Telomere attrition in heart failure: a flow-FISH longitudinal analysis of circulating monocytes.

BACKGROUND: Cross-sectional investigations report shorter telomeres in patients with heart failure (HF); however, no studies describe telomere length (TL) trajectory and its relationship with HF progression. Here we aimed to investigate telomere shortening over time and its relationship to outcomes. METHODS: Our study cohort included 101 ambulatory patients with HF. Blood samples were collected at baseline (n = 101) and at the 1-year follow-up (n = 54). Using flow-FISH analysis of circulating monocytes, we simultaneously measured three monocyte subsets-classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++)-and their respective TLs based on FITC-labeled PNA probe hybridization. The primary endpoints were all-cause death and the composite of all-cause death or HF-related hospitalization, assessed at 2.3 ± 0.6 years. All statistical analyses were executed by using the SPSS 15.0 software, and included Student's t test and ANOVA with post hoc Scheffe analysis, Pearson or Spearman rho correlation and univariate Cox regression when applicable. RESULTS: We found high correlations between TL values of different monocyte subsets: CD14++CD16+ vs. CD14++CD16-, R = 0.95, p < 0.001; CD14++CD16+ vs. CD14+CD16++, R = 0.90, p < 0.001; and CD14++CD16- vs. CD14+CD16++, R = 0.89, p < 0.001. Mean monocyte TL exhibited significant attrition from baseline to the 1-year follow-up (11.1 ± 3.3 vs. 8.3 ± 2.1, p < 0.001). TL did not significantly differ between monocyte subsets at either sampling time-point (all p values > 0.1). Cox regression analyses did not indicate that TL or ΔTL was associated with all-cause death or the composite endpoint. CONCLUSIONS: Overall, this longitudinal study demonstrated a ~ 22% reduction of TL in monocytes from ambulatory patients with HF within 1 year. TL and ΔTL were not related to outcomes over long-term follow-up.

Brilliant violet fluorochromes in simultaneous multicolor flow cytometry-fluorescence in situ hybridization measurement of monocyte subsets and telomere length in heart failure.

Conventional analytical methods to determine telomere length (TL) have been replaced by more precise and reproducible procedures, such as fluorescence in situ hybridization coupled with flow cytometry (flow-FISH). However, simultaneous measurement of TL and cell phenotype remains difficult. Relatively expensive and time-consuming cell-sorting purification is needed to counteract the loss, due to stringent FISH conditions, of prehybridization fluorescence by the organic fluorochromes conventionally used in the phenotyping step. Here, we sought to assess whether the newly developed Brilliant Violet (BV) dyes are valuable to specifically and simultaneously assess the distribution and telomere attrition of monocyte subsets circulating in the blood of a cohort of patients with heart failure. We performed flow-FISH on blood samples from 28 patients with heart failure. To differentiate among monocyte subsets, we used BV and conventional fluorochromes conjugated to antibodies against CD86, CD14, CD16, and CD15. We simultaneously assessed the TLs of the monocyte subsets with a telomere-specific peptide nucleic acid probe labeled with fluorescein isothiocyanate. The BV dyes completely tolerated the harsh conditions required for adequate DNA denaturation and simultaneously provided accurate identification of monocyte subpopulations and respective TLs. The presented protocol may be faster and less expensive than those used currently for purposes such as establishing associations among patient categories, disease progression, monocyte heterogeneity, and aging in the context of heart failure.

Incidental Arrhythmias During Atrial Fibrillation Screening With Repeat 7-Day Holter ECGs in a Hospital-Based Patient Population.

BACKGROUND: Screening for atrial fibrillation (AF) may reveal incidental arrhythmias of relevance. The aim of this study was to describe incidental arrhythmias detected during screening for AF in the STAR-FIB (Predicting SilenT AtRial FIBrillation in Patients at High Thrombembolic Risk) cohort study. METHODS AND RESULTS: In the STAR-FIB cohort study, we screened hospitalized patients for AF with 3 repeat 7-day Holter ECGs. We analyzed all Holter ECGs for the presence of the following incidental arrhythmias: (1) sinus node dysfunction, defined as sinus pause of ≥3 seconds' duration; (2) second-degree (including Wenckebach) or higher-degree atrioventricular block (AVB); (3) sustained supraventricular tachycardia of ≥30 seconds' duration; and (4) sustained ventricular tachycardia of ≥30 seconds' duration. We furthermore report treatment decisions because of incidental arrhythmias. A total of 2077 Holter ECGs were performed in 794 patients (mean age, 74.7 years; 49% women), resulting in a mean cumulative duration of analyzable ECG signal of 414±136 hours/patient. We found incidental arrhythmias in 94 patients (11.8%). Among these were sinus node dysfunction in 14 patients (1.8%), AVB in 41 (5.2%), supraventricular tachycardia in 42 (5.3%), and ventricular tachycardia in 2 (0.3%). Second-degree AVB was found in 23 patients (2.9%), 2:1 AVB in 10 (1.3%), and complete AVB in 8 (1%). Subsequently, 8 patients underwent pacemaker implantation, 1 for sinus node dysfunction (post-AF conversion pause of 9 seconds) and 7 for advanced AVB. One patient had an implantable cardioverter-defibrillator implanted for syncopal ventricular tachycardia. CONCLUSIONS: Incidental arrhythmias were frequently detected during screening for AF in the STAR-FIB study and resulted in device therapy in 1.1% of our cohort patients.

Impact of tafamidis on myocardial function and CMR tissue characteristics in transthyretin amyloid cardiomyopathy.

AIMS: Tafamidis improves clinical outcomes in transthyretin amyloid cardiomyopathy (ATTR-CM), yet how tafamidis affects cardiac structure and function remains poorly described. This study prospectively analysed the effect of tafamidis on 12-month longitudinal changes in cardiac structure and function by cardiac magnetic resonance (CMR) compared with the natural course of disease in an untreated historic control cohort. METHODS AND RESULTS: ATTR-CM patients underwent CMR at tafamidis initiation and at 12 months. Untreated patients with serial CMRs served as reference to compare biventricular function, global longitudinal strain (GLS), LV mass and extracellular volume fraction (ECV). Thirty-six tafamidis-treated (n = 35; 97.1% male) and 15 untreated patients (n = 14; 93.3% male) with a mean age of 78.3 ± 6.5 and 76.9 ± 6.5, respectively, and comparable baseline characteristics were included. Tafamidis was associated with preserving biventricular function (LVEF (%): 50.5 ± 12 to 50.7 ± 11.5, P = 0.87; RVEF (%): 48.2 ± 10.4 to 48.2 ± 9.4, P = 0.99) and LV-GLS (-9.6 ± 3.2 to -9.9 ± 2.4%; P = 0.595) at 12 months, while a significantly reduced RV-function (50.8 ± 7.3 to 44.2 ± 11.6%, P = 0.028; P (change over time between groups) = 0.032) and numerically worsening LVGLS (-10.9 ± 3.3 to -9.1 ± 2.9%, P = 0.097; P (change over time between groups) = 0.048) was observed without treatment. LV mass significantly declined with tafamidis (184.7 ± 47.7 to 176.5 ± 44.3 g; P = 0.011), yet remained unchanged in untreated patients (163.8 ± 47.5 to 171.2 ± 39.7 g P = 0.356, P (change over time between groups) = 0.027). Irrespective of tafamidis, ECV and native T1-mapping did not change significantly from baseline to 12-month follow-up (P > 0.05). CONCLUSIONS: Compared with untreated ATTR-CM patients, initiation of tafamidis preserved CMR-measured biventricular function and reduced LV mass at 12 months. ECV and native T1-mapping did not change significantly comparable to baseline in both groups.

Acute Heart Failure During the Peripartum Period Due to Aggravated Tricuspid Regurgitation.

Latent valvular heart disease may be aggravated or demasked during pregnancy because of physiologic hemodynamic changes, including higher circulating volume, heart rate, and cardiac index, as well as stress during labor. The presence of valvular heart disease increases the risk of maternal and fetal/newborn adverse events. Early diagnosis, risk assessment, and specific management are crucial. We present a case of acute peripartal heart failure caused by idiopathic severe tricuspid regurgitation in a 38-year-old woman.

Assessment of New Onset Arrhythmias After Transcatheter Aortic Valve Implantation Using an Implantable Cardiac Monitor.

Background: Transcatheter aortic valve implantation (TAVI) is associated with new onset brady- and tachyarrhythmias which may impact clinical outcome. Aims: To investigate the true incidence of new onset arrhythmias within 12 months after TAVI using an implantable cardiac monitor (ICM). Methods: One hundred patients undergoing TAVI received an ICM within 3 months before or up to 5 days after TAVI. Patients were followed-up for 12 months after discharge from TAVI for the occurrence of atrial fibrillation (AF), bradycardia (≤30 bpm), advanced atrioventricular (AV) block, sustained ventricular and supraventricular tachycardia. Results: A previously undiagnosed arrhythmia was observed in 31 patients (31%) and comprised AF in 19 patients (19%), advanced AV block in 3 patients (3%), and sustained supraventricular and ventricular tachycardia in 10 (10%) and 2 patients (2%), respectively. Three patients had a clinical diagnosis of sick-sinus-syndrome. A permanent pacemaker (PPM) was implanted in six patients (6%). The prevalence of pre-existing AF was 28%, and 47% of the patients had AF at the end of the study period. AF burden was significantly higher in patients with pre-existing [26.7% (IQR 0.3%; 100%)] compared to patients with new-onset AF [0.0% (IQR 0.0%; 0.06%); p = 0.001]. Three patients died after TAVI without evidence of an arrhythmic cause according to the available ICM recordings. Conclusions: Rhythm monitoring for 12 months after TAVI revealed new arrhythmias, mainly AF, in almost one third of patients. Atrial fibrillation burden was higher in patients with prevalent compared to incident AF. Selected patients may benefit from short-term remote monitoring. Trial Registration: https://clinicaltrials.gov/: NCT02559011.

Differences in Atrial Remodeling in Hypertrophic Cardiomyopathy Compared to Hypertensive Heart Disease and Athletes' Hearts.

Background: Hypertrophic cardiomyopathy (HCM), hypertensive heart disease (HHD) and athletes' heart share an increased prevalence of atrial fibrillation. Atrial cardiomyopathy in these patients may have different characteristics and help to distinguish these conditions. Methods: In this single-center study, we prospectively collected and analyzed electrocardiographic (12-lead ECG, signal-averaged ECG (SAECG), 24 h Holter ECG) and echocardiographic data in patients with HCM and HHD and in endurance athletes. Patients with atrial fibrillation were excluded. Results: We compared data of 27 patients with HCM (70% males, mean age 50 ± 14 years), 324 patients with HHD (52% males, mean age 75 ± 5.5 years), and 215 endurance athletes (72% males, mean age 42 ± 7.5 years). HCM patients had significantly longer filtered P-wave duration (153 ± 26 ms) and PR interval (191 ± 48 ms) compared to HHD patients (144 ± 16 ms, p = 0.012 and 178 ± 31, p = 0.034, respectively) and athletes (134 ± 14 ms, p = 0.001 and 165 ± 26 ms, both p < 0.001, respectively). HCM patients had a mean of 4.9 ± 16 premature atrial complexes per hour. Premature atrial complexes per hour were significantly more frequent in HHD patients (27 ± 86, p < 0.001), but not in athletes (2.7 ± 23, p = 0.639). Left atrial volume index (LAVI) was 43 ± 14 mL/m2 in HCM patients and significantly larger than age- and sex-corrected LAVI in HHD patients 30 ± 10 mL/m2; p < 0.001) and athletes (31 ± 9.5 mL/m2; p < 0.001). A borderline interventricular septum thickness ≥13 mm and ≤15 mm was found in 114 (35%) HHD patients, 12 (6%) athletes and 3 (11%) HCM patients. Conclusions: Structural and electrical atrial remodeling is more advanced in HCM patients compared to HHD patients and athletes.

Cardiac tamponade secondary to Dressler's syndrome.

A 56-year-old woman presented to hospital with chest pain. Following review and investigations in the medical assessment unit, she was diagnosed with costochondritis and discharged home. She represented 10 days later and was mottled and hypotensive with a high lactate, raised inflammatory markers, an acute kidney injury and bilateral loin pain. A CT of the thorax, abdomen and pelvis showed pleural effusions and a large pericardial effusion with features of cardiac tamponade on subsequent echocardiography. A pericardiocentesis was performed and she was admitted to intensive care for haemofiltration. Once the patient was stable, an inpatient cardiac MRI was requested to further investigate an enhancing pericardium and echo-bright areas in the inferior, inferoseptal and inferolateral walls of the left ventricle demonstrated on echocardiography. The cardiac MRI showed evidence of a recent infarction in the right coronary artery (RCA) territory with pericardial inflammation and a resolved pericardial effusion. Overall, the findings were in keeping with Dressler's syndrome.

Permanent pacemaker implantation late after transcatheter aortic valve implantation.

BACKGROUND: Impairment of atrioventricular (AV) conduction may occur late after transcatheter aortic valve implantation (TAVI), and progression to complete AV block is a matter of concern. OBJECTIVE: The purpose of this study was to describe the incidence of permanent pacemaker (PPM) implantation late after TAVI. METHODS: In a prospective TAVI registry, we retrospectively identified patients with PPM implantation after hospital discharge for TAVI and analyzed serial electrocardiograms for AV conduction impairment before PPM implantation. RESULTS: Among 1059 patients discharged after TAVI without PPM between January 2012 and December 2017, 62 patients (5.9%) underwent PPM implantation at a median of 305 days after discharge for TAVI. Indications for PPM implantation late after TAVI were AV conduction impairment in 46 patients (74.2%); sick sinus syndrome in 10 (16.1%); cardiac resynchronization or implantable cardioverter-defibrillator indication in 2 (3.2%); and a pace and ablate strategy in 4 (6.5%). Clinical symptoms leading to PPM implantation late after TAVI included syncope in 19 patients (30.7%), presyncope in 7 (11.3%), and dyspnea in 8 (12.9%). First-degree AV block and new left bundle branch block (LBBB) after TAVI as well as valve-in-valve procedure during follow-up were independent predictors of PPM implantation late after TAVI due to AV conduction impairment. CONCLUSION: PPM implantation late after TAVI is infrequent and is associated with clinical symptoms in half of patients. Impairment of AV conduction was the indication in three-quarters of patients. First-degree AV block and new LBBB after TAVI as well as valve-in-valve procedure during follow-up emerged as independent predictors.

Age and Sex Specific Prevalence of Clinical and Screen-Detected Atrial Fibrillation in Hospitalized Patients.

BACKGROUND: The prevalence of atrial fibrillation (AF) is high in older patients. The present study aimed to estimate the age and sex specific prevalence of clinical and screen-detected atrial fibrillation (AF) in hospitalized patients. METHODS: The STAR-FIB cohort study was a prospective cohort study recruiting participants from a large source population of hospitalized patients aged 65-84 years. The estimated size of the source population was 26,035 (95% CI 25,918-26,152), and 795 consenting patients without clinical AF were included in the cohort study after stratification by sex and age (49.2% females; mean age 74.7 years). Patients in the cohort study underwent three seven-day Holter ECGs in intervals of two months to screen for AF. RESULTS: In the source population, the estimated prevalence of clinical AF was 22.2% (95% CI 18.4-26.1), 23.8% for males (95% CI 20.9-26.6) and 19.8% for females (95% CI 17.3-22.4; p for difference between sexes, 0.004). There was a linear trend for an increase in the prevalence of clinical AF with increasing age, overall and in both sexes. In the cohort study, AF was newly diagnosed in 38 patients, for an estimated prevalence of screen-detected AF of 4.9% overall (95% CI 3.3-6.6), 5.5% in males (95% CI 3.2-7.8) and 4.0% in females (95% CI 2.0-6.0; p for difference between sexes, 0.041). The estimated prevalence of screen-detected AF in the source population was 3.8% overall, 4.2% in males and 3.2% in females. CONCLUSION: In a large hospital-based patient population aged 65-84 years, the prevalence of clinical AF and of screen-detected AF was 22.2% and 3.8%, respectively, and significantly higher in males than females.

The SilenT AtRial FIBrillation (STAR-FIB) study programme - design and rationale.

AIMS OF THE STUDY: Anticoagulation of patients with screen-detected atrial fibrillation may prevent ischaemic strokes. The STAR-FIB study programme aims to determine the age- and sex-specific prevalence of silent atrial fibrillation and to develop a clinical prediction model to identify patients at risk of undiagnosed atrial fibrillation in a hospitalised patient population. METHODS: The STAR-FIB study programme includes a prospective cohort study and a case-control study of hospitalised patients aged 65–84 years, evenly distributed for both age and sex. We recruited 795 patients without atrial fibrillation for the cohort study (49.2% females; median age 74.8 years). All patients had three serial 7-day Holter ECGs to screen for silent atrial fibrillation. The primary endpoint will be any episode of atrial fibrillation or atrial flutter of ≥30 seconds duration. The age- and sex-specific prevalence of newly diagnosed atrial fibrillation will be estimated. For the case-control study, 120 patients with paroxysmal atrial fibrillation were recruited as cases (41.7% females; median age 74.6 years); controls will be randomly selected from the cohort study in a 2:1 ratio. All participants in the cohort study and all cases were prospectively evaluated including clinical, laboratory, echocardiographic and electrical parameters. A clinical prediction model for undiagnosed atrial fibrillation will be derived in the case-control study and externally validated in the cohort study. CONCLUSIONS: The STAR-FIB study programme will estimate the age- and sex-specific prevalence of silent atrial fibrillation in a hospitalised patient population, and develop and validate a clinical prediction model to identify patients at risk of silent atrial fibrillation.

Circulating monocyte subsets and heart failure prognosis.

Monocytes are a heterogeneous population of effector cells with key roles in tissue integrity restoration and maintenance. Here, we explore the association of monocyte subsets and prognosis in patients with ambulatory heart failure (HF). Monocyte subsets were classified as classical (CD14++/CD16-), intermediate (CD14++/CD16+), or non-classical (CD14+/CD16++). Percentage distribution and absolute cell count were assessed in each subset, and multivariable Cox regression analyses were performed with all-cause death, HF-related hospitalization, and the composite end-point of both as dependent variables. 400 patients were consecutively included (72.8% male, age 69.4±12.2 years, 45.5% from ischemic aetiology, left ventricle ejection fraction (LVEF) 41.6% ±14.5, New York Heart Association (NYHA) class II 62.8% and III 30.8%). During a mean follow-up of 2.6±0.9 years, 107 patients died, 99 had a HF-related hospitalization and 160 suffered the composite end-point of all-cause death or HF-related hospitalization. Monocyte subsets assessed in percentages were not independently associated to any of the end-points. When considering number of cells/µL, intermediate subset was independently associated with an increase of all-cause death (HR 1.25 [95% CI 1,02-1.52], p = 0.03), and the composite end-point HR 1.20 [95% CI 1,03-1.40], p = 0.02). The presented findings show that absolute cell count of monocyte subsets was preferred over monocyte percentage for prognosis stratification for outpatients with HF. The intermediate monocyte subset provides information on increased risk of all-cause death and the composite end-point.