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Background: Transthyretin-related cardiac amyloidosis (TTR-CA) is thought to be particularly common in specific at-risk conditions, including aortic stenosis (AS), heart failure with preserved ejection fraction (HFpEF), carpal tunnel syndrome (CTS) and left ventricular hypertrophy or hypertrophic cardiomyopathy (LVH/HCM)., Methods: We performed a systematic revision of the literature, including only prospective studies performing TTR-CA screening with bone scintigraphy in the above-mentioned conditions. Assessment of other forms of CA was also evaluated. For selected items, pooled estimates of proportions or means were obtained using a meta-analytic approach., Results: Nine studies (3 AS, 2 HFpEF, 2 CTS and 2 LVH/HCM) accounting for 1375 screened patients were included. One hundred fifty-six (11.3%) TTR-CA patients were identified (11.4% in AS, 14.8% in HFpEF, 2.6% in CTS and 12.9% in LVH/HCM). Exclusion of other forms of CA and use of genetic testing was overall puzzled. Age at TTR-CA recognition was significantly older than that of the overall screened population in AS (86 vs. 83 years, p = .04), LVH/HCM (75 vs. 63, p < .01) and CTS (82 vs. 71), but not in HFpEF (83 vs. 79, p = .35). In terms of comorbidities, hypertension, diabetes and atrial fibrillation were highly prevalent in TTR-CA-diagnosed patients, as well as in those with an implanted pacemaker., Conclusions: Screening with bone scintigraphy found an 11-15% TTR-CA prevalence in patients with AS, HFpEF and LVH/HCM. AS and HFpEF patients were typically older than 80 years at TTR-CA diagnosis and frequently accompanied by comorbidities. Several studies showed limitations in the application of recommended TTR-CA diagnostic algorithm, which should be addressed in future prospective studies., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

The intracellular tyrosine kinase inhibitor nintedanib has shown great efficacy for the treatment of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases. However, the incidence rate of myocardial infarction (MI) among participants in landmark IPF trials was remarkable, peaking at 3/100 patient-years. Although subjects with IPF often have a high cardiovascular (CV) risk profile, the occurrence of MI in nintedanib-treated patients may not be fully explained by clustering of CV risk factors. Nintedanib inhibits the vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor pathways, which play important roles in the biology of the atherosclerotic plaque and in the response of the heart to ischaemia. Hence, unwanted CV effects may partly account for nintedanib-related MI. We review the evidence supporting this hypothesis and discuss possible actions for a safe implementation of nintedanib in clinical practice, building on the experience with tyrosine kinase inhibitors acquired in cardio-oncology., (© 2021 British Pharmacological Society.)

Background: Women with breast cancer (BC) represent a special population particularly exposed to cardiovascular disease (CVD) risk. However, cardiologic assessment in BC is mostly limited to detection of left ventricular dysfunction cardiotoxicity (LVD-CTX) due to anticancer treatments. Our aim was to comprehensively investigate CV profile and events in a contemporary BC cohort. Methods and Results: Records of BC patients referred for a Cardio-Oncologic evaluation before starting anticancer treatments, between 2016 and 2019, were retrospectively reviewed ( n = 508). Information regarding prevalence and control of CV risk factors, and novel CVD diagnoses were extracted. Occurrence of LVD-CTX, CV events other than LVD-CTX and mortality was assessed. Mean age of study population was 64 ± 13 years; 287 patients were scheduled to receive anthracycline and 165 anti-HER2 therapy. Overall, 53% of BC women had ≥2 CV risk factors, and 67% had at least one of arterial hypertension, dyslipidaemia or diabetes mellitus not adequately controlled. Eighteen (4%) patients were diagnosed a previously unknown CVD. Over a mean follow-up of 2.5 ± 1 years, 3% of BC patients developed LVD-CTX, 2% suffered from other CV events and 11% died. CV risk factors were not associated with LVD-CTX, except for family history of CAD. On the contrary, patients with other CV events exhibited a worse CV profile. Those who died more commonly experienced CV events other than LVD-CTX ( p = 0.02). Conclusions: BC women show a suboptimal CV risk profile and are at risk of CV events not limited to LVD-CTX. A baseline Cardio-Oncologic evaluation was instrumental to implement CV prevention and to optimize CV therapies., 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 © 2021 Tini, Ameri, Buzzatti, Sarocchi, Murialdo, Guglielmi, Arboscello, Ballestrero, Del Mastro, Spallarossa and Porto.)

Takotsubo syndrome (TTS) is an intriguing clinical entity, characterized by usually transient and reversible abnormalities of the left ventricular systolic function, mimicking the myocardial infarction with non-obstructive coronary arteries. TTS was initially regarded as a benign condition, however recent studies have unveiled adverse outcomes in the short- and long-term, with rates of morbidity and mortality comparable to those experienced after an acute myocardial infarction. Given the usual transient nature of TTS, this is an unexpected finding. Moreover, long-term mortality seems to be mainly driven by non-cardiovascular causes. The uncertain long-term prognosis of TTS warrants a comprehensive outpatient follow-up after the acute event, although there are currently no robust data indicating its modality and timing. The aim of the present review is to summarize recent available evidence regarding long-term prognosis in TTS. Moreover methods, timing and findings of the long-term management of TTS will be discussed., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by IMR Press.)

Takotsubo syndrome (TTS) is an increasingly recognized condition burdened by significant acute and long-term adverse events. The availability of novel techniques expanded the knowledge on TTS and allowed a more accurate risk-stratification, potentially guiding clinical management. The present review aims to summarize the recent advances in TTS prognostic evaluation with a specific focus on novel imaging and genetic markers. Parametric deformation analysis by speckle-tracking echocardiography, as well as tissue characterization by cardiac magnetic resonance imaging T1 and T2 mapping techniques, currently appear the most clinically valuable applications. Notwithstanding, computed tomography and nuclear imaging studies provided limited but promising data. A genetic predisposition to TTS has been hypothesized, though available evidence is still not sufficient. Although a genetic predisposition appears likely, further studies are needed to fully characterize the genetic background of TTS, in order to identify genetic markers that could assist in predicting disease recurrences and help in familial screening., 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 © 2021 Arcari, Limite, Adduci, Sclafani, Tini, Palano, Cosentino, Cristiano, Cacciotti, Russo, Rubattu, Volpe, Autore, Musumeci and Francia.)

Aims: The use of beta-blocker therapy in cardiac amyloidosis (CA) is debated. We aimed at describing patterns of beta-blocker prescription through a nationwide survey., Methods and Results: From 11 referral centres, we retrospectively collected data of CA patients with a first evaluation after 2016 (n = 642). Clinical characteristics at first and last evaluation were collected, with a focus on medical therapy. For patients in whom beta-blocker therapy was started, stopped, or continued between first and last evaluation, the main reason for beta-blocker management was requested. Median age of study population was 77 years; 81% were men. Arterial hypertension was found in 58% of patients, atrial fibrillation (AF) in 57%, and coronary artery disease in 16%. Left ventricular ejection fraction was preserved in 62% of cases, and 74% of patients had advanced diastolic dysfunction. Out of the 250 CA patients on beta-blockers at last evaluation, 215 (33%) were already taking this therapy at first evaluation, while 35 (5%) were started it, in both cases primarily because of high-rate AF. One-hundred-nineteen patients (19%) who were on beta-blocker at first evaluation had this therapy withdrawn, mainly because of intolerance in the presence of heart failure with advanced diastolic dysfunction. The remaining 273 patients (43%) had never received beta-blocker therapy. Beta-blockers usage was similar between CA aetiologies. Patients taking vs. not taking beta-blockers differed only for a greater prevalence of arterial hypertension, coronary artery disease, AF, and non-restrictive filling pattern (P < 0.01 for all) in the former group., Conclusions: Beta-blockers prescription is not infrequent in CA. Such therapy may be tolerated in the presence of co-morbidities for which beta-blockers are routinely used and in the absence of advanced diastolic dysfunction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Radiomics uses high-dimensional sets of imaging features to predict biological characteristics of tumors and clinical outcomes. The choice of the algorithm used to analyze radiomic features and perform predictions has a high impact on the results, thus the identification of adequate machine learning methods for radiomic applications is crucial. In this study we aim to identify suitable approaches of analysis for radiomic-based binary predictions, according to sample size, outcome balancing and the features-outcome association strength. Simulated data were obtained reproducing the correlation structure among 168 radiomic features extracted from Computed Tomography images of 270 Non-Small-Cell Lung Cancer (NSCLC) patients and the associated to lymph node status. Performances of six classifiers combined with six feature selection (FS) methods were assessed on the simulated data using AUC (Area Under the Receiver Operating Characteristics Curves), sensitivity, and specificity. For all the FS methods and regardless of the association strength, the tree-based classifiers Random Forest and Extreme Gradient Boosting obtained good performances (AUC ≥ 0.73), showing the best trade-off between sensitivity and specificity. On small samples, performances were generally lower than in large-medium samples and with larger variations. FS methods generally did not improve performances. Thus, in radiomic studies, we suggest evaluating the choice of FS and classifiers, considering specific sample size, balancing, and association strength.

Introduction: Bilateral carpal tunnel syndrome (CTS), particularly in male individuals with left ventricular hypertrophy (LVH), has been recognized as a red flag for transthyretin cardiac amyloidosis (TTR-CA). Nonetheless, the opportunity of screening CTS patients for TTR has yet to be determined., Methods: Medical records of 1689 CTS surgeries performed at our institution between 2008 and 2018 were reviewed. Eighty-three males who underwent bilateral CTS surgery were considered eligible for the study, and offered a screening examination including electrocardiography and echocardiography. Individuals with LVH (diastolic septal wall thickness > 12 mm) were offered second-line diagnostic testing including blood testing and bone scintigraphy., Results: Study population consisted of 53 bilateral CTS male patients, with median age of 73 years. LVH was found in 6 (11%) individuals. None of them had monoclonal gammopathy or reported CTS occupational risk factors. Two declined to undergo further testing, whereas 2 had negative and 2 had positive bone scintigraphy (both Perugini 2 uptake) and tested negative for TTR gene mutations (wild-type TTR-CA)., Conclusions: Prevalence of TTR-CA in the entire study population was 4%, but among bilateral CTS patients with LVH peaked at 33%. In this latter population, screening for TTR-CA appeared feasible and effective., Competing Interests: Declaration of Competing Interest Dr. Canepa received speaker and advisor fees from Akcea Therapeutics, Menarini, Novartis, Pfizer, Sanofi and Sanofi Genzyme, Vifor Pharma. All other Authors reported non conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

While most patients with hypertrophic cardiomyopathy (HCM) show a relatively stable morphologic and clinical phenotype, in some others, progressive changes in the left ventricular (LV) wall thickness, cavity size, and function, defined, overall, as "LV remodeling", may occur. The interplay of multiple pathophysiologic mechanisms, from genetic background to myocardial ischemia and fibrosis, is implicated in this process. Different patterns of LV remodeling have been recognized and are associated with a specific impact on the clinical course and management of the disease. These findings underline the need for and the importance of serial multimodal clinical and instrumental evaluations to identify and further characterize the LV remodeling phenomenon. A more complete definition of the stages of the disease may present a chance to improve the management of HCM patients.

The increasing scope of genetic testing allowed by next-generation sequencing (NGS) dramatically increased the number of genetic variants to be interpreted as pathogenic or benign for adequate patient management. Still, the interpretation process often fails to deliver a clear classification, resulting in either variants of unknown significance (VUSs) or variants with conflicting interpretation of pathogenicity (CIP); these represent a major clinical problem because they do not provide useful information for decision-making, causing a large fraction of genetically determined disease to remain undertreated. We developed a machine learning (random forest)-based tool, RENOVO, that classifies variants as pathogenic or benign on the basis of publicly available information and provides a pathogenicity likelihood score (PLS). Using the same feature classes recommended by guidelines, we trained RENOVO on established pathogenic/benign variants in ClinVar (training set accuracy = 99%) and tested its performance on variants whose interpretation has changed over time (test set accuracy = 95%). We further validated the algorithm on additional datasets including unreported variants validated either through expert consensus (ENIGMA) or laboratory-based functional techniques (on BRCA1/2 and SCN5A). On all datasets, RENOVO outperformed existing automated interpretation tools. On the basis of the above validation metrics, we assigned a defined PLS to all existing ClinVar VUSs, proposing a reclassification for 67% with >90% estimated precision. RENOVO provides a validated tool to reduce the fraction of uninterpreted or misinterpreted variants, tackling an area of unmet need in modern clinical genetics., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Intracardiac thrombosis is reported to occur frequently in cardiac amyloidosis (CA). However, data regarding arterial thrombo-embolic events (AEs) in CA are limited. We aimed at assessing prevalence, clinical characteristics and predictors of AEs in a large multicentric CA cohort., Methods and Results: Four-hundred-six consecutive CA patients (134 AL, 73 ATTRm and 199 ATTRwt) from 5 Italian referral centres were retrospectively evaluated and followed-up for a median time of 19 months. Thirty-one patients (7.6%) suffered from an AE, of whom 10 (32.2%) were in sinus rhythm and had no history of AF. There were no significant differences in terms of age, gender and type of CA between patients with or without AEs. Fourteen (7.6%) of 185 patients on anticoagulation had an AE despite therapy. Anticoagulation therapy did not appear to fully protect from the risk of events (HR 1.23, 95%CI 0.52-2.92, p  = .64). The only predictor of AEs, in particular among CA patients in sinus rhythm, was a CHA2DS2-VASC score ≥ 3 (HR 2.84, 95%CI 1.02-7.92, p  = .05 in overall population; HR 10.13, 95%CI 1.12-91.19, p  = .04 in patients in sinus rhythm)., Conclusions: In our large, multicentric, real-world cohort, prevalence and incidence rate of AEs was high. A consistent proportion of events occurred despite anticoagulation therapy or in patients in sinus rhythm. A higher CHA2DS2-VASc score might identify patients at risk of AEs also among those in sinus rhythm.

Background: Increased adipogenesis and altered adipocyte function contribute to the development of obesity and associated comorbidities. Fructose modified adipocyte metabolism compared to glucose, but the regulatory mechanisms and consequences for obesity are unknown. Genome-wide methylation and global transcriptomics in SGBS pre-adipocytes exposed to 0, 2.5, 5, and 10 mM fructose, added to a 5-mM glucose-containing medium, were analyzed at 0, 24, 48, 96, 192, and 384 h following the induction of adipogenesis., Results: Time-dependent changes in DNA methylation compared to baseline (0 h) occurred during the final maturation of adipocytes, between 192 and 384 h. Larger percentages (0.1% at 192 h, 3.2% at 384 h) of differentially methylated regions (DMRs) were found in adipocytes differentiated in the glucose-containing control media compared to adipocytes differentiated in fructose-supplemented media (0.0006% for 10 mM, 0.001% for 5 mM, and 0.005% for 2.5 mM at 384 h). A total of 1437 DMRs were identified in 5237 differentially expressed genes at 384 h post-induction in glucose-containing (5 mM) control media. The majority of them inversely correlated with the gene expression, but 666 regions were positively correlated to the gene expression., Conclusions: Our studies demonstrate that DNA methylation regulates or marks the transformation of morphologically differentiating adipocytes (seen at 192 h), to the more mature and metabolically robust adipocytes (as seen at 384 h) in a genome-wide manner. Lower (2.5 mM) concentrations of fructose have the most robust effects on methylation compared to higher concentrations (5 and 10 mM), suggesting that fructose may be playing a signaling/regulatory role at lower concentrations of fructose and as a substrate at higher concentrations.

Background The burden of cancer in heart failure with reduced ejection fraction is apparently growing. Randomized controlled trials (RCTs) may help understanding this observation, since they span decades of heart failure treatment. Methods and Results We assessed cancer, cardiovascular, and total mortality in phase 3 heart failure RCTs involving ≥90% individuals with left ventricular ejection fraction <45%, who were not acutely decompensated and did not represent specific patient subsets. The pooled odds ratios (ORs) of each type of death for the control and treatment arms were calculated using a random-effects model. Temporal trends and the impact of patient and RCT characteristics on mortality outcomes were evaluated by meta-regression analysis. Cancer mortality was reported for 15 (25%) of 61 RCTs, including 33 709 subjects, and accounted for 6% to 14% of all deaths and 17% to 67% of noncardiovascular deaths. Cancer mortality rate was 0.58 (95% CI, 0.46-0.71) per 100 patient-years without temporal trend ( P =0.35). Cardiovascular ( P =0.001) and total ( P =0.001) mortality rates instead decreased over time. Moreover, cancer mortality was not influenced by treatment (OR, 1.08; 95% CI, 0.92-1.28), unlike cardiovascular (OR, 0.88; 95% CI, 0.79-0.98) and all-cause (OR, 0.91; 95% CI, 0.84-0.99) mortality. Meta-regression did not reveal significant sources of heterogeneity. Possible reasons for excluding patients with malignancy overlapped among RCTs with and without published cancer mortality, and malignancy was an exclusion criterion only for 4 (8.7%) of the RCTs not reporting cancer mortality. Conclusions Cancer is a major, yet overlooked cause of noncardiovascular death in heart failure with reduced ejection fraction, which has become more prominent with cardiovascular mortality decline.

Background: Over the last 50 years, the epidemiology of hypertrophic cardiomyopathy (HCM) has changed because of increased awareness and availability of advanced diagnostic tools. We aim to describe the temporal trends in age, sex, and clinical characteristics at HCM diagnosis over >4 decades., Methods: We retrospectively analyzed records from the ongoing multinational Sarcomeric Human Cardiomyopathy Registry. Overall, 7286 patients with HCM diagnosed at an age ≥18 years between 1961 and 2019 were included in the analysis and divided into 3 eras of diagnosis (<2000, 2000-2010, >2010)., Results: Age at diagnosis increased markedly over time (40±14 versus 47±15 versus 51±16 years, P <0.001), both in US and non-US sites, with a stable male-to-female ratio of about 3:2. Frequency of familial HCM declined over time (38.8% versus 34.3% versus 32.7%, P <0.001), as well as heart failure symptoms at presentation (New York Heart Association III/IV: 18.1% versus 15.8% versus 12.6%, P <0.001). Left ventricular hypertrophy became less marked over time (maximum wall thickness: 20±6 versus 18±5 versus 17±5 mm, P <0.001), while prevalence of obstructive HCM was greater in recent cohorts (peak gradient >30 mm Hg: 31.9% versus 39.3% versus 39.0%, P =0.001). Consistent with decreasing phenotypic severity, yield of pathogenic/likely pathogenic variants at genetic testing decreased over time (57.7% versus 45.6% versus 38.4%, P <0.001)., Conclusions: Evolving HCM populations include progressively greater representation of older patients with sporadic disease, mild phenotypes, and genotype-negative status. Such trend suggests a prominent role of imaging over genetic testing in promoting HCM diagnoses and urges efforts to understand genotype-negative disease eluding the classic monogenic paradigm.

Immune-checkpoint inhibitors (ICIs) represent a successful paradigm in the treatment of cancer. ICIs elicit an immune response directed against cancer cells, by targeting the so-called immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Such response, however, is not entirely tumor-specific and may result in immune-related adverse events (irAEs), involving a number of organs and systems. Cardiovascular (CV) irAEs are rare, although potentially severe. In particular, several cases of ICI-related myocarditis with life-threatening course have been reported: the possibility of fulminant cases, thus, requires a high level of awareness among both oncologists and cardiologists. Aggressive work-up and management of symptomatic patients taking ICIs is fundamental for early recognition and initiation of specific immunosuppressive therapies. Notably, myocarditis occurs within few weeks from ICIs initiation, offering opportunity for a targeted screening. Troponin testing is the cornerstone of this screening, yet uncertainties remain regarding timing and candidates. Moreover, troponins positivity should be carefully interpreted. We herein review the main aspects of ICI-related myocarditis and suggest a practical approach. In particular, we focus on the opportunities that a baseline CV evaluation offers for subsequent management by collecting clinical and instrumental data, essential for the interpretation of troponin results, for differential diagnosis and for the formulation of a diagnostic and therapeutic workup., (Copyright © 2020 Spallarossa, Sarocchi, Tini, Arboscello, Toma, Ameri and Porto.)

Objectives: The aim of this study was to assess the diagnostic accuracy of bone scintigraphy in a large multicenter cohort of patients with cardiac amyloidotic involvement and Phe64Leu transthyretin (TTR) mutation., Background: Diagnostic accuracy of bone scintigraphy for transthyretin-related cardiac amyloidosis (TTR-CA) is considered extremely high, enabling this technique to be the noninvasive diagnostic standard for TTR-CA. Nevertheless, this approach has not been systematically validated across the entire spectrum of TTR mutations., Methods: A total of 55 patients with Phe64Leu TTR mutation were retrospectively analyzed and evaluated between 1993 and 2018 at 7 specialized Italian tertiary centers. Cardiac involvement was defined as presence of an end-diastolic interventricular septum thickness ≥12 mm, without other possible causes of left ventricular hypertrophy (i.e., arterial hypertension or valvulopathies). A technetium-99m (99mTc)-diphosphonate (DPD) or 99mTc-hydroxyl-methylene-diphosphonate (HMDP) bone scintigraphy was reviewed, and visual scoring was evaluated according to Perugini's method., Results: Among 26 patients with definite cardiac involvement, 19 underwent 99mTc-DPD or 99mTc-HMDP bone scintigraphy. Of them, 17 (89.5%) patients had low or absent myocardial bone tracer uptake, whereas only 2 (10.5%) showed high-grade myocardial uptake. The sensitivity and the accuracy of bone scintigraphy in detecting TTR-CA were 10.5% and 37%, respectively. Patients with cardiac involvement and low or absent bone tracer uptake were similar to those with high-grade myocardial uptake in terms of age, sex, and electrocardiographic and echocardiographic findings., Conclusions: The sensitivity of bone scintigraphy (DPD and HMDP) in detecting TTR-CA is extremely low in patients with Phe64Leu TTR mutation, suggesting the need to assess diagnostic accuracy of bone scintigraphy to identify cardiac involvement across a wider spectrum of TTR mutations., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Methods: This review is based on the material obtained via MEDLINE (PubMed), EMBASE, and Clinical Trials databases, from January 1980 until May 2019. The search term used was "Alzheimer's disease," combined with "cardiovascular disease," "hypertension," "dyslipidaemia," "diabetes mellitus," "atrial fibrillation," "coronary artery disease," "heart valve disease," and "heart failure." Out of the 1,328 papers initially retrieved, 431 duplicates and 216 records in languages other than English were removed. Among the 681 remaining studies, 98 were included in our research material on the basis of the following inclusion criteria: (a) the community-based studies; (b) using standardized diagnostic criteria; (c) reporting raw prevalence data; (d) with separate reported data for sex and age classes., Results: While AD and CVD alone may be considered deleterious to health, the study of their combination constitutes a clinical challenge. Further research will help to clarify the real impact of vascular factors on these diseases. It may be hypothesized that there are various mechanisms underlying the association between AD and CVD, the main ones being hypoperfusion and emboli, atherosclerosis, and the fact that, in both the heart and brain of AD patients, amyloid deposits may be present, thus causing damage to these organs., Conclusions: AD and CVD are frequently associated. Further studies are needed in order to understand the effect of CVD and its risk factors on AD in order to better comprehend the effects of subclinical and clinical CVD on the brain. Finally, we need to clarify the impact of the underlying hypothesized mechanisms of this association and to investigate gender issues., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Giacomo Tini et al.)

Introduction: Treatment with antihypertensive drugs may be associated with different dermatological adverse reactions., Evidence Acquisition: We systematically reviewed the literature available on the MEDLINE (PubMED) databases, up to July 2018. We searched for the terms "calcium-channel blockers" or "angiotensin-converting enzyme inhibitors" or "angiotensin II receptors blockers" or "diuretics" or "beta blockers" AND "dermatological effects" or "skin disease.", Evidence Synthesis: The most important cutaneous events occurring during treatment with calcium-channel blockers are represented by pedal edema and photosensitivity with consequent increased risk of skin cancer. Moreover, other adverse reactions are eczematous and psoriasiform dermatitis, subacute cutaneous lupus erythematosus, and rarely toxic epidermal necrolysis. In patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptors blockers, angioedema, psoriasis and pemphigus can be exacerbated. Furthermore, some authors associated the use of these medications with the onset of skin neoplasms. As for diuretics, the most relevant cutaneous reactions are represented by subacute cutaneous lupus erythematosus and leukocytoclastic vasculitis. Photosensitivity is another important event related to diuretics use. Eventually, itching is often related to the use of thiazides, particularly in elderly patients. With regards to beta blockers, we should remember a significant association with psoriasis, lichen planus, subacute cutaneous lupus erythematosus, and an increased risk of skin cancer., Conclusions: During antihypertensive treatment, several dermatological reactions may occur. Clinicians should inform their patients of the increased risk of cutaneous lesions associated with the use of these drugs, and perform periodic examination of the skin.

The rapid rise to fame of immuno-oncology (IO) drugs has generated unprecedented interest in the industry, patients and doctors, and has had a major impact in the treatment of most cancers. An interesting aspect in the clinical development of many IO agents is the increasing reliance on nonconventional trial design, including the so-called 'master protocols' that incorporate various adaptive features and often heavily rely on biomarkers to select patient populations most likely to benefit. These novel designs promise to maximize the clinical benefit that can be reaped from clinical research, but are not without costs. Their acceptance as solid evidence basis for use outside of the research context requires profound cultural changes by multiple stakeholders, including regulatory bodies, decision-makers, statisticians, researchers, doctors and, most importantly, patients. Here we review characteristics of recent and ongoing trials testing IO drugs with unconventional design, and we highlight trends and critical aspects., Competing Interests: Competing interests: GC received honoraria for speaker, consultancy or advisory role from Roche, Pfizer, Novartis, Seattle Genetics, Lilly, Ellipses Pharma, Foundation Medicine, and Samsung., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tyr78Phe is a rare pathogenic transthyretin (TTR) mutation. Few previous reports described a late-onset hereditary transthyretin-related amyloidosis (ATTR-m) form with a variable phenotype, mainly dominated by neurological manifestations. We describe the case of a 69-year-old male with massive but asymptomatic cardiac infiltration and only subclinical neurological involvement, and review the literature to depict characteristics of the Tyr78Phe TTR mutation.

With the recent developments in the field of multi-omics integration, the interest in factors such as data preprocessing, choice of the integration method and the number of different omics considered had increased. In this work, the impact of these factors is explored when solving the problem of sample classification, by comparing the performances of five unsupervised algorithms: Multiple Canonical Correlation Analysis, Multiple Co-Inertia Analysis, Multiple Factor Analysis, Joint and Individual Variation Explained and Similarity Network Fusion. These methods were applied to three real data sets taken from literature and several ad hoc simulated scenarios to discuss classification performance in different conditions of noise and signal strength across the data types. The impact of experimental design, feature selection and parameter training has been also evaluated to unravel important conditions that can affect the accuracy of the result., (© The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The great therapeutical success achieved by oncology is counterbalanced by growing evidences of cardiovascular (CV) toxicity due to many antineoplastic treatments. Cardiac adverse events may cause premature discontinuation of effective oncologic treatments or occur as late events undermining the oncologic success. Arterial hypertension is both the most common comorbidity in cancer patients and a frequent adverse effect of anticancer therapies. A pre-existing hypertension is known to increase the risk of other cardiac adverse events due to oncologic treatments, in particular heart failure. Moreover, as a strict association between cancer and CV diseases has emerged over the recent years, various analyses have shown a direct relationship between hypertension and cancer incidence and mortality. Finally, many antineoplastic treatments may cause a rise in blood pressure (BP) values, particularly the novel anti VEGF agents, this possibly compromising efficacy of chemotherapy. Aim of this review is to revise the topic and the many aspects linking arterial hypertension and cancer, and to provide a comprehensive and practical guide of the current treatment approaches., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Scope: Flexitarian dieting is increasingly associated with health benefits. The study of postprandial metabolic response to vegan and animal diets is essential to decipher how specific diet components may mediate metabolic changes., Methods and Results: A randomized, crossover, controlled vegan versus animal diet challenge is conducted on 21 healthy participants. Postprandial metabolic measurements are conducted at seven timepoints. Area under the curve analysis of the vegan diet response demonstrates higher glucose (EE 0.35), insulin (EE 0.38), triglycerides (EE 0.72), and nine amino acids at breakfast (EE 4.72-209.32); and six lower health-promoting fatty acids at lunch (EE -0.1035 to -0.13) (p < 0.05)., Conclusions: Glycemic and lipid parameters vary irrespective of diet type, demonstrating that vegan and animal meals contain health-promoting and suboptimal nutrient combinations. The vegan breakfast produces the same pattern of elevated branched chain amino acids, insulin, and glucose as the animal diet from the fasting results, reflecting the low protein load in the animal and the higher branched-chain amino acid load of the vegan breakfast. Liberalization of the vegan menu to vegetarian and the animal menu to a Nordic-based diet can result in optimal metabolic signatures for both flexitarian diet strategies in future research., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In hypertrophic cardiomyopathy (HC), a process of left ventricular (LV) remodeling carrying an adverse prognosis has been described. Conversely, a gradual and benign LV wall thinning has been suggested but never investigated. Therefore, we studied a HC cohort over a long period of time to evaluate the occurrence of a LV remodeling with a benign clinical course. Data of HC patients aged 18 to 65 years and without any condition known to influence LV remodeling were analyzed over a mean follow-up of 7.6 ± 5.7 years. Of 231 HC patients (65% males, mean age 46 ± 12 years), 47 (20%) developed LV remodeling, of whom 23 (10%) had a thinning ≥15% of LV maximal wall thickness from baseline without systolic dysfunction (MWT thinning); 13 (6%) progressed to a LV ejection fraction <50% (end-stage HC) and 11 (5%) developed an apical aneurysm. Follow-up length (odds ratio 1.07, 95% confidence interval 1.00 to 1.15, p = 0.06) and maximal LV wall thickness at baseline (odds ratio 1.14, 95% confidence interval 1.04 to 1.25, p = 0.004) were the main predictors of MWT thinning. Compared with patients with end-stage HC and apical aneurysm, those with MWT thinning showed lower HC-related morbidity (92% and 36% vs 22%, p = 0.003) and mortality (31% and 27% vs 4%, p = 0.02). Furthermore, they showed a combined HC-related morbidity and mortality similar to patients without LV remodeling (incidence 29/1000 vs 26/1000 patient-year, p = 0.77). In conclusion, a process of LV wall thinning with a benign outcome can occur over the long term in patients with HC. The prognostic importance of LV remodeling varies in relation to the different changes in LV morphology and function., (Copyright © 2018. Published by Elsevier Inc.)

BACKGROUND Mitral valve aneurysms (MVAs) are uncommon conditions frequently associated with aortic valve endocarditis. They may be complicated by perforation and severe mitral regurgitation (MR). Optimal treatment of MVA, and in particular the best timing for surgery, are uncertain. CASE REPORT A 62-year-old man with a recent history of dental surgery presented to the Emergency Department complaining relapsing fever. A first echocardiogram demonstrated infective endocarditis of the aortic valve. The patient was primarily managed with specific antibiotic therapy. Despite this, a few days later he suffered from splenic embolization and an MVA with MR was detected. Surgical replacement of the mitral and aortic valves was therefore performed. CONCLUSIONS MVAs are infrequent but potentially severe complications of AV endocarditis. In the absence of definite treatment indication, the correct time for surgery should depend on concomitant clinical and infective features.

Background: Valve-in-valve transcatheter aortic valve implantation for degenerated aortic bioprostheses is an effective option for patients at high risk for redo surgery, even if it may be burdened by complications more common in specific settings, such as, coronary artery obstruction., Case Presentation: We present the case of a Caucasic 84-year-old woman with degeneration of a previously implanted aortic Mitroflow bioprosthesis. She underwent a valve-in-valve transcatheter aortic valve implantation with a CoreValve® bioprosthesis. End-procedure coronary angiography demonstrated maintained perfusion of both coronary arteries. However, few hours later, she experienced sudden cardiac death. An autopsy showed that Mitroflow prosthesis leaflets were higher than the left main coronary ostium, and no other possible cause for the sudden death. Fatality was thus ascribed to left main coronary ostium obstruction due to apposition of the Mitroflow leaflet pushed upward by the late expansion of CoreValve®., Conclusions: Coronary artery obstruction is a frequently fatal complication which usually presents just after valve implantation, but, as reported in our case, it may also have a delayed presentation. Accurate patient's selection and intraoperative preventive measures can reduce this eventuality.

BACKGROUND Spontaneous coronary artery dissection is the most common etiology of pregnancy-associated myocardial infarction. It is characterized by high rates of maternal morbidity and mortality and may cause fetal complications and death as well. CASE REPORT A 44-year-old female (G2P1) suffered from pregnancy-related spontaneous coronary artery dissection with dissection of distal left anterior descending coronary artery. The patient was hemodynamically stable and did not required revascularization, but signs of fetal distress were detected and thus an urgent cesarean delivery was performed. This emergency procedure was undertaken in the catheterization laboratory (Cath-Lab) right after coronary angiography, thanks to a multidisciplinary team. Health conditions of the newborn were good. The patient instead suffered from a recurrence of spontaneous coronary artery dissection 6 days later, complicated by left ventricular apical thrombus and epistenocardial pericarditis. The dissection self-healed in 1 month. CONCLUSIONS Careful evaluation of pregnancy-related spontaneous coronary artery dissection is needed to assess and manage both maternal and fetal complications. Under specific circumstances, a cesarean delivery may be required and be even performed in the Cath-Lab after coronary catheterization.

Background: Pulmonary hypertension (PH) in patients with hypertrophic cardiomyopathy (HCM) has been investigated in a small number of studies. Purpose of this study was to assess the prevalence and its association with outcome in a population of consecutive HCM outpatients., Methods: We retrospectively analyzed data of 361 consecutive HCM outpatients in whom echocardiographic measurements of pulmonary artery systolic pressure (PASP) were available at initial and most recent evaluation. Four different clinical groups were specifically investigated: patients without left ventricular outflow tract obstruction (group A, 165), with obstruction (group B, 126), patients diagnosed at the age≥65 (group C, 50) and patients with end stage (ES) HCM (group D, 20)., Results: PH was identified in 41 (11.4%) of the 361 patients at initial evaluation while it has been recognized in 25 (7,8% [1.1%/year]) during a median follow-up of 3.4years. Analysis of subgroups showed that prevalence of PH increased from patient group A to D (8%, group A, 19%, group B, 28% group C, 70%, group D, respectively, p<0,01). During follow-up, patients with PH showed a significant higher HCM-related mortality (p=0.01) and morbidity (p<0.001) as compared with those without PH, but in multivariable analysis, PH resulted an independent risk factor only for HCM-related morbidity (HR=2.50, 95% CI 1.08-5.79, p=0.03)., Conclusion: PH affects a significant proportion of patients with HCM. Its prevalence varies according to different clinical profiles. It is associated with an unfavorable clinical outcome and is an independent predictor of morbidity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Acute coronary syndromes (ACS) in young patients are uncommon and their influence on morbidity and mortality in this population is still debated., Aim: We investigated clinical and angiographic characteristics, risk factors and outcome in young patients diagnosed with ACS, compared with those of older patients, evaluating survival free from death and/or nonfatal myocardial infarction (MI) and/or coronary revascularization (primary endpoint), and then with respect to each component of the primary endpoint., Methods: We retrospectively analyzed 1696 patients diagnosed with ACS between 2007 and 2013. 116 were aged ≤45 years (young adults), 1116 were >45 and <75 years (older adults) and 464 were ≥75 years., Results: Young adults were mostly male, with a prevalent diagnosis of STEMI, had less frequently typical cardiovascular risk factors and lower prevalence of extensive coronary artery disease. Over a median 3 years follow up, survival free from composite endpoint was better in young than in older adult patients (11.2 vs. 24.2%; p = 0.001), mainly due to a lower rate of death while the occurrence of non fatal MI and of coronary revascularization was similar (7.8 vs. 8.7%, p = 0.86; 8.7 vs. 12.9%, p = 0.23 respectively). Diabetes was the strongest independent risk factor of worse prognosis in the young cohort (OR 3.47; 95% CI 1.01-11.9; p = 0.04)., Conclusions: Young adults showed peculiar clinical features and lower mortality compared with older adults. Morbidity was not different between the two populations, with diabetes independently associated with a worse prognosis.

Objectives: Whether periopathogenic bacteria occur in the lung and gums simultaneously and what impact periodontitis has is unknown., Methods: In consecutive outpatients scheduled for bronchoscopies we performed a periodontal screening index. PCR to determine four periopathogens and seven less pathogenic species in both the periodontal pocket and bronchial protected specimen brush was used. Activated MMP8 in saliva and bronchial fluid was measured., Results: Periopathogens were detectable in gums and in the bronchial protected specimen brush in 75 (80%) and 27 (30%) of the cases, respectively. The concentration of activated MMP 8 was above 40 ng/ml in the saliva and in the bronchial fluid sample in six and 31 subjects, respectively. Significant agreement between the periodontal and bronchial compartment was found in three out of the four periopathogens. Patients with periopathogens in the lung suffered from periodontitis more frequently (p = 0.01). In patients with periopathogens detectable in the lung the concentration of aMMP8 tends to be more frequently above 40 ng/ml in the bronchial fluid (p = 0.09)., Conclusions: Agreement between periodontal and bronchial microbiome is more distinct for periopathogens than for less pathogenic species. Periodontitis itself represents a risk factor for pulmonary colonization with certain periopathogens. Pulmonary colonization with periopathogens seems to be associated with increased local inflammation., (Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

History and Admission Findings: A 72-year-old man with nausea, fever and elevated inflammatory parameters was transferred for further diagnostic assessment and treatment. On examination a palpable purpura was obvious without any signs of infection., Investigations: Creatininekinase was 350 mmol/l with a proteinuria of 20 g per day. Histological examination revealed hypersensitivity vasculitis in the cutis and a membranoproliferative glomerulonephritis. In addition there was a mixed cryoglobulinemia with a negative test for hepatitis C virus. Further investigation revealed hepatitis C virus RNA genotype 1 b in the cryoprecipitate., Diagnosis and Treatment: The patient was successfully treated with with interferon alpha for 12 month. The nephrotic syndrome improved and the proteinuria ceased, Conclusion: Mixed cryoglobulinemias are associated with hepatitis C virus infection in over 80% of cases. Normally it is easy to make the diagnosis serologically with an ELISA test. But in a few cases the virus RNA is only detectable in the cryoprecipitate. If there is a high suspicion of an hepatitis C infection with cryoglobulinemia but HCV serology is negative, it is essential that virus antigen and antibodies are searched for in the cryoprecipitate.