Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. ...Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.
Introduction
Thoracic impedance (TI) drops measured by implantable cardioverter‐defibrillators (ICDs) have been reported to correlate with ventricular tachycardia/fibrillation (VT/VF). The aim of our ...study was to assess the temporal association of decreasing TI trends with VT/VF episodes through a longitudinal analysis of daily remote monitoring data from ICDs and cardiac resynchronization therapy defibrillators (CRT‐Ds).
Methods and Results
Retrospective data from 2384 patients were randomized 1:1 into a derivation or validation cohort. The TI decrease rate was defined as the percentage of rolling weeks with a continuously decreasing TI trend. The derivation cohort was used to determine a TI decrease rate threshold for a ≥99% specificity of arrhythmia prediction. The associated risk of VT/VF episodes was estimated in the validation cohort by dividing the available follow‐up into 60‐day assessment intervals. Analyses were performed separately for 1354 ICD and 1030 CRT‐D patients. During a median follow‐up of 2.0 years, 727 patients (30.4%) experienced 3298 confirmed VT/VF episodes. In the ICD group, a TI decrease rate of >60% was associated with a higher risk of VT/VF episode in a 60‐day assessment interval (stratified hazard ratio, 1.42; 95% confidence interval (CI), 1.05–1.92; p = .023). The TI decrease preceded (40.8%) or followed (59.2%) the VT/VF episodes. In the CRT‐D group, no association between TI decrease and VT/VF episodes was observed (p = .84).
Conclusion
In our longitudinal analysis, TI decrease was associated with VT/VF episodes only in ICD patients. Preventive interventions may be difficult since episodes can occur before or after TI decrease.
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.
Amyloid cardiomyopathy (AC) prevalence according to selected group. CKD, chronic kidney disease; CTS, carpal tunnel syndrome; FP, filling pattern; IAS, interatrial septum; IVS, interventricular septum; LV, left ventricle; LVEDVi, left ventricular end‐diastolic volume index; LVEF, left ventricular ejection fraction.
The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aims of this study were to assess the clinical impact of ...mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE.
We reviewed all records in the Italian Thyroid Cancer Observatory database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines.
At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio OR 1.16,
= 0.65), tumor size >2 cm (OR 1.45,
= 0.34), aggressive PTC histology (OR 0.55,
= 0.15), and age at diagnosis (OR 0.90,
= 0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27 95% confidence interval,
= 0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and nontreated patients (
= 0.24).
This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.
•The discordance between ECG and echocardiogram mass is a red flag of amyloid cardiomyopathy and can be measured by numerous ECG/echo indexes•The best performing ECG/echo index among subjects with ...echocardiographic suspicion of amyloid cardiomyopathy was the ratio between the sum of all QRS voltages and maximum left ventricle wall thickness <7,8•The best performing ECG/echo index added to a clinical model of few easy-accessible variables greatly increased the diagnostic accuracy for amyloid cardiomyopathy
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.
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.
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).
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.
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Abstract
Aims
Clinicians needs to identify patients with cardiac amyloidosis (CA) at an early stage, due to the availability of disease modifying therapies. Some echocardiographic findings may rise ...the suspicion of CA, also in patients with mild or no symptoms, addressing second level diagnostic tests. To investigate the prevalence of CA in consecutive patients ≥55 years undergoing clinically indicated, routine transthoracic echocardiogram (TTE) in Italy with echocardiographic signs suggestive of CA.
Methods and results
This is a prospective multicentric study conducted in Italy. It comprises two phases: 1) an observational phase consisting in a national survey on prevalence of possible echocardiographic red flags of CA in consecutive patients ≥55 years undergoing routine TTE (previously published) and 2) a CA diagnostic phase. Preliminary results of phase 2 are herein presented. Patients that in the phase 1 presented a CA-suggestive TTE (i.e. at least one red flag of CA in hypertrophic, non-dilated left ventricles) were re-evaluated for a cardiological visit. Those who consented to proceed in the study, underwent clinical evaluation, blood and urine tests and scintigraphy with bone tracer. Diagnosis of transthyretin related-CA (TTR-CA) was made in presence of Grades 2–3 Perugini uptake at scintigraphy and absence of monoclonal protein. The study was registered at ClinicalTrials.gov (#NCT04738266). Of the 5315 screened echocardiograms, 381 exams (7.2%) were classified as AC-suggestive. Two-hundred-twelve of the 381 patients with a CA-suggestive TTE underwent phase 2 study. Main reasons for the 169 non-entering patients into the phase 2 were death (n = 53) and refusal to participate (n = 85). Sixty-five of these 212 patients (31%; 17% considering also the 169 non-entering patients into the phase 2) had a diagnosis of CA. Finally, TTR-CA was diagnosed in 53 (25%) and AL-CA in 12 (5.7%) patients.
Conclusions
Among a cohort of consecutive unselected patients ≥55 years with echocardiographic findings suggestive of CA, the real prevalence of CA ranged from 17 up to 31%. Although TTR-CA was predominant, AL-CA was diagnosed in a significant amount of cases. TTE has a fundamental role in screening patients, raising the suspicion of CA and orienting diagnostic work-up for CA.
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