Italian institutions., Methods and Results: This is an Italian prospective multicentre study, involving a clinical and instrumental work-up to assess AC prevalence among patients ≥55 years old with an echocardiogram suggestive of AC (i.e. at least one echocardiographic red flag of AC in hypertrophic, non-dilated left ventricles with preserved ejection fraction). The study was registered at ClinicalTrials.gov (NCT04738266). Overall, 381 patients with an echocardiogram suggestive of AC were identified among a cohort of 5315 screened subjects, and 217 patients completed the investigations. A final diagnosis of AC was made in 62 patients with an estimated prevalence of 29% (95% confidence interval 23%-35%). Transthyretin-related AC (ATTR-AC) was diagnosed in 51 and light chain-related AC (AL-AC) in 11 patients. Either apical sparing or a combination of ≥2 other echocardiographic red flags, excluding interatrial septum thickness, provided a diagnostic accuracy >70%., Conclusion: In a cohort of consecutive adults with echocardiographic findings suggestive of AC and preserved left ventricular ejection fraction, the prevalence of AC (either ATTR or AL) was 29%. Easily available echocardiographic red flags, when combined together, demonstrated good diagnostic accuracy., (© 2022 European Society of Cardiology.)

Background: Subcutaneous implantable cardioverter defibrillator (S-ICD) is a suitable alternative for transvenous ICD (TV-ICD) patients who have undergone transvenous lead extraction (TLE). Limited data are available on the outcome of S-ICD patients implanted after TLE. We assessed the safety, efficacy, and outcome of S-ICD implantation after TLE of TV-ICD., Methods: The study population consisted of 36 consecutive patients with a median age of 52 (44-66) years who underwent S-ICD implantation after TLE of TV-ICD., Results: Indications for TLE were infection (63.9%) and lead malfunction (36.1%). During a median follow-up of 31 months, 3 patients (8.3%) experienced appropriate therapy and 7 patients (19.4%) experienced complications including inappropriate therapy (n = 4; 11.1%), isolated pocket erosion (n = 2; 5.5%), and ineffective therapy (n = 1; 2.8%). No lead/hardware dysfunction was reported. Premature device explantation occurred in 4 patients (11%). Eight patients (22.2%) died during follow-up, six of them (75%) because of refractory heart failure (HF). There were no S-ICD-related deaths. Predictors of mortality included NYHA class ≥ 2 (HR 5.05; 95% CI 1.00-26.38; p = 0.04), hypertension (HR 22.72; 95% CI 1.05-26.31; p = 0.02), diabetes (HR 10.64; 95% CI 2.05-55.60; p = 0.001) and ischemic heart disease (HR 5.92; 95% CI 1.17-30.30; p = 0.01)., Conclusion: Our study provides evidences on the use of S-ICD as an alternative after TV-ICD explantation for both infection and lead failure. Mortality of S-ICD patients who underwent TV-ICD explantation does not appear to be correlated with the presence of a prior infection, S-ICD therapy (appropriate or inappropriate), or S-ICD complications but rather to worsening of HF or other comorbidities., (© 2022. The Author(s).)

Background: Distinct contributions by functional or structural alterations of coronary microcirculation in heart transplantation (HT) and their prognostic role have not been fully elucidated. We aimed to identify the mechanisms of coronary microvascular dysfunction (CMD) in HT and their prognostic implications., Methods: 134 patients, surviving at least 5 years after HT, without evidence of angiographic vasculopathy or symptoms/signs of rejection were included. 50 healthy volunteers served as controls. All underwent the assessment of rest and hyperemic coronary diastolic peak flow velocity (DPV r and DPV h ) and coronary flow velocity reserve (CFVR) and its inherent companion that is based on the adjusted quadratic mean: CCFVR = √{(DPV r ) 2 + (DPV h ) 2 }. Additionally, basal and hyperemic coronary microvascular resistance (BMR and HMR) were estimated., Results: Based on CFVR and DPV h , HT patients can be assigned to four endotypes: endotype 1, discordant with preserved CFVR (3.1 ± 0.4); endotype 2, concordant with preserved CFVR (3.4 ± 0.5); endotype 3, concordant with impaired CFVR (1.8 ± 0.3) and endotype 4, discordant with impaired CFVR (2.0 ± 0.2). Intriguingly, endotype 1 showed lower DPV r ( p < 0.0001) and lower DPV h ( p < 0.0001) than controls with lower CFVR ( p < 0.0001) and lower CCFVR ( p < 0.0001) than controls. Moreover, both BMR and HMR were higher in endotype 1 than in controls ( p = 0.001 and p < 0.0001, respectively), suggesting structural microvascular remodeling. Conversely, endotype 2 was comparable to controls. A 13/32 (41%) patients in endotype 1 died in a follow up of 28 years and mortality rate was comparable to endotype 3 (14/31, 45%). However, CCFVR was < 80 cm/s in all 13 deaths of endotype 1 (characterized by preserved CFVR). At multivariable analysis, CMD, DPVh < 75 cm/s and CCFVR < 80 cm/s were independent predictors of mortality. The inclusion of CCFVR < 80 cm/s to models with clinical indicators of mortality better predicted survival, compared to only adding CMD or DPV h < 75 cm/s ( p < 0.0001 and p = 0.03, respectively)., Conclusion: A normal CFVR could hide detection of microvasculopathy with high flow resistance and low flow velocities at rest. This microvasculopathy seems to be secondary to factors unrelated to HT (less rejections and more often diabetes). The combined use of CFVR and CCFVR provides more complete clinical and prognostic information on coronary microvasculopathy in HT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cecere, Kerkhof, Civieri, Angelini, Gambino, Fraiese, Bottio, Osto, Famoso, Fedrigo, Giacomin, Toscano, Montisci, Iliceto, Gerosa and Tona.)

The interpretation of 12-lead resting electrocardiogram (ECG) in patients with a definitive diagnosis or with the suspicion of a cardiomyopathy represents a cornerstone for the diagnostic work up and management of patients. Although low electrocardiographic QRS voltages (LQRSV) detected by 12-lead resting ECG have historically been acknowledged by physicians, in view of recent evidence on the demonstration of myocardial scar by cardiac magnetic resonance and its relevance as a cause of sudden cardiac death even in young individuals, a new interest has been raised about the utility of LQRSV in the clinical practice. Beyond their diagnostic value, LQRSV have also demonstrated a prognostic role in different cardiomyopathies. The present review summarizes the diagnostic and prognostic value of LQRSV in cardiomyopathies, reporting the new evidence, primarily based on advanced imaging studies, supporting the clinical utility of this parameter., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

The impressive advances in the knowledge of biomarkers and molecular targets has enabled significant progress in drug therapy for crucial diseases such as cancer. Specific areas of pharmacology have contributed to these therapeutic outcomes-mainly targeted therapy, immunomodulatory therapy, and gene therapy. This review focuses on the pharmacological profiles of these therapeutic classes and intends, on the one hand, to provide a systematic definition and, on the other, to highlight some aspects related to pharmacovigilance, namely the monitoring of safety and the identification of potential toxicities and adverse drug reactions. Although clinicians often consider pharmacovigilance a non-priority area, it highlights the risk/benefit ratio, an essential factor, especially for these advanced therapies, which represent the most innovative and promising horizon in oncology.

Background: Thyroid cancer is the most common endocrine neoplasia and represents approximately 1.5% to 2.1% of all cancers diagnosed annually worldwide. Iodine Refractory Differentiated Thyroid Carcinoma (RR-DTC) and advanced/metastatic medullary thyroid carcinoma are relatively uncommon yet prognostically significant thyroid cancers. Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers, including thyroid cancer. Many Multi-Kinase Inhibitors (MKIs) which are now FDA-/EMA approved for thyroid cancer have shown clinical benefit in patients with advanced cancer. Treatment related toxicities occur frequently with these drugs and can be severe or life-threatening., Objectives: This review summarizes the role of targeted therapy with MKIs in the management of RRDTC and advanced/metastatic MTC patients, focusing on side-effect profiles of these drugs, with a presentation of several recent patents published in this field., Methods: We review the scientific literature on advanced thyroid cancer and analyze the International Pharmacovigilance database (FAERS, Eudravigilance, and WHO Vigibase) for adverse drug reactions., Results: This systematic analysis highlights the difference in the safety profile of the recent drugs used in the treatment of advanced thyroid cancer and the recent discoveries for diagnosis or treatment of the thyroid cancer., Conclusion: It is essential to investigate the safety profile of recent anticancer drugs for advanced thyroid cancer to allow health professionals to make the best choice for each patient by conducting risk/benefit assessment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel solvent-free formulation of paclitaxel, which was developed to avoid toxicities associated with Cremophor EL® vehicle used in solvent-based paclitaxel. It is approved as monotherapy for treatment of metastatic breast cancer (MBC) in Europe and the US; in combination therapy for non-small-cell lung cancer (NSCLC) and for first-line treatment of advanced pancreatic cancer (PC) only in the US. The European Medicines Agency has recently released only a positive opinion for use of nab-paclitaxel in PC., Areas Covered: This review reports the clinical findings and the safety data of nab-paclitaxel for MBC, NSCLC and PC., Expert Opinion: In MBC, nab-paclitaxel has demonstrated a good safety and an efficacy profile compared with other taxanes, but no strong data on overall survival are available. Considering the role of markers or predictive factors for nab-paclitaxel effectiveness in the metastatic setting would be useful. In PC, nab-paclitaxel and gemcitabine represent a new therapeutic choice with significant improvement in survival. In a Phase III study with NSCLC patients, nab-paclitaxel showed better results in a subgroup of patients with squamous histology, for whom results with conventional therapies are still poor and improved therapeutic options are needed.

Background: Little remains known about the role of overweight to promote progressive atrial and ventricular myocardial dysfunction. Aim of this study was to investigate the potential influence of overweight on left ventricular (LV) and atrial (LA) function, as assessed by speckle tracking strain analysis, in patients at low-to-moderate global cardiovascular risk., Methods: Seventy patients presenting 1 or more cardiovascular risk factor, with preserved ejection fraction, were enrolled. Peak atrial longitudinal strain (PALS) and Peak ventricular longitudinal strain (PVLS) were calculated by averaging values observed in all LV or LA segments, in four- and two-chamber views (global PALS and global PVLS), using a commercially available semiautomated two-dimensional (2D) strain software., Results: Global PALS was similar in the 2 groups, while global PVLS was significantly lower in the overweight group as compared to normal weight (-17.2 ± 3.3 vs. -18.7 ± 2.8, P < 0.05). Univariate analysis of correlation showed a significantly correlation between global PALS and PVLS (r = -0.43, P < 0.01), as well as with E/A ratio (r = 0.40, P < 0.01) and with LV mass index (r = -0.34, P < 0.05). In multivariate linear regression analysis, these parameters were confirmed as independent predictors of PALS., Conclusion: In subjects at low-to-moderate cardiovascular risk, overweight is a key determinant of the reduction of global LV longitudinal function as assessed by 2D strain., (© 2013, Wiley Periodicals, Inc.)

Purpose: Left ventricular hypertrophy (LVH) can develop in response to training with morphological changes in the heart and to pathological increase in afterload such as in essential hypertension. Deformation analysis using two-dimensional (2D) strain echocardiography can detect early systolic function abnormalities in patients with LVH. The aim of this study was to characterize left ventricular twisting (LVT) modifications, in professional athletes, compared with control subjects and with patients with hypertensive cardiopathy., Methods: Seventy-six patients were enrolled: 37 professional athletes with cardiac hypertrophy (group A), 22 patients with early hypertensive cardiopathy (group B) cross-matched for LV mass index, and 17 healthy controls (group C), with no evidence of cardiac hypertrophy. All patients had no concomitant cardiac disease. All patients were investigated at rest using transthoracic echocardiography. LVT was obtained with speckle tracking analysis, using dedicated software., Results: LVT was reduced in group A compared to group B and C (group A: 8.0° ± 2.4°; group C: 10.3° ± 2.3°; group B: 16.0° ± 4.2°; P < 0.01). In overall population, LVT showed a significant correlation with transmitral flow pattern (r =-0.58, P < 0.01) and with age (r =-0.57, P < 0.01). LVT showed the best predictive value to diagnose diastolic dysfunction (AUC: 0.86, P < 0.0001)., Conclusions: 2D strain can identify specific patterns of myocardial deformation in professional athletes, controls, and patients with early hypertensive cardiopathy. In our study LVT showed a parallel trend with modifications of diastolic function and could represent a promising tool to differentiate functional cardiac hypertrophy from hypertensive cardiac hypertrophy., (© 2011, Wiley Periodicals, Inc.)

Background: Speckle tracking echocardiography (STE) is a novel method for the angle-independent and objective quantification of myocardial deformation; it has recently evolved, enabling the quantification of longitudinal myocardial left atrial (LA) deformation dynamics. To investigate the effects of chronic mitral regurgitation (MR) on these functional atrial indices, we analyzed LA function by STE in a group of asymptomatic patients with chronic degenerative MR., Methods: The study population included 36 patients with mild MR, 38 with moderate MR, and 42 with severe MR. 52 age-matched controls were also recruited. Global peak atrial longitudinal strain (global PALS) was measured in all subjects by averaging all atrial segments., Results: Age, gender, and LV ejection fraction in all pathological groups were comparable to those in the controls. Global PALS was higher in the mild MR group (46.7 ± 9.1%) in comparison with the controls (40.5 ± 6.2%; P < 0.001); instead global PALS was lower in the moderate MR group (25.7 ± 7.1%) and further reduced in the severe MR group (13.2 ± 5.2%) in comparison with the controls (40.5 ± 6.2%; overall P < 0.0001 by ANOVA, P < 0.05 for all pairwise comparisons). In multivariate analysis, E/Em ratio emerged as the principal independent determinant of global PALS., Conclusions: Our study provides new insight for the LA function analysis in response to different degrees of MR, showing that STE measurements of LA longitudinal strain may be considered a promising tool for the early detection of impairment of LA compliance in patients with asymptomatic chronic MR., (© 2011, Wiley Periodicals, Inc.)

The topic of this review covers a very important branch of cancer research, cancer vaccination. The growing knowledge in tumor immunology has evolved rapidly, starting from nonspecific generic stimulation of the immune system to more specific approaches based on the availability of tumor antigens. The review covers molecular and cell biology, and pharmaceutical technology of cancer vaccines. Particularly, it is aimed at highlighting the results of cancer vaccines from phase II and III clinical trials, an issue that is of relevance to better understand how cancer vaccines can successfully complement antitumor therapy, including conventional chemotherapy and the recently developed target-based drugs.

Background: Left ventricular (LV) diastolic function represents a complex performance that involves long axis displacement, myocardial lengthening velocities as well as cavity filling. The aim of this study was to assess the various diastolic event interrelations in a group of patients with different degrees of diastolic dysfunction., Methods: 128 consecutive subjects with various degrees of diastolic impairment were studied by Doppler echocardiography. The amplitude of early diastolic (El) and late diastolic (Al) long axis lengthening was measured by M-mode and corresponding myocardial velocities (Ea and Aa) by Tissue Doppler. LV filling velocities were also acquired by spectral pulsed wave Doppler., Results: Early diastolic long axis amplitudes and velocities correlated (r=0.73, P<0.0001) as did late diastolic ones (r=0.67, P<0.0001). El of ≤5.6 mm was 80.6% sensitive and 70.5% specific in predicting Ea of <8.0 cm/s, a feature of LV impaired relaxation. El/Al correlated with Ea/Aa (r=0.78, P<0.0001), as did E/El with E/Ea ratios (r=0.74, P<0.0001). An E/El ratio>17.3 cm/s/mm had 94.1% sensitivity and 87.4% specificity for predicting an E/Ea ratio>15, a marker for raised LV filling pressures. El≤6.8 mm, total amplitude of diastolic motion (El+Al)≤11.5 mm, and E/El>14.2 cm/s/mm were the best criteria to discriminate between normal diastolic function and pseudonormal/restrictive LV filling., Conclusion: Diastolic LV components of motion, amplitude and velocities are not independent, neither from each other nor from filling pressures. An integrated approach towards using them all in assessing diastolic function, particularly in patients with raised filling pressure should be of great clinical value., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: The assessment of the longitudinal component of left ventricular (LV) function is of major clinical importance for the early detection of LV contractile impairment. The aim of this study was to compare the impact of isolated type-2 diabetes, isolated hypertension, and co-existence of both on LV longitudinal systolic performance, with particular focus on their potential interaction effect., Methods: The study population included 163 consecutive patients: 84 patients with hypertension, 36 with diabetes, and 43 who have both hypertension and diabetes; 70 healthy controls were also recruited. Systolic mitral annulus velocity (S(m)) by Tissue Doppler and left atrioventricular plane displacement (AVPD) by M-mode were measured in all subjects., Results: AVPD was similarly reduced in hypertensives (13.2±2.2mm) and diabetics (13.5±2.3mm) when compared with the controls (15.1±2.4mm), and further depressed in diabetic hypertensives (11.5±3.0mm). Similar results were found for S(m). General linear model analysis revealed no significant interaction terms between diabetes and hypertension., Conclusions: Normotensive diabetics and nondiabetic hypertensives show comparable depression in LV longitudinal systolic indices when compared with age- and gender-matched healthy controls; the co-existence of diabetes and hypertension leads to further impairment in LV longitudinal systolic function in an additive manner., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Research into mTOR, mammalian Target Of Rapamycin as an important drug target continues to be extremely interesting, both in terms of the increased molecular knowledge being acquired at the basis of various human diseases, and also for possible applications in drug cancer therapy. The mTOR signaling system plays a key role in several transduction pathways that are necessary for cell cycle progression and cellular proliferation. Drugs known as mTOR inhibitors have been included in ongoing and in recently completed cancer trials. New insights into the mTOR signaling system are helping to clarify the functionality of key mTOR components, and especially their possible role in apoptosis, angiogenesis and tumor progression. Three other molecules, already approved for therapeutic use and being commercialized (Everolimius, Temsirolimus and Zotarolimus) are added to Rapamycin (also known as Sirolimus), the parent drug of the mTOR inhibitors. Of these, only Temsirolimus is currently approved in the treatment of renal cell carcinoma, while the others are approved for organ transplant rejection and coronary artery restenosis. There are at least 10 other molecules currently under development for clinical and preclinical studies. This review offers an updated synopsis of the mTOR signaling system, in particular as regards relevant aspects of cancer research, looks at the known mTOR inhibitors and gives a systematic vision of current trials for each individual molecule subject to clinical investigation.

Background: Few data exist regarding the direct effects of caffeine and smoking on cardiac function. We sought to explore the acute effects of caffeine assumption, cigarette smoking, or both on left ventricular (LV) and right ventricular (RV) function in a population of young normal subjects., Methods: Forty-five healthy subjects aged 25 +/- 2 years underwent echocardiography. Fifteen of them were non-smokers and habitual coffee consumers (group 1), 15 were smokers and not habitual coffee consumers (group 2), and 15 were smokers and habitual coffee consumers (group 3). Peak systolic (Sa), early diastolic Ea, and late diastolic (Aa) velocity of mitral annulus were measured by pulsed Tissue Doppler, and left atrioventricular plane displacement was determined by M-mode. Tricuspid annular velocities and systolic excursion (TAPSE) were also determined. Measurements were performed at baseline and after oral assumption of caffeine 100 mg in group 1, one cigarette smoking in group 2, and both in group 3., Results: No changes in ventricular function were observed in group 1 after caffeine administration. In group 2, cigarette smoking yielded an acute increase in mitral Aa (+12.1%, p = 0.0026), tricuspid Sa (+9.8%, p = 0.012) and TAPSE (+7.9%, p = 0.017), and a decrease in the mitral Ea/Aa ratio (-8.5%, p = 0.0084). Sequential caffeine assumption and cigarette smoking in group 3 was associated with an acute increase in mitral Aa (+13.0%, p = 0.015) and tricuspid Aa (+11.6%, p < 0.0001) and a reduction in mitral Ea/Aa ratio (-8.5%, p = 0.0084) tricuspid Ea (-6.6%, p = 0.048) and tricuspid Ea/Aa ratio (-9.6%, p = 0.0003). In a two-way ANOVA model controlling for hemodynamic confounding factors, changes in the overall population remained significant for mitral Aa and Ea/Aa ratio, and for tricuspid Aa and Ea/Aa ratio., Conclusion: In young healthy subjects, one cigarette smoking is associated to an acute impairment in LV diastolic function and a hyperdynamic RV systolic response. Caffeine assumption alone does not exert any acute effect on ventricular long-axis function, but potentiates the negative effect of cigarette smoking by abolishing RV supernormal response and leading to a simultaneous impairment in both LV and RV diastolic function.

Background: Depressed circumferential midwall performance and impaired left ventricular (LV) longitudinal function are both early markers of LV systolic dysfunction in patients with hypertension. The relation between midwall and longitudinal indices in these patients has never been analyzed., Methods: In 126 patients with hypertension, midwall fractional shortening (mFS), stress-corrected mFS, M-mode left atrioventricular plane displacement, and tissue Doppler-derived peak mitral annular systolic velocity were determined., Results: Regression analysis showed that the relations of midwall indices to atrioventricular plane displacement and mitral annular systolic velocity were all nonlinear. Reductions in atrioventricular plane displacement or mitral annular systolic velocity within their higher ranges corresponded to relatively smaller decreases in mFS and stress-corrected mFS. Relative wall thickness was the strongest determinant of the relative efficiency of circumferential and longitudinal LV contraction., Conclusion: The relation between circumferential midwall and longitudinal function in patients with hypertension is nonlinear and dependent on LV geometry. In these patients, systolic impairment occurs earlier in longitudinal than circumferential performance.