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A wide range of etiologies, both ischemic and nonischemic, can produce an electrocardiographic pattern of ST-segment elevation (STE), including Takotsubo syndrome (TTS) and electrolyte imbalances. Instances of hypocalcemia-induced TTS and STE are exceedingly rare in medical literature. This paper presents the case of a 75-year-old woman with advanced ovarian cancer and no prior heart issues, who exhibited diffuse STE on electrocardiogram, resembling acute coronary syndrome. Additionally, echocardiography suggested left ventricle apical ballooning, as per TTS, in the context of severe hypocalcemia and elevated troponin I level. After confirming no coronary artery disease via angiography, we administered calcium supplementation. Subsequently, the electrocardiogram displayed widespread giant T-wave inversions, and the patient's cardiac function fully recovered on normalization of calcium levels within few days. This case serves to highlight the importance of recognizing rare causes of STE (eg, hypocalcemia-induced cardiomyopathy), particularly in patients with neoplastic condition. However, the precise mechanism underlying a potential hypocalcemia-induced TTS remains to be elucidated, and there are only a limited number of case reports in the literature. In light of the aforementioned considerations, we propose a comprehensive examination of cases associated with hypocalcemia and STE and left ventricular systolic impairment., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

The perspective on cardiac amyloidosis has deeply changed over the last 10 years following major advances in diagnosis and treatment options. This heterogeneous disease requires the interaction among experts of different specialties and subspecialties. Suspicion of disease, timely recognition and confirmation of final diagnosis, prognostic stratification, overall management and therapeutic strategies represent ongoing challenges in the clinical setting. Missing or delayed diagnosis may have significant impact on patient outcome, especially in light-chain amyloidosis. The present inter-society consensus document aims to provide a standardized approach to the diagnosis of cardiac amyloidosis in Italy, and to discuss the challenging clinical scenarios encountered in routine activity for cardiologists and physicians of different specialties dealing with patients with suspected or established cardiac amyloidosis. This document may be adapted to the setting of each specific region.

Anderson-Fabry disease (AFD) remains a therapeutic challenge despite advances in early diagnosis and the availability of enzyme replacement therapies (ERTs). While early initiation of therapy can mitigate disease progression, resistance mechanisms-such as the development of anti-drug antibodies-limit the efficacy of current treatments, particularly in patients with severe genetic variants. Chaperone therapy provides a targeted option for a subset of patients, yet significant gaps remain in treating those with complete enzyme deficiency. This perspective article explores the existing therapeutic landscape and reflects on emerging treatments, such as mRNA and gene therapies, which hold promise for overcoming the resistance mechanisms. By addressing the limitations of current pharmacological options and considering future innovations, this article aims to outline the path forward for more effective and personalized treatment strategies in Anderson-Fabry disease.

Cardiac amyloidosis (CA) is a cardiac storage disease caused by the progressive extracellular deposition of misfolded proteins in the myocardium. Despite the increasing interest in this pathology, it remains an underdiagnosed condition. Non-invasive diagnostic techniques play a central role in the suspicion and detection of CA, also thanks to the continuous scientific and technological advances in these tools. The 12-lead electrocardiography is an inexpensive and reproducible test with a diagnostic accuracy that, in some cases, exceeds that of imaging techniques, as recent studies have shown. Echocardiography is the first-line imaging modality, although none of its parameters are pathognomonic. According to the 2023 ESC Guidelines, a left ventricular wall thickness ≥ 12 mm is mandatory for the suspicion of CA, making this technique crucial. Cardiac magnetic resonance provides high-resolution images associated with tissue characterization. The use of contrast and non-contrast sequences enhances the diagnostic power of this imaging modality. Nuclear imaging techniques, including bone scintigraphy and positron emission tomography, allow the detection of amyloid deposition in the heart, and their role is also central in assessing the prognosis and response to therapy. The role of computed tomography was recently evaluated by several studies, above in population affected by aortic stenosis undergoing transcatheter aortic valve replacement, with promising results. Finally, machine learning and artificial intelligence-derived algorithms are gaining ground in this scenario and provide the basis for future research. Understanding the new insights into non-invasive diagnostic techniques is critical to better diagnose and manage patients with CA and improve their survival.

Premature ventricular contractions (PVCs) are a common form of arrhythmic events, often representing an idiopathic and benign condition without further therapeutic interventions. However, in certain circumstances PVCs may represent the epiphenomenon of a concealed structural heart disease (SHD). Surface 12‑leads EKG and 24-h dynamic EKG are necessary to assess their main characteristics such as site of origin, frequency and complexity. Echocardiography represents the first-line imaging tool recommended to evaluate cardiac structures and function. Cardiac Magnetic Resonance (CMR) is recognized as a superior modality for detecting structural cardiac alterations, that might evade detection by conventional echocardiography. Moreover, in specific populations such as athletes, CMR may have a crucial role to exclude a concealed SHD and the risk of serious arrhythmic events during sport activity. Some clinical characteristics such as male sex, older age or family history of sudden cardiac death (SCD) or cardiomyopathy, and some electrocardiographic features of PVCs, in particular a right branch bundle block (RBBB) with superior/intermediate axis morphology, the reproducibility of VAs during exercise test (ET) or the evidence of complex ventricular arrhythmias, may warrant a CMR evaluation, due to the high probability of SHD. In this systematic review our objective was to provide an exhaustive overview on the role of CMR in detecting a concealed SHD in patients with high daily burden of PVCs and a normal echocardiographic evaluation, paving the way for a more extensive utilization of CMR in presence of certain high-risk clinical and/or EKG features identified during the diagnostic workup., Competing Interests: Declaration of competing interest The authors have no relevant financial and non-financial interests to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have revolutionized the therapeutic scenario of heart failure, demonstrating favorable effects on mortality and quality of life. Previous studies have yielded conflicting data regarding the effects on ventricular arrhythmias., Methods: A prospective observational study was conducted to investigate the anti-arrhythmic properties of SGLT2 inhibitors evaluating the intra-patient difference in major adverse arrhythmic cardiac events (MAACE) over a six-month period in patients with chronic heart failure who were undergoing continuous monitoring using a cardiac implantable electronic device., Results: From January 2022 to January 2023, 82 patients [median age 63 years (IQR 15), male 87 %] were enrolled in the study, with a median follow-up of 28 weeks (IQR 5). The rate of MAACE at baseline was 11 %, without relevant differences in the follow up in terms of major and minor arrhythmic events. In patients with an arrhythmic phenotype at baseline, a mild but non statistically significant reduction of MAACE (from 36 % to 28 %, p = 0.727) was observed and a significant decrease of non-sustained ventricular tachycardia (from 68 % to 32 %, p = 0.022)., Conclusions: Our findings suggest potential anti-arrhythmic properties of SGLT2 inhibitors, evident in patients with arrhythmic events before the initiation of the drug., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene-phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of LMNA gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups ( p value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.

Aims : TOMM40 single nucleotide polymorphism (SNP) rs2075650 consists of allelic variation c.275-31A > G and it has been linked to Alzheimer disease, apolipoprotein and cholesterol levels and other risk factors. However, data on its role in cardiovascular disorders are lacking. The first aim of the study is to evaluate mortality according to TOMM40 genotype in a cohort of selected patients affected by advanced atherosclerosis. Second aim was to investigate the relationship between Xg and AA alleles and the presence of conduction disorders and implantation of defibrillator (ICD) or pacemaker (PM) in our cohort. Materials and Methods : We enrolled 276 patients (mean age 70.16 ± 7.96 years) affected by hemodynamic significant carotid stenosis and/or ischemia of the lower limbs of II or III stadium Fontaine. We divided the population into two groups according to the genotype (Xg and AA carriers). We evaluated several electrocardiographic and echocardiographic parameters, including heart rate, rhythm, presence of right and left bundle branch block (LBBB and RBBB), PR interval, QRS duration and morphology, QTc interval, and left ventricular ejection fraction (LVEF). We clinically followed these patients for 82.53 ± 30.02 months and we evaluated the incidence of cardiovascular events, number of deaths and PM/ICD implantations. Results: We did not find a difference in total mortality between Xg and AA carriers (16.3 % vs. 19.4%; p = 0.62). However, we found a higher mortality for fatal cardiovascular events in Xg carriers (8.2% vs. 4.4%; HR = 4.53, 95% CI 1.179-17.367; p = 0.04) with respect to AA carriers. We noted a higher percentage of LBBB in Xg carriers (10.2% vs. 3.1%, p = 0.027), which was statistically significant. Presence of right bundle branch block (RBBB) was also higher in Xg (10.2% vs. 4.4%, p = 0.10), but without reaching statistically significant difference compared to AA patients. We did not observe significant differences in heart rate, presence of sinus rhythm, number of device implantations, PR and QTc intervals, QRS duration and LVEF between the two groups. At the time of enrolment, we observed a tendency for device implant in Xg carriers at a younger age compared to AA carriers (58.50 ± 0.71 y vs. 72.14 ± 11.11 y, p = 0.10). During the follow-up, we noted no statistical difference for new device implantations in Xg respect to AA carriers (8.2% vs. 3.5%; HR = 2.384, 95% CI 0.718-7.922; p = 0.156). The tendency to implant Xg at a younger age compared to AA patients was confirmed during follow-up, but without reaching a significant difference(69.50 ± 2.89 y vs. 75.63 ± 8.35 y, p = 0.074). Finally, we pointed out that Xg carriers underwent device implantation 7.27 ± 4.43 years before AA (65.83 ± 6.11 years vs. 73.10 ± 10.39 years) and that difference reached a statistically significant difference ( p = 0.049) when we considered all patients, from enrollment to follow-up. Conclusions : In our study we observed that TOMM40 Xg patients affected by advanced atherosclerosis have a higher incidence of developing fatal cardiovascular events, higher incidence of LBBB and an earlier age of PM or ICD implantations, as compared to AA carriers. Further studies will be needed to evaluate the genomic contribution of TOMM40 SNPs to cardiovascular deaths and cardiac conduction diseases.

Telemedicine and remote monitoring devices, including implantable loop recorders (ILR), are increasingly adopted in the cardiologic setting. These are valuable tools in the arrhythmic stratification of patients at risk of sudden cardiac death, providing a tailored therapeutic management to prevent lethal arrhythmias. We report a case of an asymptomatic 18-year-old boy with a family history of syncope and cardiac arrest, who had a diagnosis of Brugada syndrome with an inducible type 1 pattern and carrier of a missense mutation of the SCN5A gene. In light of the risk factors, although not recommended by current guidelines, we decided to proceed with the implantation of an ILR with remote monitoring service. A few months later, an episode of asymptomatic sustained polymorphic ventricular tachycardia was promptly observed by the remote monitoring, leading to a timely implantation of a subcutaneous cardiac implantable defibrillator.

Cardiomyopathies (CMPs) are a group of myocardial disorders that are characterized by structural and functional abnormalities of the heart muscle. These abnormalities occur in the absence of coronary artery disease (CAD), hypertension, valvular disease, and congenital heart disease. CMPs are an increasingly important topic in the field of cardiovascular diseases due to the complexity of their diagnosis and management. In 2023, the ESC guidelines on cardiomyopathies were first published, marking significant progress in the field. The growth of techniques such as cardiac magnetic resonance imaging (CMR) and genetics has been fueled by the development of multimodal imaging approaches. For the diagnosis of CMPs, a multimodal imaging approach, including CMR, is recommended. CMR has become the standard for non-invasive analysis of cardiac morphology and myocardial function. This document provides an overview of the role of CMR in CMPs, with a focus on tissue mapping. CMR enables the characterization of myocardial tissues and the assessment of cardiac functions. CMR sequences and techniques, such as late gadolinium enhancement (LGE) and parametric mapping, provide detailed information on tissue composition, fibrosis, edema, and myocardial perfusion. These techniques offer valuable insights for early diagnosis, prognostic evaluation, and therapeutic guidance of CMPs. The use of quantitative CMR markers enables personalized treatment plans, improving overall patient outcomes. This review aims to serve as a guide for the use of these new tools in clinical practice.

One of the most common complications of tricuspid valve replacement is atrioventricular block (AVB), often requiring permanent pacing. The endocardial pacemaker lead, placed in the right ventricle, may sometimes interfere with the implanted prosthesis, causing its early dysfunction and the need for alternative sites of pacing. To the best of our knowledge, we present the first case of a successful combined percutaneous procedure consisting of the implantation of two leads in the coronary sinus for univentricular bifocal pacing and a transcatheter tricuspid valve-in-valve implantation in a young patient with severe dysfunction of the tricuspid bioprosthesis, requiring permanent pacing for a postsurgical complete atrioventricular block.

The association between cardiomyopathies (CMPs) and psychiatric disorders is a complex and bidirectional phenomenon that involves multiple mechanisms and factors. CMPs may raise the risk of psychiatric disorders due to the psychological stress, physical limitations, social isolation, or poor prognosis associated with the underlying disease. Psychiatric disorders, on the other hand, can increase the possibility of developing or worsening CMPs due to the behavioral, neuroendocrine, inflammatory, or pharmacological effects of mental illness or its treatment. Moreover, some common genetic or environmental factors may have a relevant influence on both conditions. With this comprehensive review, we sought to provide an overview of the current evidence on the strict and intriguing interconnection between CMPs and psychiatric disorders, focusing on the epidemiology, pathophysiology, clinical implications, and management strategies., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: The discordance between QRS voltages on electrocardiogram (ECG) and left ventricle (LV) wall thickness (LVWT) on echocardiogram (echo) is a recognized red flag (RF) of amyloid cardiomyopathy (AC) and can be measured by specific indexes. No head-to-head comparison of different ECG/echo indexes among subjects with echocardiographic suspicion of AC has yet been undertaken. The study aimed at evaluating the performance and the incremental diagnostic value of different ECG/echo indexes in this subset of patients., Methods: Electrocardiograms of subjects with LV hypertrophy, preserved ejection fraction and ≥ 1 echocardiographic RF of AC participating in the AC-TIVE study, an Italian prospective multicenter study, were independently analyzed by two cardiologists. Low QRS voltages and 8 different ECG/echo indexes were evaluated. Cohort specific cut-offs were computed., Results: Among 170 patients, 55 (32 %) were diagnosed with AC. Combination of low QRS voltages with interventricular septum ≥ 1,6 cm was the most specific (specificity 100 %, positive predictive value 100 %) ECG/echo index, while the ratio between the sum of all QRS voltages and LVWT <7,8 was the most sensitive and accurate (sensitivity 94 %, negative predictive value 97 %, accuracy 82 %). When the latter index was added to a model using easily-accessible clinical variables, the diagnostic accuracy for AC greatly increased (AUC from 0,84 to 0,95; p = 0,007)., Conclusions: Among patients with non-dilated hypertrophic ventricles with normal ejection fraction and echocardiographic RF of AC, easily-measurable ECG/echo indexes, mainly when added to few clinical variables, can help the physician orient second level investigations. External validation of the results is warranted., Competing Interests: Declaration of Competing Interest No conflicts of interest to declare for any Author in relation to the submitted work., (Copyright © 2023. Published by Elsevier B.V.)

Between 15-20% of patients with end stage renal disease (ESRD) do not know the cause of the primary kidney disease and can develop complications after kidney transplantation. We performed a genetic screening in 300 patients with kidney transplantation, or undiagnosed primary renal disease, in order to identify the primary disease cause and discriminate between overlapping phenotypes. We used a custom-made panel for next-generation sequencing (Agilent technology, Santa Clara, CA, USA), including genes associated with Fabry disease, podocytopaties, complement-mediated nephropathies and Alport syndrome-related diseases. We detected candidate diagnostic variants in genes associated with nephrotic syndrome and Focal Segmental Glomerulosclerosis (FSGS) in 29 out of 300 patients, solving about 10% of the probands. We also identified the same genetic cause of the disease ( PAX2 : c.1266dupC) in three family members with different clinical diagnoses. Interestingly we also found one female patient carrying a novel missense variant, c.1259C>A (p.Thr420Lys), in the GLA gene not previously associated with Fabry disease, which is in silico defined as a likely pathogenic and destabilizing, and associated with a mild alteration in GLA enzymatic activity. The identification of the specific genetic background may provide an opportunity to evaluate the risk of recurrence of the primary disease, especially among patient candidates living with a donor kidney transplant.

Aim: Micra AV represents a leadless endocardial pacing system able to detect atrial contractions providing atrioventricular synchrony. A reduction of myocardial contractility may be detected in case of first-degree atrioventricular block (AVB). Materials & methods: In six patients with first-degree AVB (PQ interval ≥220 msec) was evaluated the left ventricle global longitudinal strain (LV GLS) by speckle tracking (ST) echocardiography during single-lead atrial sensing ventricular pacing (VDD) stimulation as compared with spontaneous rhythm (SR), 24-48 h after Micra AV implantation. Results: A statistically significant difference between the two modalities was observed (LV GLS during SR: -14.7% [interquartile range (IQR) 5.5], LV GLS during VDD pacing: -16.1% [IQR 5.2]; p value = 0.041). Conclusion: Our preliminary results suggest an improvement of myocardial contractility with VDD pacing as compared with SR.

Non-ischemic dilated cardiomyopathy (DCM) is a disease characterized by left ventricular dilation and systolic dysfunction. Patients with DCM are at higher risk for ventricular arrhythmias and sudden cardiac death (SCD). According to current international guidelines, left ventricular ejection fraction (LVEF) ≤ 35% represents the main indication for prophylactic implantable cardioverter defibrillator (ICD) implantation in patients with DCM. However, LVEF lacks sensitivity and specificity as a risk marker for SCD. It has been seen that the majority of patients with DCM do not actually benefit from the ICD implantation and, on the contrary, that many patients at risk of SCD are not identified as they have preserved or mildly depressed LVEF. Therefore, the use of LVEF as unique decision parameter does not maximize the benefit of ICD therapy. Multiple risk factors used in combination could likely predict SCD risk better than any single risk parameter. Several predictors have been proposed including genetic variants, electric indexes, and volumetric parameters of LV. Cardiac magnetic resonance (CMR) can improve risk stratification thanks to tissue characterization sequences such as LGE sequence, parametric mapping, and feature tracking. This review evaluates the role of CMR as a risk stratification tool in DCM patients referred for ICD.

Purpose of Review: Heart failure (HF) and erectile dysfunction (ED) are two common conditions that affect millions of men worldwide and impair their quality of life. ED is a frequent complication of HF, as well as a possible predictor of cardiovascular events and mortality. ED deserves more attention from clinicians and researchers., Recent Findings: The pathophysiology of ED in HF involves multiple factors, such as endothelial dysfunction, reduced cardiac output, neurohormonal activation, autonomic imbalance, oxidative stress, inflammation, and drug side effects. The diagnosis of ED in HF patients should be based on validated questionnaires or objective tests, as part of the routine cardiovascular risk assessment. The therapeutic management of ED in HF patients should be individualized and multidisciplinary, considering the patient's preferences, expectations, comorbidities, and potential drug interactions. The first-line pharmacological treatment for ED in HF patients with mild to moderate symptoms (NYHA class I-II) is phosphodiesterase type 5 inhibitors (PDE5Is), which improve both sexual function and cardiopulmonary parameters. PDE5Is are contraindicated in patients who use nitrates or nitric oxide donors for angina relief, and these patients should be advised to avoid sexual activity or to use alternative treatments for ED. Non-pharmacological treatments for ED, such as psychotherapy or couples therapy, should also be considered if there are significant psychosocial factors affecting the patient's sexual function or relationship. This review aims to summarize the most recent evidence regarding the prevalence of ED, the pathophysiology of this condition with an exhaustive analysis of factors involved in ED development in HF patients, a thorough discussion on diagnosis and management of ED in HF patients, providing practical recommendations for clinicians., (© 2023. The Author(s).)

In recent years, the increasing number of studies on the relationship between the gut microbiota and atherosclerosis have led to significant interest in this subject. The gut microbiota, its metabolites (metabolome), such as TMAO, and gut dysbiosis play an important role in the development of atherosclerosis. Furthermore, inflammation, originating from the intestinal tract, adds yet another mechanism by which the human ecosystem is disrupted, resulting in the manifestation of metabolic diseases and, by extension, cardiovascular diseases. The scientific community must understand and elucidate these mechanisms in depth, to gain a better understanding of the relationship between atherosclerosis and the gut microbiome and to promote the development of new therapeutic targets in the coming years. This review aims to present the knowledge acquired so far, to trigger others to further investigate this intriguing topic.

Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes BRCA1 and BRCA2 , many other predisposition genes that confer a moderate risk of BC have been identified. Advances in multigene panel testing have allowed the simultaneous sequencing of BRCA1/2 with these genes in a cost-effective way. Germline DNA from 521 cases with BC fulfilling diagnostic criteria for hereditary BC were screened with multigene NGS testing. Pathogenic (PVs) and likely pathogenic (LPVs) variants in moderate penetrance genes were identified in 15 out of 521 patients (2.9%), including 2 missense, 7 non-sense, 1 indel, and 3 splice variants, as well as two different exon deletions, as follows: ATM ( n = 4), CHEK2 ( n = 5), PALB2 ( n = 2), RAD51C ( n = 1), and RAD51D ( n = 3). Moreover, the segregation analysis of PVs and LPVs into first-degree relatives allowed the detection of CHEK2 variant carriers diagnosed with in situ melanoma and clear cell renal cell carcinoma (ccRCC), respectively. Extended testing beyond BRCA1/2 identified PVs and LPVs in a further 2.9% of BC patients. In conclusion, panel testing yields more accurate genetic information for appropriate counselling, risk management, and preventive options than assessing BRCA1/2 alone.

Background: Evaluation of the right ventricle (RV) in patients with acute myocarditis (MY) remains challenging with both 2D transthoracic echocardiography (TTE) and cardiovascular magnetic resonance (CMR). We examined the incremental diagnostic value of CMR feature tracking (FT) to evaluate RV involvement in patients with myocarditis. Methods: We enrolled 54 patients with myocarditis and preserved left ventricle (LV) ejection fraction (EF). The CMR protocol included T2-weighted images for edema detection and late gadolinium enhancement (LGE) images. Global longitudinal strain (GLS) of the left ventricle (LV) and RV free wall strain (CMR-FWS) were obtained with CMR-FT. We identified 34 patients (62%) with inferior and lateral segment (IL-MY) involvement and 20 (38%) noIL-MY in case of any other myocardial segment involved. Here, 20 individuals who underwent CMR for suspected cardiac disease, which was not confirmed thereafter, were considered as the control population. Results: TTE and CMR showed normal RV function in all patients without visible RV involvement at the LGE or T2-weighted sequences. At CMR, LV-GLS values were significantly lower in patients with MY compared to the control group (median -19.0% vs. -21.0%, p = 0.029). Overall, CMR RV-FWS was no different between MY patients and controls (median -21.2% vs. -23.2 %, p = 0.201) while a significant difference was found between RV FWS in IL-MY and noIL-MY (median -18.17% vs. -24.2%, p = 0.004). Conclusions: CMR-FT has the potential to unravel subclinical RV involvement in patients with acute myocarditis, specifically in those with inferior and lateral injuries that exhibit lower RV-FWS values. In this setting, RV deformation analysis at CMR may be effectively implemented for a comprehensive functional assessment.

Background: We previously demonstrated that an Italian family affected by a severe dilated cardiomyopathy (DCM) with history of sudden deaths at young age, carried a mutation in the Lmna gene encoding for a truncated variant of the Lamin A/C protein (LMNA), R321X. When expressed in heterologous systems, such variant accumulates into the endoplasmic reticulum (ER), inducing the activation of the PERK-CHOP pathway of the unfolded protein response (UPR), ER dysfunction and increased rate of apoptosis. The aim of this work was to analyze whether targeting the UPR can be used to revert the ER dysfunction associated with LMNA R321X expression in HL-1 cardiac cells., Methods: HL-1 cardiomyocytes stably expressing LMNA R321X were used to assess the ability of 3 different drugs targeting the UPR, salubrinal, guanabenz and empagliflozin to rescue ER stress and dysfunction. In these cells, the state of activation of both the UPR and the pro-apoptotic pathway were analyzed monitoring the expression levels of phospho-PERK, phospho-eIF2α, ATF4, CHOP and PARP-CL. In addition, we measured ER-dependent intracellular Ca 2+ dynamics as indicator of proper ER functionality., Results: We found that salubrinal and guanabenz increased the expression levels of phospho-eIF2α and downregulated the apoptosis markers CHOP and PARP-CL in LMNA R321X-cardiomyocytes, maintaining the so-called adaptive UPR. These drugs also restored ER ability to handle Ca 2+ in these cardiomyocytes. Interestingly, we found that empagliflozin downregulated the apoptosis markers CHOP and PARP-CL shutting down the UPR itself through the inhibition of PERK phosphorylation in LMNA R321X-cardiomyocytes. Furthermore, upon empagliflozin treatment, ER homeostasis, in terms of ER ability to store and release intracellular Ca 2+ was also restored in these cardiomyocytes., Conclusions: We provided evidence that the different drugs, although interfering with different steps of the UPR, were able to counteract pro-apoptotic processes and to preserve the ER homeostasis in R321X LMNA-cardiomyocytes. Of note, two of the tested drugs, guanabenz and empagliflozin, are already used in the clinical practice, thus providing preclinical evidence for ready-to-use therapies in patients affected by the LMNA R321X associated cardiomyocytes., (© 2023. The Author(s).)

Background: Pre-operative embolization prior to surgical resection of carotid body tumors was meant to decrease intraoperative blood loss and operative time. Yet, potential confounders such as different Shamblin classes have never been analyzed. Aim of our meta-analysis was to investigate effectiveness of a pre-operative embolization according to different Shamblin classes., Methods: Five studies comprising 245 patients were included. A random effects model meta-analysis was conducted, and the I 2 statistic was used to assessment for heterogeneity., Results: Pre-operative embolization was associated with a significant reduction in blood loss (WM: 276.4 mL; 95% CI, 201.9-378.3, p < 0.01); an absolute mean reduction, though not statistically significant, was observed in both Shamblin 2 and 3 classes. No difference in operative time was found between the two strategies (WM: 192.0 min; 95% CI, 157.7-234.1, p = 1.0)., Conclusions: Embolization proved an overall significant reduction in perioperative bleeding, which did not reach threshold for statistical significance when Shamblin classes were singularly considered., (© 2023 Wiley Periodicals LLC.)

Isotretinoin or 13-cis-retinoic acid (RA) is one of the most effective and widely used drugs for the treatment of severe acne vulgaris. Despite being deemed safe, no definite consensus has been reached on the cardiovascular risk of RA derivatives. We report a case of heart failure due to dilated cardiomyopathy (DCM) and concomitant renal infarction occurring after 5 months of isotretinoin use in a previously healthy 18-year-old male. The patient, with a history of acne vulgaris, presented to our emergency department with left iliac fossa pain and effort dyspnea. A trans-thoracic echocardiogram showed DCM and severely reduced left ventricle ejection fraction (LVEF: 29%). During hospitalization, a total body computed tomography (CT) showed an ischemic lesion in the left kidney. Ischemic, autoimmune, infective, and heritable causes of DCM were ruled out. Cardiac magnetic resonance (CMR) evidenced LV circumferential mid-wall late gadolinium enhancement. Heart failure therapy was promptly started and up-titrated, but only poor LVEF improvement was detected overtime. Our case aims to raise awareness on rare life-threatening cardiovascular events possibly associated with isotretinoin use. To the best of our knowledge, this is the first described case of renal thromboembolism and severe DCM leading to implantable cardioverter-defibrillator (ICD) implantation occurring during isotretinoin treatment.

(1) Background: Glucagone-Like Peptide-1 Receptor Agonists (GLP-1 RAs) (GLP-1 RAs) are incretine-based medications recommended in the treatment of type 2 Diabetes Mellitus (DM2) with atherosclerotic cardiovascular disease (ASCVD) or high or very high cardiovascular (CV) risk. However, knowledge of the direct mechanism of GLP-1 RAs on cardiac function is modest and not yet fully elucidated. Left ventricular (LV) Global Longitudinal Strain (GLS) with Speckle Tracking Echocardiography (STE) represents an innovative technique for the evaluation of myocardial contractility. (2) Methods: an observational, perspective, monocentric study was conducted in a cohort of 22 consecutive patients with DM2 and ASCVD or high/very high CV risk, enrolled between December 2019 and March 2020 and treated with GLP-1 RAs dulaglutide or semaglutide. The echocardiographic parameters of diastolic and systolic function were recorded at baseline and after six months of treatment. (3) Results: the mean age of the sample was 65 ± 10 years with a prevalence of the male sex (64%). A significant improvement in the LV GLS (mean difference: -1.4 ± 1.1%; p value < 0.001) was observed after six months of treatment with GLP-1 RAs dulaglutide or semaglutide. No relevant changes were seen in the other echocardiographic parameters. (4) Conclusions: six months of treatment with GLP-1 RAs dulaglutide or semaglutide leads to an improvement in the LV GLS in subjects with DM2 with and high/very high risk for ASCVD or with ASCVD. Further studies on larger populations and with a longer follow-up are warranted to confirm these preliminary results.

Background: Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA -related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA- mutated patients, analysing our new data with previous literature to give a comprehensive picture., Methods: We performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ , GNA11 , RASA1 and TEK . Additionally, 914 patients previously reported were systematically reviewed., Results: 93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ , GNA11 , RASA1 or TEK ., Conclusion: We confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping 'vascular' phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Left atrial appendage (LAA) closure represents a novel therapeutic chance for patients with contraindications to long-term anticoagulation therapy, such as those affected by hereditary hemorrhagic telangiectasia (HHT) and atrial fibrillation (AF). Nevertheless, current experts' indications suggest the postprocedural administration of antithrombotic therapies to minimize the residual thromboembolic risk due to AF and to the need for device endothelialization. The aim of our study was to investigate the safety and effectiveness of LAA closure in preventing arterial thromboembolism in a very high-bleeding risk group, such as HHT patients, who are at risk not to tolerate even the mild postprocedural antithrombotic therapy usually recommended., Methods: Eight HHT-affected patients with non-valvular AF, high-bleeding risk and/or known intolerance to antiplatelet and anticoagulant therapy were treated with interventional LAA occlusion with the Amplatzer™ Cardiac Plug™ and Amplatzer™ Amulet™ devices. Device implantation was successful in all patients., Results: Postprocedural antiplatelet/anticoagulation therapy was attempted in seven patients: adherence to therapy exceeded 6 months only for one, while four patients suspended all antithrombotic medications within 30 days from the procedure due to an increase in bleeding frequency and/or severity and the other two discontinued treatment within 6 months; a single patient was not prescribed any antithrombotic therapy. At a medium follow-up of 22.4±14.3 months no thromboembolic episodes attributable to AF or device related thrombosis were reported. Two deaths were recorded 1231 and 783 days after the procedure which were classified as unrelated to any cerebral or cardiovascular accident., Conclusions: Our study suggests that the percutaneous LAA closure in HHT patients with AF could be safe and effective in preventing arterial systemic thromboembolism, also in the presence of reduced or absent postinterventional antithrombotic treatment. LAA occluder implantation can represent a valid and potentially life-saving alternative to lifelong anticoagulant therapy in HHT, as in other very high-bleeding risk patients.

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.

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.)

In this work, we studied an lmna nonsense mutation encoding for the C-terminally truncated Lamin A/C (LMNA) variant Q517X, which was described in patients affected by a severe arrhythmogenic cardiomyopathy with history of sudden death. We found that LMNA Q517X stably expressed in HL-1 cardiomyocytes abnormally aggregates at the nuclear envelope and within the nucleoplasm. Whole-cell patch clamp experiments showed that LMNA Q517X-expressing cardiomyocytes generated action potentials with reduced amplitude, overshoot, upstroke velocity and diastolic potential compared with LMNA WT-expressing cardiomyocytes. Moreover, the unique features of these cardiomyocytes were 1) hyper-polymerized tubulin network, 2) upregulated acetylated α-tubulin, and 3) cell surface Nav1.5 downregulation. These findings pointed the light on the role of tubulin and Nav1.5 channel in the abnormal electrical properties of LMNA Q517X-expressing cardiomyocytes. When expressed in HEK293 with Nav1.5 and its β1 subunit, LMNA Q517X reduced the peak Na + current (I Na ) up to 63% with a shift toward positive potentials in the activation curve of the channel. Of note, both AP properties in cardiomyocytes and Nav1.5 kinetics in HEK293 cells were rescued in LMNA Q517X-expressing cells upon treatment with colchicine, an FDA-approved inhibitor of tubulin assembly. In conclusion, LMNA Q517X expression is associated with hyper-polymerization and hyper-acetylation of tubulin network with concomitant downregulation of Nav1.5 cell expression and activity, thus revealing 1) new mechanisms by which LMNA may regulate channels at the cell surface in cardiomyocytes and 2) new pathomechanisms and therapeutic targets in cardiac laminopathies., 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 De Zio, Pietrafesa, Milano, Procino, Bramerio, Pepe, Forleo, Favale, Svelto, Gerbino and Carmosino.)

Background: Dual antiplatelet therapy (DAPT) with acetylsalicylic acid and oral P2Y12 inhibitor (P2Y12-I) represents the standard of care for patients with acute coronary syndromes (ACS) or with chronic coronary syndromes (CCS) treated with percutaneous coronary intervention (PCI). Cangrelor, the first intravenous P2Y12-I, is deemed to overcome the drawbacks of the oral administration; nevertheless, real world data on this new drug are scanty. We sought to investigate routine clinical use of cangrelor in four interventional centers of Italy., Methods: We enrolled 241 consecutive patients (196 ACS, 45 CCS) treated with cangrelor during PCI. Drug administration modalities and in-hospital clinical outcomes were evaluated. A subanalysis in patients selected based on the CHAMPION Phoenix trial inclusion/exclusion criteria (CHAMPION-like subpopulation) was also performed., Results: Cangrelor was mainly utilized in ACS patients, who presented poorer clinical conditions and higher bleeding risk. Cangrelor was given only in P2Y12-I naïve patients; switch to clopidogrel was always done at the end of the infusion, while ticagrelor or prasugrel were prevalently given 30 minutes before. In-hospital mortality was 10.0% and GUSTO moderate/severe bleeding was 2.5%. Bleeding data showed nevertheless to be in line with the CHAMPION Phoenix results in the "CHAMPION-like" subpopulation., Conclusions: Cangrelor was predominantly used in ACS with modalities substantially in accord with the label indications. Poor clinical outcomes are due to the prevalent utilization in highly challenging clinical settings, nevertheless the rate of bleeding and stent thrombosis are in line with the randomized trials if analyzed in a subpopulation of comparable risk profile.

Background: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2 . Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice., Methods: We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing., Results: Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2 , whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively., Conclusion: We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results.

The aim of this study was to clarify the relative contribution of elevated left ventricle (LV) filling pressure (FP) estimated by pulmonary venous (PV) and mitral flow, transesophageal Doppler recording (TEE), and other extracardiac factors like obesity and renal insufficiency (KI) to exercise capacity (ExC) evaluated by cardiopulmonary exercise testing (CPX) in patients with dilated cardiomyopathy (DCM). During the CPX test, 119 patients (pts) with DCM underwent both peak VO 2 consumption and then TEE with color-guided pulsed-wave Doppler recording of PVF and transmitral flow. In 78 patients (65%), peak VO 2 was normal or mildly reduced (>14 mL/kg/min) (group 1) while it was markedly reduced (≤14 mL/kg/min) in 41 (group 2). In univariate analysis, systolic fraction (S Fract), a predictor of elevated pre-a LV diastolic FP, appeared to be the best diastolic parameter predicting a significantly reduced peak VO 2 . Logistic regression analysis identified five parameters yielding a unique, statistically significant contribution in predicting reduced ExC: creatinine clearance < 52 mL/min (odds ratio (OR) = 7.4, p = 0.007); female gender (OR = 7.1, p = 0.004); BMI > 28 (OR = 5.8, p = 0.029), age > 62 years (OR = 5.5, p = 0.03), S Fract < 59% (OR = 4.9, p = 0.02). Conclusion: KI was the strongest predictor of reduced ExC. The other modifiable factors were obesity and severe LV diastolic dysfunction expressed by blunted systolic venous flow. Contrarily, LV ejection fraction was not predictive, confirming other previous studies. This has important clinical implications.

Mutations in Lamin A/C gene (lmna) cause a wide spectrum of cardiolaminopathies strictly associated with significant deterioration of the electrical and contractile function of the heart. Despite the continuous flow of biomedical evidence, linking cardiac inflammation to heart remodelling in patients harbouring lmna mutations is puzzling. Therefore, we profiled 30 serum cytokines/chemokines in patients belonging to four different families carrying pathogenic lmna mutations segregating with cardiac phenotypes at different stages of severity (n = 19) and in healthy subjects (n = 11). Regardless lmna mutation subtype, high levels of circulating granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6) were found in all affected patients' sera. In addition, elevated levels of Interleukins (IL) IL-1Ra, IL-1β IL-4, IL-5 and IL-8 and the granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured in a large subset of patients associated with more aggressive clinical manifestations. Finally, the expression of the pro-inflammatory 70 kDa heat shock protein (Hsp70) was significantly increased in serum exosomes of patients harbouring the lmna mutation associated with the more severe phenotype. Overall, the identification of patient subsets with overactive or dysregulated myocardial inflammatory responses could represent an innovative diagnostic, prognostic and therapeutic tool against Lamin A/C cardiomyopathies., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Laminopathies are rare diseases, whose cardiac manifestations are heterogeneous and, especially in their initial stage, similar to those of more common conditions, such as ischemic heart disease. Early diagnosis is essential, as these conditions can first manifest themselves with sudden cardiac death. Electrical complications usually appear before structural complications; therefore, it is important to take into consideration these rare genetic disorders for the differential diagnosis of brady and tachyarrhythmias, even when left ventricle systolic function is still preserved., Case Summary: A 60-year-old man, without history of previous disorders, presented in September 2019 to the emergency department because of the onset of syncope associated with hypotension. The patient was diagnosed with a high-grade atrioventricular block. A dual chamber pacemaker was implanted, but after the onset of a sustained ventricular tachycardia during physical exertion, a drug eluting stent was implanted on an intermediate stenosis on the left anterior descending artery, which had previously been considered non-haemodynamically significant. During the follow-up, the treating cardiologist, suspicious of the overall clinical picture, recommended a genetic test for the diagnosis of cardiomyopathies, which tested positive for a pathogenetic mutation of the lamin A/C gene. While awaiting the result of the genetic test and, later, the pacemaker to be upgraded to a biventricular defibrillator, a remote monitoring device was given to the patient in order to minimize in-person clinical evaluations during the coronavirus disease 2019-related lockdown., Conclusion: This case aims to raise awareness of the cardiological manifestations of laminopathies, which can be dangerously misdiagnosed as other, more common conditions., Competing Interests: Conflict-of-interest statement: No conflicts of interest to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: Despite the relation between autoimmune diseases and increased atherosclerotic risk is established, the influence of autoimmune disorders on in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is only partly known. ISR is an aberrant reparative process mainly characterized by an increased number of vascular smooth muscle cells and excessive deposition of extracellular proteoglycans and type III collagen. Chronic inflammation, always present in autoimmune diseases, modulates the endothelial response to PCI. Aim of this review is to resume the current evidence on the association between ISR and autoimmune diseases, focusing on pathogenic mechanisms and therapeutic targets., Methods: We conducted a comprehensive review of the literature on the relationship between ISR and insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid-antibodies syndrome (APS), inflammatory bowel diseases (IBD), and Hashimoto's thyroiditis (HT)., Results: Patients affected with IDDM, RA, SLE, APS, IBD and HT proved to face higher rates of ISR compared to the general population. The endothelial dysfunction seems the principal common pathogenic pathway for ISR and is attributed to both the immune system disorder and the systemic inflammation. Some evidence suggested that methotrexate and anti-tumor necrosis factor treatments can be effective in reducing ISR, while antibodies against vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 showed to reduce neointimal hyperplasia in animal models., Conclusions: Autoimmune diseases are a risk factor for ISR. The study of the potential cardiovascular benefits of the current therapies, mainly anti-inflammatory drugs, and the pursuit of innovative treatments appear of paramount interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.)

Inflammatory bowel disease (IBD) is a pathological condition that first involves the gastrointestinal wall but can also trigger a systemic inflammatory state and thus extraintestinal manifestations. Systemic inflammation is probably secondary to the passage of bacterial products into the bloodstream because of altered intestinal permeability and the consequent release of proinflammatory mediators. Inflammation, through several diverse pathophysiological pathways, determines both a procoagulative state and systemic endothelial dysfunction, which are both deemed to be responsible for venous and arterial thromboembolic adverse events. The management of systemic thrombotic complications is particularly challenging in this category of patients, who also present a high bleeding risk; what is more, both bleeding and thrombotic risks peak during the active phases of the disease. The literature suggests that treating physicians have been, so far, more heavily influenced by concerns about bleeding than by the thrombotic risk. Despite the absence of data provided by large cohorts or randomized studies, the high risk of arterial and venous atherothrombosis in patients with IBD seems unquestionable. Moreover, several reports suggest that when arterial thromboembolism involves the coronary vessels, causing acute coronary syndromes, ischemic complications from antithrombotic drug undertreatment are frequent and severe. This review aims to shed light on the tricky balance between the ischemic and hemorrhagic risks of patients with IBD and to highlight how difficult it is for clinicians to define a tailored therapy based on a case-by-case, careful, and unprejudiced clinical evaluation., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)