Current Perspectives on Atrial Amyloidosis: A Narrative Review.

Amyloidosis is a systemic disease caused by low molecular weight protein accumulation in the extracellular space, which can lead to different degrees of damage, depending of the organ or tissue involved. The condition is defined cardiac amyloidosis (CA) when heart is affected, and it is associated with an unfavorable outcome. Different types of CA have been recognized, the most common (98%) are those associated with deposition of light chain (AL-CA), and the form secondary to transthyretin deposit. The latter can be classified into two types, a wild type (transthyretin amyloidosis wild type (ATTRwt)-CA), which mainly affects older adults, and the hereditary or variant type (ATTRh-CA or ATTRv-CA), which instead affects more often young people and is associated with genetic alterations. The atrial involvement can be isolated or linked to CA with a nonspecific clinical presentation represented by new onset atrial fibrillation (AF), diastolic dysfunction and heart failure with preserved ejection fraction, or thromboembolism and stroke. Untreated patients have a median survival rate of 9 years for AL-CA and 7 years for ATTR-CA. By contrast, AL-CA and ATTR-CA treated patients have a median survival rate of 24 and 10 years, respectively. Atrial involvement in CA is a common but poor studied event, and alterations of performance can anticipate the anatomical damage. Recently, numerous advances have been made in the diagnostic field with improvements in the available techniques. An early diagnosis therefore allows a more effective therapeutic strategy with a positive impact on prognosis and mortality rate. A multimodality approach to the diagnosis of atrial involvement from CA is therefore recommended, and standard echocardiography, advanced Doppler-echocardiography (DE) and cardiac magnetic resonance (CMR) can be useful to detect early signs of CA and to estabilish an appropriate treatment.

Risk assessment tools for bleeding in patients with unprovoked venous thromboembolism: an analysis of the PLATO-VTE study.

BACKGROUND: Guidelines suggest indefinite anticoagulation after unprovoked venous thromboembolism (VTE) unless the bleeding risk is high, yet there is no consistent guidance on assessing bleeding risk. OBJECTIVES: This study aimed to evaluate the performance of 5 bleeding risk tools (RIETE, VTE-BLEED, CHAP, VTE-PREDICT, and ABC-Bleeding). METHODS: PLATO-VTE, a prospective cohort study, included patients aged ≥40 years with a first unprovoked VTE. Risk estimates were calculated at VTE diagnosis and after 3 months of treatment. Primary outcome was clinically relevant bleeding, as per International Society on Thrombosis and Haemostasis criteria, during 24-month follow-up. Discrimination was assessed by the area under the receiver operating characteristic curve (AUROC). Patients were classified as having a "high risk" and "non-high risk" of bleeding according to predefined thresholds; bleeding risk in both groups was compared by hazard ratios (HRs). RESULTS: Of 514 patients, 38 (7.4%) had an on-treatment bleeding. AUROCs were 0.58 (95% CI, 0.48-0.68) for ABC-Bleeding, 0.56 (95% CI, 0.46-0.66) for RIETE, 0.53 (95% CI, 0.43-0.64) for CHAP, 0.50 (95% CI, 0.41-0.59) for VTE-BLEED, and 0.50 (95% CI, 0.40-0.60) for VTE-PREDICT. The proportion of high-risk patients ranged from 1.4% with RIETE to 36.9% with VTE-BLEED. The bleeding incidence in the high-risk groups ranged from 0% with RIETE to 13.0% with ABC-Bleeding, and in the non-high-risk groups, it varied from 7.7% with ABC-Bleeding to 9.6% with RIETE. HRs ranged from 0.93 (95% CI, 0.46-1.9) for VTE-BLEED to 1.67 (95% CI, 0.86-3.2) for ABC-Bleeding. Recalibration at 3-month follow-up did not alter the results. CONCLUSION: In this cohort, discrimination of currently available bleeding risk tools was poor. These data do not support their use in patients with unprovoked VTE.

Thromboembolic and bleeding risk in cardiac amyloidosis.

Cardiac amyloidosis represents a spectrum of conditions characterized by the accumulation of insoluble fibrils, resulting in progressive deposition and myocardial dysfunction. The exact mechanisms contributing to the heightened risk of thromboembolic events and bleeding tendencies in cardiac amyloidosis remain unclear. Proteins such as transthyretin in transthyretin amyloidosis and light chains in light-chain amyloidosis, along with acute phase proteins in amyloid A (AA) amyloidosis, play complex roles in the coagulation cascade, affecting both coagulation initiation and fibrinolysis regulation. The increased occurrence of atrial fibrillation, systolic and diastolic left ventricular dysfunction, and atrial myopathy in patients with cardiac amyloidosis may predispose them to thrombus formation. This predisposition can occur regardless of sinus rhythm status or even with proper anticoagulant management. Bleeding events are often linked to amyloid deposits around blood vessels, which may increase capillary fragility and cause coagulation disturbances, leading to unstable international normalized ratio levels during anticoagulant therapy. Thus, comprehensive risk assessment for both thrombotic and hemorrhagic complications, especially before commencing anticoagulant therapy, is imperative. This review will explore the essential pathophysiological, epidemiologic, and clinical aspects of thromboembolic and bleeding risk in cardiac amyloidosis, evaluating the existing evidence and uncertainties regarding thrombotic and bleeding risk assessment and antithrombotic treatment.

Unmet needs and barriers in venous thromboembolism education and awareness among people living with cancer: a global survey.

BACKGROUND: Venous thromboembolism (VTE) is a major preventable cause of morbidity, disability, and mortality in subjects with cancer. A global appraisal of cancer-associated VTE education and awareness is not available. OBJECTIVES: To evaluate VTE-related education, awareness, and unmet needs from the perspective of people living with cancer using a quantitative and qualitative approach. METHODS: This cross-sectional study used data from an online-based survey covering multidimensional domains of cancer-associated VTE. Data are presented descriptively. Potential differences across participant subgroups were explored. RESULTS: Among 2262 patients with cancer from 42 countries worldwide, 55.3% received no VTE education throughout their cancer journey, and an additional 8.2% received education at the time of VTE diagnosis only, leading to 63.5% receiving no or inappropriately delayed education. When education was delivered, only 67.8% received instructions to seek medical attention in case of VTE suspicion, and 36.9% reported scarce understanding. One-third of participants (32.4%) felt psychologically distressed when becoming aware of the potential risks and implications connected with cancer-associated VTE. Most responders (78.8%) deemed VTE awareness highly relevant, but almost half expressed concerns about the quality of education received. While overall consistent, findings in selected survey domains appeared to numerically differ across age group, ethnicity, continent of residence, educational level, metastatic status, and VTE history. CONCLUSION: This study involving a large and diverse population of individuals living with cancer identifies important unmet needs in VTE-related education, awareness, and support across healthcare systems globally. These findings unveil multilevel opportunities to expedite patient-centered care in cancer-associated VTE prevention and management.

Inflammasome Signaling, Thromboinflammation, and Venous Thromboembolism.

Venous thromboembolism (VTE) remains a major health burden despite anticoagulation advances, suggesting incomplete management of pathogenic mechanisms. The NLRP3 (NACHT-, LRR- and pyrin domain-containing protein 3) inflammasome, interleukin (IL)-1, and pyroptosis are emerging contributors to the inflammatory pathogenesis of VTE. Inflammasome pathway activation occurs in patients with VTE. In preclinical models, inflammasome signaling blockade reduces venous thrombogenesis and vascular injury, suggesting that this therapeutic approach may potentially maximize anticoagulation benefits, protecting from VTE occurrence, recurrence, and ensuing post-thrombotic syndrome. The nonselective NLRP3 inhibitor colchicine and the anti-IL-1ß agent canakinumab reduce atherothrombosis without increasing bleeding. Rosuvastatin reduces primary venous thrombotic events at least in part through lipid-lowering independent mechanisms, paving the way to targeted anti-inflammatory strategies in VTE. This review outlines recent preclinical and clinical evidence supporting a role for inflammasome pathway activation in venous thrombosis, and discusses the, yet unexplored, therapeutic potential of modulating inflammasome signaling to prevent and manage VTE.

Imaging findings of right cardiac amyloidosis: impact on prognosis and clinical course.

Cardiac involvement from amyloidosis is of growing interest in the overall literature. Despite cardiac amyloidosis (CA) has been considered for a long time a rare disease, the diagnostic awareness is increasing mainly thanks to the improvement of diagnostic softwares and of imaging techniques such as cardiac magnetic resonance  (CMR). Some authors have observed an increase of prevalence rate of CA; moreover it's often underestimated because clinical manifestations are aspecific. The interstitial infiltration of the left ventricle has been extensively studied, while the involvement of the right ventricle (RV) has been less investigated. Involvement of the RV, even in the absence of pulmonary hypertension or clearly left ventricle infiltration, plays an important role as prognostic factor and is useful to achieve an early diagnosis. Therefore, the use of fast and low-cost diagnostic methods such as ultrasound strain of the right ventricle could be used to recognize cardiac amyloidosis early. Herein the importance of evaluating the right ventricular involvement, which can predict the most severe course of the disease also without overt clinical manifestations. The role of imaging, in particular of echocardiography, CMR, and scintigraphy is here reported.

Apixaban thromboprophylaxis in ambulatory patients with cancer and obesity: Insights from the AVERT trial.

BACKGROUND: The use of direct oral anticoagulants (DOACs) in obese patients is uncertain. It is unclear if body mass index (BMI) affects the safety and efficacy of DOACs for the primary prevention of venous thromboembolism (VTE) in high-risk ambulatory patients with cancer. We sought to determine the outcomes associated with the use of apixaban for the primary prevention of cancer-associated VTE according to BMI. METHODS: The randomized, double-blinded, placebo-controlled AVERT trial evaluated apixaban thromboprophylaxis in intermediate-to-high risk ambulatory cancer patients receiving chemotherapy. For this post-hoc analysis, the primary efficacy and safety outcomes were objectively confirmed VTE and clinically relevant bleeding (major and clinically relevant non-major bleeding), respectively. Obesity was defined as BMI ≥30 kg/m2. RESULTS: Among 574 patients randomized, 217 (37.8 %) patients had BMI ≥30 kg/m2. Obese patients were overall younger, more likely to be female, had higher creatinine clearance and hemoglobin, lower platelet count, and better ECOG performance status. Compared to placebo, apixaban thromboprophylaxis was associated with reduced VTE in both obese (hazard ratio [HR] 0.26; 95 % confidence interval [CI], 0.14-0.46; p < 0.0001) and non-obese (HR 0.54; 95%CI, 0.29-1.00; p = 0.049) patients. The HR for clinically relevant bleeding (apixaban vs. placebo) was numerically higher in obese (2.09; 95%CI, 0.96-4.51; p = 0.062) than non-obese subjects (1.23; 95%CI, 0.71-2.13; p = 0.46), but overall in line with the risks observed in the general trial population. CONCLUSIONS: In the AVERT trial enrolling ambulatory cancer patients receiving chemotherapy, we found no substantial differences in the efficacy or safety of apixaban thromboprophylaxis across obese and non-obese subjects.

Age- versus clinical pretest probability-adjusted D-dimer to rule out lower-extremity deep vein thrombosis in ambulatory patients with active cancer.

BACKGROUND: In patients with suspected deep vein thrombosis (DVT), D-dimer thresholds adjusted to age or clinical pretest probability (CPTP) increase the proportion of patients in whom DVT can be safely excluded compared to a standard approach using a fixed D-dimer threshold. Performance of these diagnostic strategies among cancer patients is uncertain. AIM: To compare the performance of age- and CPTP-adjusted D-dimer approaches among cancer outpatients with clinically suspected DVT, and derive a cancer-specific CPTP rule. PATIENTS AND METHODS: Consecutive ambulatory patients with active cancer and clinically suspected DVT of the lower extremity underwent CPTP assessment using the Wells rule, D-dimer testing, and whole-leg compression ultrasonography. Patients with normal ultrasonography were followed-up for 3 months for the occurrence of symptomatic venous thromboembolism. RESULTS: Upon referral, DVT was diagnosed in 48 of 239 (20.1 %) patients. The age-adjusted approach showed higher specificity and efficiency than the standard approach. Compared to the standard and age-adjusted strategies, the CPTP-adjusted approach had 35 % and 21 % higher specificity, and 34 % and 21 % higher efficiency, respectively. Failure rate, sensitivity, and predictive values were similar across strategies. A simplified CPTP score derived from the Wells rule reduced unnecessary imaging with similar accuracy and efficiency, but higher failure rate. CONCLUSIONS: In this prospective cohort of ambulatory cancer patients with clinically suspected DVT, the CPTP-adjusted D-dimer approach held the highest specificity and efficiency, potentially safely reducing unnecessary ultrasonography examinations compared to other approaches. Additional studies are warranted to evaluate the use of a simplified clinical prediction rule in this setting.

Platelet RNA sequencing for cancer screening in patients with unprovoked venous thromboembolism: a prospective cohort study.

BACKGROUND: Platelet RNA sequencing has been shown to accurately detect cancer in previous studies. OBJECTIVES: To compare the diagnostic accuracy of platelet RNA sequencing with standard-of-care limited cancer screening in patients with unprovoked venous thromboembolism (VTE). METHODS: Patients aged ≥40 years with unprovoked VTE were recruited at 13 centers and followed for 12 months for cancer. Participants underwent standard-of-care limited cancer screening, and platelet RNA sequencing analysis was performed centrally at study end for cases and selected controls. Sensitivity and specificity were calculated, using the predefined primary positivity threshold of 0.54 for platelet RNA sequencing aiming at 86% test sensitivity, and an additional predefined threshold of 0.89 aiming at 99% test specificity. RESULTS: A total of 476 participants were enrolled, of whom 25 (5.3%) were diagnosed with cancer during 12-month follow-up. For each cancer patient, 3 cancer-free patients were randomly selected for the analysis. The sensitivity of limited screening was 72% (95% CI, 52-86) at a specificity of 91% (95% CI, 82-95). The area under the receiver operator characteristic for platelet RNA sequencing was 0.54 (95% CI, 0.41-0.66). At the primary positivity threshold, all patients had a positive test, for a sensitivity estimated at 100% (95% CI, 87-99) and a specificity of 8% (95% CI, 3.7-16.4). At the secondary threshold, sensitivity was 68% (95% CI, 48-83; p value compared with limited screening 0.71) at a specificity of 36% (95% CI, 26-47). CONCLUSION: Platelet RNA sequencing had poor diagnostic accuracy for detecting occult cancer in patients with unprovoked VTE with the current algorithm.

Anamnestic frailty phenotype and adverse outcomes in patients treated with direct oral anticoagulants: Validation and comparative performance with frailty phenotype.

AIMS: The anamnestic frailty phenotype (AFP) is a quick, instrument-free tool derived from frailty phenotype (FP). We prospectively evaluated the discriminative capacity and prognostic value of AFP in ambulatory patients receiving DOACs for atrial fibrillation (AF) or venous thromboembolism (VTE), and compared AFP performance with that of FP. METHODS AND RESULTS: Sensitivity, specificity, positive and negative predictive value (PPV, NPV) with corresponding 95% confidence intervals (95%CI), were estimated for bleeding, thromboembolism, and all-cause mortality. Risk ratios (RRs) were calculated in frail versus non-frail patients. Of 236 patients (median age 78 years), 98 (42%) and 89 (38%) were classified as frail according to FP and AFP, respectively (Kappa= 0.76). Frailty, as assessed by AFP, was associated with higher risk of bleeding (RR 2.3; 95%CI, 1.2 to 4.6), and mortality (RR 4.4; 95%CI, 1.3 to 19.7). Similarly, to FP, AFP exhibited modest sensitivity and specificity, but high NPV that was 91% (95%CI, 85 to 95) for bleeding, 98% (95%CI, 94 to 100) for thromboembolism, and 98% (95%CI, 94 to 100) for mortality. CONCLUSION: Among patients receiving DOACs for AF or VTE, AFP was associated with an increased risk of adverse outcomes. AFP exhibited modest sensitivity and specificity, but excellent NPV. If confirmed, these findings suggest that AFP may represent a rapid, easy-to-use and unexpensive tool that may potentially help identify patients at lower risk for adverse outcomes and tailor anticoagulation management.

Clinical and Cardiovascular Magnetic Resonance Imaging Features of Cardiac Amyloidosis.

Amyloidosis is a systemic disease characterized by the accumulation of insoluble aggregates in various organs, leading to parenchymal damage. When these amyloid fibrils are deposited in the extracellular matrix of the cardiac structures, the condition is referred to as cardiac amyloidosis (CA). The extent of organ involvement determines the degree of cardiac impairment, which can significantly impact prognosis. The two most implicated proteins in CA are transthyretin and misfolded monoclonal immunoglobulin light chains. These proteins give rise to two distinct clinical forms of CA: transthyretin amyloidosis (ATTR-CA) and light-chain amyloidosis (AL-CA). ATTR-CA is further classified into two subtypes: ATTRm-CA, which occurs at a younger age and is caused by hereditary misfolded mutated proteins, and ATTRwt-CA, which is an acquired wild-type form more commonly observed in older adults, referred to as senile amyloidosis. While AL-CA was considered the most prevalent form for many years, recent autopsy studies have revealed an increase in cases of ATTRwt-CA. This narrative review aims to describe the clinical and imaging features of CA, with a particular focus on cardiac complications and mortality associated with the AL form. Early identification and differentiation of CA from other disorders are crucial, given the higher risk and severity of cardiac involvement in AL-CA. Furthermore, emphasis is placed on the potential utility of cardiovascular magnetic resonance imaging in detecting early cases of CA.

Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and therapeutic implications.

A hyperinflammatory response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection crucially worsens clinical evolution of coronavirus disease 2019 (COVID-19). The interaction between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) triggers the activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Enhanced inflammasome activity has been associated with increased disease severity and poor prognosis. Evidence suggests that inflammasome activation and interleukin-1ß (IL-1ß) release aggravate pulmonary injury and induce hypercoagulability, favoring progression to respiratory failure and widespread thrombosis eventually leading to multiorgan failure and death. Observational studies with the IL-1 blockers anakinra and canakinumab provided promising results. In the SAVE-MORE trial, early treatment with anakinra significantly shortened hospital stay and improved survival in patients with moderate-to-severe COVID-19. In this review, we summarize current evidence supporting the pathogenetic role of the NLRP3 inflammasome and IL-1ß in COVID-19, and discuss clinical trials testing IL-1 inhibition in COVID-19.

Frailty phenotype as a predictor of bleeding and mortality in ambulatory patients receiving direct oral anticoagulants.

BACKGROUND: Limited prospective data exist about the clinical relevance of frailty in patients with atrial fibrillation (AF) or venous thromboembolism (VTE) receiving direct oral anticoagulants (DOACs). The aim of this study was to evaluate whether frailty phenotype identifies DOAC-treated patients at higher risk of adverse clinical outcomes. METHODS: Consecutive, adult outpatients treated with DOACs for AF or VTE were prospectively enrolled. Patients were classified as frail, pre-frail, or non-frail according to frailty phenotype. Study outcomes were clinically relevant bleeding, including major and clinically relevant non-major bleeding, arterial and venous thromboembolism, and all-cause mortality. RESULTS: 236 patients (median age 78 years, 44% females) were included, of whom 156 (66%) had AF and 80 (34%) VTE. Ninety-eight (41%) patients were frail, 115 (49%) pre-frail, and 23 (10%) non-frail. Inappropriately high or low dose DOAC was used in 33% of frail and in 20% of non-frail or pre-frail patients. Over a median follow-up of 304 days, the incidence of clinically relevant bleeding, thromboembolism, and mortality were 20%, 4%, 9% in frail, and 10%, 3%, and 2% in pre-frail, respectively, while no study outcome occurred among non-frail patients. Risk ratios (95% confidence intervals) for these outcomes in frail versus pre-frail and non-frail patients were respectively 2.5 (1.8, 3.7), 1.9 (0.9, 4.0), and 6.3 (2.9, 13.6). CONCLUSION: In a prospective cohort of ambulatory patients receiving DOAC treatment for AF or VTE, frailty phenotype identified patients at higher risk of bleeding and all-cause mortality. Frailty assessment could be valuable to guide targeted interventions potentially improving patient prognosis.

Gastrointestinal manifestations of SARS-CoV-2 infection in an Italian population of hospitalized patients.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters the cells via angiotensin-converting enzyme 2 receptor; therefore, tissues expressing this receptor are potential targets for infection. Although many studies have observed gastrointestinal (GI) symptoms in coronavirus disease 2019 (COVID-19) patients, prevalence and clinical impact are still uncertain due to the heterogeneity of reports and obstacles to generalization. Methods: In this cross-sectional study, we included symptomatic patients requiring hospital admission, with a confirmed diagnosis of COVID-19 by nasopharyngeal polymerase chain reaction test, between 18 March and 30 May 2020. Demographic data, symptoms at onset, vital signs, and laboratory tests at admission were recorded. Results: In all, 300 patients were included (57%M, 43%F). GI symptoms were mainly diarrhea (13%), anorexia (4.3%), vomiting (3%), and abdominal pain (2.3%). Overall, males were younger (68 years versus 76 years; p = 0.01); patients with GI manifestations at disease onset required significantly faster hospital admission and showed larger GI complication rates. GI symptoms were associated with abnormal high aspartate aminotransferase and alanine aminotransferase serum titers, especially in male patients. Conclusion: Our study on an Italian population during the outbreak of the COVID-19 pandemic shows that GI symptoms are part of the spectrum of the SARS-CoV-2 infection and could be the only manifestations at disease onset. Although patients with GI symptoms were associated with faster hospital admission and liver involvement, prognosis was not affected.

Diabetes mellitus and heart failure: an update on pathophysiology and therapy.

Diabetes mellitus (DM) is frequent among heart failure (HF) patients with a further projected increase in prevalence in next years. DM promotes the development of both HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) through different mechanisms. As the general prevalence of both DM and HF is growing worldwide, it is important to define the pathophysiologic mechanisms driving the development of HF in DM patients. These include changes in the cardiac metabolism, mitochondrial dysfunction, impairment in insulin signaling, maladaptive inflammation, coronary microvascular dysfunction, endoplasmic reticulum stress, autophagy suppression, and structural changes, among the main ones. In recent years, novel glucose-lowering treatments, especially sodium-glucose cotransporter 2 inhibitors (SGLT-2is), have shown a strikingly positive impact on the natural history of HF. This has led to a progressive change in choosing SGLT-2is in DM patients at high risk for cardiovascular disease, supported by recent guidelines. The knowledge about novel pathophysiological mechanisms linking DM and HF may open the way to the development of new targeted therapies in the future. In this review, we will summarize general aspects dealing with incidence, prevalence, and pathophysiology of DM in HF patients. As well, we discuss the therapeutic targets to reduce the disease burden and the current evidence of glucose-lowering drugs in patients with DM and HF.

Direct oral anticoagulant plasma levels in hospitalized COVID-19 patients treated with dexamethasone.

Direct oral anticoagulants (DOACs) are not recommended in COVID-19 patients receiving dexamethasone because of potential drug-drug and drug-disease interactions affecting anticoagulant concentration and activity. To evaluate short- and long-term pharmacokinetic interactions, serial through and peak DOAC plasma levels were prospectively measured during and after dexamethasone therapy, as well as during the acute phase and after recovery from COVID-19 in hospitalized, non-critically ill patients undergoing treatment with DOACs. Thirty-three (18 males, mean age 79 years) consecutive patients received DOACs (17 apixaban, 12 rivaroxaban, 4 edoxaban) for atrial fibrillation (n = 22), venous thromboembolism (n = 10), and acute myocardial infarction (n = 1). Twenty-six patients also received dexamethasone at a dose of 6 mg once daily for a median of 14 days. Trough DOAC levels on dexamethasone were within and below expected reference ranges respectively in 87.5 and 8.3% of patients, with no statistically significant differences at 48-72 h and 14-21 days after dexamethasone discontinuation. Peak DOAC levels on dexamethasone were within expected reference ranges in 58.3% of patients, and below ranges in 33.3%, of whom over two thirds had low values also off dexamethasone. No significant differences in DOAC levels were found during hospitalization and after resolution of COVID-19. Overall, 28 patients were discharged alive, and none experienced thrombotic or bleeding events. In this study, dexamethasone administration or acute COVID-19 seemed not to affect DOAC levels in hospitalized, non-critically ill COVID-19 patients.