Practical approach for atrial cardiomyopathy characterization in patients with atrial fibrillation.

Atrial fibrillation (AF) causes progressive structural and electrical changes in the atria that can be summarized within the general concept of atrial remodeling. In parallel, other clinical characteristics and comorbidities may also affect atrial tissue properties and make the atria susceptible to AF initiation and its long-term persistence. Overall, pathological atrial changes lead to atrial cardiomyopathy with important implications for rhythm control. Although there is general agreement on the role of the atrial substrate for successful rhythm control in AF, the current classification oversimplifies clinical management. The classification uses temporal criteria and does not establish a well-defined strategy to characterize the individual-specific degree of atrial cardiomyopathy. Better characterization of atrial cardiomyopathy may improve the decision-making process on the most appropriate therapeutic option. We review current scientific evidence and propose a practical characterization of the atrial substrate based on 3 evaluation steps starting with a clinical evaluation (step 1), then assess outpatient complementary data (step 2), and finally include information from advanced diagnostic tools (step 3). The information from each of the steps or a combination thereof can be used to classify AF patients in 4 stages of atrial cardiomyopathy, which we also use to estimate the success on effective rhythm control.

Non-invasive electromechanical assessment during atrial fibrillation identifies underlying atrial myopathy alterations with early prognostic value.

Electromechanical characterization during atrial fibrillation (AF) remains a significant gap in the understanding of AF-related atrial myopathy. This study reports mechanistic insights into the electromechanical remodeling process associated with AF progression and further demonstrates its prognostic value in the clinic. In pigs, sequential electromechanical assessment during AF progression shows a progressive decrease in mechanical activity and early dissociation from its electrical counterpart. Atrial tissue samples from animals with AF reveal an abnormal increase in cardiomyocytes death and alterations in calcium handling proteins. High-throughput quantitative proteomics and immunoblotting analyses at different stages of AF progression identify downregulation of contractile proteins and progressive increase in atrial fibrosis. Moreover, advanced optical mapping techniques, applied to whole heart preparations during AF, demonstrate that AF-related remodeling decreases the frequency threshold for dissociation between transmembrane voltage signals and intracellular calcium transients compared to healthy controls. Single cell simulations of human atrial cardiomyocytes also confirm the experimental results. In patients, non-invasive assessment of the atrial electromechanical relationship further demonstrate that atrial electromechanical dissociation is an early prognostic indicator for acute and long-term rhythm control.

Valor pronóstico del intervalo Tpeak-Tend en el desarrollo de arritmias ventriculares subagudas intrahospitalarias en el síndrome de tako-tsubo / Prognostic value of the Tpeak-Tend interval for in-hospital subacute ventricular arrhythmias in tako-tsubo syndrome

Introducción y objetivos El valor de los parámetros del electrocardiograma (ECG) de repolarización asociados al riesgo de arritmias ventriculares (AVs) en el síndrome de tako-tsubo es controvertido. Nuestro objetivo fue identificar predictores ECG de AVs subagudas, definidas como aquellas ocurridas después de las primeras 48 horas desde el ingreso. Métodos Estudio observacional unicéntrico de pacientes ingresados en el servicio de cardiología entre 2012 y 2018 con diagnóstico de síndrome de tako-tsubo. La recogida de datos incluyó el ECG de 12 derivaciones al ingreso y a las 48 horas, registros de telemetría continua, analíticas, ecocardiografía transtorácica y angiografía coronaria durante la hospitalización. Los eventos de AVs se definieron como: extrasístoles ventriculares ≥ 2.000 en registros de telemetría de 24 horas, fibrilación ventricular, taquicardia ventricular (TV) sostenida, TV polimórfica y TV no sostenida. Resultados Se incluyeron 87 pacientes (edad 72±12 años). Durante una hospitalización mediana de 8 días se registraron AVs subagudas en 22 pacientes (25%) tras una mediana de 91 horas desde el ingreso. Las AVs subagudas se asociaron a aumento de la mortalidad hospitalaria (p=0,030). El intervalo Tpeak-Tend corregido global (promedio de las 12 derivaciones del ECG) a las 48 horas del ingreso fue un predictor independiente de AVs subagudas, superior al intervalo QT corregido (p=0,040). Un valor de corte 108ms en el Tpeak-Tend corregido global mostró una sensibilidad del 71% y especificidad del 72% para AVs subagudas. Conclusiones En pacientes con síndrome de tako-tsubo, las AVs subagudas se asocian a alteraciones de la repolarización que pueden detectarse en el ECG convencional mediante el intervalo Tpeak-Tend (AU)

Introduction and objectives The clinical value of electrocardiogram (ECG) repolarization parameters associated with ventricular arrhythmias (VAs) in tako-tsubo syndrome is still under debate. We aimed to evaluate ECG predictors of subacute VAs, defined as those occurring after the first 48hours from admission. Methods This single-center observational study enrolled patients admitted to the cardiology department between 2012 and 2018 with a confirmed diagnosis of tako-tsubo syndrome. Data collection included a 12-lead ECG on admission and at 48hours, continuous telemetry monitoring, blood testing, transthoracic echocardiography, and coronary angiography during hospitalization. VAs events were defined as: premature ventricular contractions ≥ 2000 within a 24-hour window of telemetry monitoring, ventricular fibrillation, sustained ventricular tachycardia (VT), polymorphic VT, and non-sustained VT. Results A total of 87 patients (age 72±12 years) were enrolled. During a median of 8 days of hospitalization, subacute VAs were documented in 22 patients (25%) after a median of 91hours from admission. Subacute VAs were associated with an increase in mortality during hospitalization (P=.030). The corrected global (mean of the 12-lead ECG values) Tpeak-Tend interval at 48hours from admission was an independent predictor of subacute VAs and was statistically superior to the standard corrected QT interval (Z test, P=.040). A cut-off of 108 msec for the corrected global Tpeak-Tend yielded a 71% sensitivity and 72% specificity for subacute VAs. Conclusions In patients with tako-tsubo syndrome, subacute VAs are associated with repolarization alterations that can be identified on conventional ECG using the Tpeak-Tend interval (AU)

Prognostic value of the Tpeak-Tend interval for in-hospital subacute ventricular arrhythmias in tako-tsubo syndrome.

INTRODUCTION AND OBJECTIVES: The clinical value of electrocardiogram (ECG) repolarization parameters associated with ventricular arrhythmias (VAs) in tako-tsubo syndrome is still under debate. We aimed to evaluate ECG predictors of subacute VAs, defined as those occurring after the first 48hours from admission. METHODS: This single-center observational study enrolled patients admitted to the cardiology department between 2012 and 2018 with a confirmed diagnosis of tako-tsubo syndrome. Data collection included a 12-lead ECG on admission and at 48hours, continuous telemetry monitoring, blood testing, transthoracic echocardiography, and coronary angiography during hospitalization. VAs events were defined as: premature ventricular contractions ≥ 2000 within a 24-hour window of telemetry monitoring, ventricular fibrillation, sustained ventricular tachycardia (VT), polymorphic VT, and non-sustained VT. RESULTS: A total of 87 patients (age 72±12 years) were enrolled. During a median of 8 days of hospitalization, subacute VAs were documented in 22 patients (25%) after a median of 91hours from admission. Subacute VAs were associated with an increase in mortality during hospitalization (P=.030). The corrected global (mean of the 12-lead ECG values) Tpeak-Tend interval at 48hours from admission was an independent predictor of subacute VAs and was statistically superior to the standard corrected QT interval (Z test, P=.040). A cut-off of 108 msec for the corrected global Tpeak-Tend yielded a 71% sensitivity and 72% specificity for subacute VAs. CONCLUSIONS: In patients with tako-tsubo syndrome, subacute VAs are associated with repolarization alterations that can be identified on conventional ECG using the Tpeak-Tend interval.

Assessment of patients presenting with life-threatening ventricular arrhythmias and suspected myocarditis: The key role of endomyocardial biopsy.

BACKGROUND: Life-threatening ventricular tachyarrhythmias (VAs) represent a significant cause of death in myocarditis. OBJECTIVE: The purpose of this study was to identify predictors of sustained VAs in patients with myocarditis and ventricular phenotype diagnosed by workflow including endomyocardial biopsy (EMB) guided by 3D electroanatomic mapping (3D-EAM). METHODS: We prospectively enrolled patients with suspected myocarditis and VAs, undergoing cardiac magnetic resonance imaging, coronary angiography, 3D-EAM, and EMB guided by 3D-EAM. At follow-up, sustained VAs were detected by device interrogation and 24-hour electrocardiographic Holter monitoring. RESULTS: We enrolled 54 consecutive patients (mean age 41 ± 14 years; 32(59%) men) with normal ventricular function; left ventricular and right ventricular (RV) late gadolinium enhancement was present, respectively, in 21 (46%) and 6 (13%) of the 46 patients who underwent cardiac magnetic resonance. In 31 patients, the histological diagnosis was myocarditis, while in 14 patients, focal replacement myocardial fibrosis (FRMF); in 9 patients, specimens were inadequate (diagnostic yield of EMB 83%). 3D-EAM showed a larger endocardial scar area for both ventricles in myocarditis than in FRMF (RV bipolar mean scar area 22 ± 16 cm2 vs 3 ± 2 cm2; P = .02; left ventricular bipolar mean scar area 13 ± 5 cm2 vs 4 ± 2 cm2; P = .02, respectively). At a follow-up of 21 months, freedom from sustained VAs was 58% in myocarditis and 92% in FRMF (log-rank, P = .008). Histological diagnosis of myocarditis and RV endocardial scar were independent predictors of sustained VAs (P = .02 for both). CONCLUSION: Our data highlight the need for 3D-EAM-guided EMB in apparently healthy young patients with suspected myocarditis and VAs.

Ventricular arrhythmias in Takotsubo Syndrome: incidence, predictors and clinical outcomes.

AIMS: To investigate predictors of the occurrence of subacute ventricular arrhythmias (VAs), defined as any VAs presenting after 48 h from admission in patients with Takotsubo Syndrome (TTS), and to evaluate the related in-hospital mortality. METHODS: This is a retrospective single-center study enrolling patients admitted between 2012 and 2017 with TTS according to International Takotsubo diagnostic criteria. Data collection included ECG on admission and at 48 h, telemetry monitoring and transthoracic echocardiogram. RESULTS: We enrolled 93 patients; during in-hospital stay (mean 14 ±â€Š16 days) subacute VAs occurred in 25% of patients (VAs group). Life-threatening VAs occurred in 6% of patients (3 sustained ventricular tachycardia, 1 torsade de pointes, 1 ventricular fibrillation) and not life-threatening VAs in 19% (6 non-sustained ventricular tachycardia and 12 premature ventricular contractions > 2000 in 24 h). Mortality was higher in the VAs than in the non-VAs group (P = 0.03), without differences in terms of life-threatening and not life-threatening subacute VAs (P = 0.65) and VAs on admission (P = 0.25). Logistic regression identified the following independent predictors of subacute VAs occurrence: VAs on admission {odds ratio [OR] 22.5 (3.9-131.8), P = 0.001]}, New York Heart Association (NYHA) class III-IV on admission [OR 6.7 (1.3- 34.0), P = 0.021] and QTc at 48 h [OR 1.01 (1.00-1.03), P = 0.046]. CONCLUSION: TTS patients with VAs and NYHA class III-IV on admission and higher QTc at 48 h are at increased risk of subacute VAs occurrence, associated with higher in-hospital mortality. Awareness of this potential complication is critical for proper patients management.

Anatomical targets and expected outcomes of catheter-based ablation of atrial fibrillation in 2020.

Anatomical-based approaches, targeting either pulmonary vein isolation (PVI) or additional extra PV regions, represent the most commonly used ablation treatments in symptomatic patients with atrial fibrillation (AF) recurrences despite antiarrhythmic drug therapy. PVI remains the main anatomical target during catheter-based AF ablation, with the aid of new technological advances as contact force monitoring to increase safety and effective radiofrequency (RF) lesions. Nowadays, cryoballoon ablation has also achieved the same level of scientific evidence in patients with paroxysmal AF undergoing PVI. In parallel, electrical isolation of extra PV targets has progressively increased, which is associated with a steady increase in complex cases undergoing ablation. Several atrial regions as the left atrial posterior wall, the vein of Marshall, the left atrial appendage, or the coronary sinus have been described in different series as locations potentially involved in AF initiation and maintenance. Targeting these regions may be challenging using conventional point-by-point RF delivery, which has opened new opportunities for coadjuvant alternatives as balloon ablation or selective ethanol injection. Although more extensive ablation may increase intraprocedural AF termination and freedom from arrhythmias during the follow-up, some of the targets to achieve such outcomes are not exempt of potential severe complications. Here, we review and discuss current anatomical approaches and the main ablation technologies to target atrial regions associated with AF initiation and maintenance.

Role of extensive diagnostic workup in young athletes and nonathletes with complex ventricular arrhythmias.

BACKGROUND: Ventricular arrhythmias (VAs) are the most common cause of death in athletes. The differences in the electroanatomic substrate in athletes and nonathletes with complex VA are unknown. OBJECTIVE: The purpose of this study was to compare the electroanatomic substrate of complex VA in athletes vs nonathletes. METHODS: The study prospectively enrolled young athletes and nonathletes with VA. Patients underwent 2-dimensional echocardiography, cardiac magnetic resonance (CMR) imaging, coronary angiography, 3-dimensional electroanatomic mapping (3D-EAM), and 3D-EAM-guided endomyocardial biopsy (EMB). Follow-up included 24-hour electrocardiographic Holter or implantable cardioverter-defibrillator/loop recorder interrogation for VA recurrence. RESULTS: Thirty-three patients were enrolled: 18 competitive athletes (56%) and 15 nonathletes (44%). Left ventricular and right ventricular (RV) findings by echocardiography and CMR did not show structural disease. Nine athletes (50%) were asymptomatic compared to 1 nonathlete (7%; P <.05). Unifocal origin of VA was reported in 14 athletes (93%) and 17 nonathletes (94%). Athletes showed a larger RV unipolar than bipolar scar (18 ± 17 cm2 vs 3 ± 3.8 cm2; P = .04). Diagnostic yield of EMB was 50% in athletes and 40% in nonathletes. Among athletes, the final diagnosis was myocarditis in 2, arrhythmogenic ventricular right cardiomyopathy in 1, and focal replacement fibrosis in 1. Among nonathletes, EMB revealed focal replacement fibrosis in 4 cases. At median follow-up of 18.7 months, Kaplan-Meier curves showed lower VA recurrence in detrained athletes than nonathletes (53% vs 6%; P = .02). CONCLUSION: This study showed the need for extensive diagnostic workup in apparently healthy young patients with complex VA in order to characterize concealed cardiomyopathies.

Prognostic significance of non-sustained ventricular tachycardia on stored electrograms in pacemaker recipients.

BACKGROUND: Little is known about the prognostic significance of non-sustained ventricular tachycardia (NS-VT) in outpatients scheduled for routine pacemaker controls. We therefore sought to investigate the prognostic significance of non-sustained ventricular tachycardia on stored electrograms in pacemaker recipients. METHODS: We enrolled patients implanted with dual chamber pacemaker for atrioventricular block or sinus node dysfunction from 2010 to 2016, with LVEF> 45%, older than 18 years, with at least 3 device interrogations at follow-up. Data were collected about medical history, pharmacological therapy at implantation, pacemaker programming, NS-VT occurrence, long-term survival. RESULTS: A total of 308 patients were included in the final analysis, with median follow-up time of 56 months. No ventricular arrhythmic episodes were documented in 221 patients (Group 1), whereas 87 had at least 1 episode of NS-VT during follow-up (Group 2). As a whole, 282 episodes of NS-VT were documented. There was a higher prevalence of previous myocardial infarction and slightly lower left ventricular ejection fraction (LVEF) in Group 2. The primary endpoint (all-cause mortality) occurred in 50 patients (22%) of Group 1 and 12 (14%) patients of Group 2 (p = 0.07). Clinical predictors of all-cause mortality at univariate analysis included age, LVEF and coronary artery disease (CAD). Only age and CAD, however, remained as predictors of mortality at multivariable analysis. A sizeable, but not statistically significant, portion of patients who died had a de novo occurrence of NS-VT at the last pacemaker check. CONCLUSION: Our data do not support a prognostic role for the detection of NS-VT during pacemaker controls.

High-sensitivity cardiac troponin assays and acute coronary syndrome: a matter of sex?

: Advances in technology have led to an improvement in the ability to detect and quantify acute cardiomyocyte injury with the measurement of high-sensitivity cardiac troponin as compared with conventional assays. The upper reference limit for the high-sensitivity cardiac troponin assays is defined as the 99th percentile cutoff value in a healthy reference population. Since sex-related threshold levels of high-sensitivity cardiac troponin assays have been proposed, this review will focus on the diagnostic and prognostic implications of adopting sex-specific threshold troponin values in patients with a suspected acute coronary syndrome.

Platelet miRNA-26b down-regulates multidrug resistance protein 4 in patients on chronic aspirin treatment.

BACKGROUND: Multidrug resistance protein-4 (MRP4) is an ATP binding cassette membrane transporter, actively involved in the efflux of important pharmacological and physiological molecules. Recently, its over-expression has been associated with reduced aspirin (ASA) efficacy after by-pass surgery. MicroRNAs (miRNAs) are small molecules of non-coding RNA involved in the regulation of many physiological and pathophysiological pathways, are abundant in platelets, and can be modulated by several drugs. In the present study, we assessed the role of platelet miRNAs in modulating MRP4 function in response to ASA. METHODS: MRP4 mRNA expression has been analyzed by RealTime PCR in platelets from patients on chronic ASA treatment versus a control group. A panel of miRNAs was run on the pool of each cohort. MiRNAs validation was performed by RealTime PCR. To verify whether MRP4 is the target of miR-26b also in platelets, miR-26b was transfected in platelet and DAMI cells with miRNA mimic technology. MRP4 expression was evaluated by flow cytometry and western blotting. RESULTS: We observed a higher MRP4 mRNA expression in platelets of patients under ASA treatment compared to the control group (p<0.005). MiR-26b was found significantly down-regulated in patients on ASA treatment as compared to control group (P < 0.005) and this was validated by RealTime PCR. MiR-26b transfection in platelets was associated to a significant down-regulation of MRP4 expression (p<0.005). MiR-26b transfection in DAMI cells was associated to a significant reduction of MRP4 mRNA and protein level (P < 0.05). CONCLUSION: We found that miR-26b is down-regulated in platelets in patients on chronic ASA treatment. Importantly, miR-26b can specifically downregulate MRP4. Thus, miR-26b seems to be involved in MRP4 modulation and may contribute to ASA resistance.

Indoleamine 2,3-Dioxygenase (IDO) Enzyme Links Innate Immunity and Altered T-Cell Differentiation in Non-ST Segment Elevation Acute Coronary Syndrome.

Atherosclerosis is a chronic inflammatory disease characterized by a complex interplay between innate and adaptive immunity. Dendritic cells (DCs) play a key role in T-cell activation and regulation by promoting a tolerogenic environment through the expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme involved in tryptophan catabolism. IDO expression and activity was analyzed in monocytes derived DCs (MDDCs) from non-ST segment elevation myocardial infarction (NSTEMI) patients, stable angina (SA) patients and healthy controls (HC) by real-time quantitative polymerase chain reaction (RT-qPCR) before and after in vitro maturation with lipopolysaccharide (LPS). The amount of tryptophan catabolite; kynurenine; was evaluated in the culture supernatants of mature-MDDCs by ELISA assay. Autologous mixed lymphocyte reaction (MLR) between mature-MDDCs and naïve T-cells was carried out to study the differentiation towards T-helper 1 (Th1) and induced regulatory T-cells (iTreg). Analysis of IDO mRNA transcripts in mature-MDDCs revealed a significant reduction in cells isolated from NSTEMI (625.0 ± 128.2; mean ± SEM) as compared with those from SA (958.5 ± 218.3; p = 0.041) and from HC (1183.6 ± 231.6; p = 0.034). Furthermore; the concentration of kynurenine was lower in NSTEMI patients (2.78 ± 0.2) and SA (2.98 ± 0.25) as compared with HC (5.1 ± 0.69 ng/mL; p = 0.002 and p = 0.016; respectively). When IDO-competent mature-MDDCs were co-cultured with allogeneic naïve T-cells, the ratio between the percentage of generated Th1 and iTreg was higher in NSTEMI (4.4 ± 2.9) than in SA (1.8 ± 0.6; p = 0.056) and HC (0.9 ± 0.3; p = 0.008). In NSTEMI, the tolerogenic mechanism of the immune response related to IDO production by activated MDDCs is altered, supporting their role in T-cell dysregulation.

Where Does Inflammation Fit?

PURPOSE OF REVIEW: This review focuses on the complex relationship between inflammation and the onset of acute coronary syndrome and heart failure. RECENT FINDINGS: In the last few years, two important lines of research brought new and essential information to light in the pathogenesis of acute coronary syndrome: a) the understanding of the immune mediate mechanisms of inflammation in Ischemic Heart Disease (IHD) and b) evidence that the inflammatory mechanisms associated with atherosclerosis and its complications can be modulated by anti-inflammatory molecules. A large amount of data also suggests that inflammation is a major component in the development and exacerbation of heart failure (HF), in a symbiotic relationship. In particular, recent evidence underlies peculiar aspects of the phenomenon: oxidative stress and autophagy; DAMPS and TLR-4 signaling activation; different macrophages lineage and the contribution of NLRP-3 inflammasome; adaptive immune system. A possible explanation that could unify the pathogenic mechanism of these different conditions is the rising evidence that increased bowel permeability may allow translation of gut microbioma product into the circulation. These findings clearly establish the role of inflammation as the great trigger for two of the major cardiovascular causes of death and morbidity. Further studies are needed, to better clarify the issue and to define more targeted approaches to reduce pathological inflammation while preserving the physiological one.