bluuebunny/crossref_metadata_2025 huggingface dataset:
AMplitude Spectral Area (AMSA) is associated with one-year survival with good neurological outcome in out-of-hospital cardiac arrest
Authors: Gentile F R , Fasolino A , Aramendi E , Isasi I , Compagnoni S , Baldi E , Contri E , Palo A , Quilico E , Vicini Scajola L , Lopiano C , Primi R , Bendotti S , Currao A , Savastano S
Published: November 2023

Background

Patients resuscitated from Out-of-Hospital Cardiac Arrest (OHCA) with shockable rhythms are reported to have better survival rates. Amplitude spectral area (AMSA) of ventricular fibrillation (VF), a surrogate for the metabolic status of the myocardium, can predict shock success and return of spontaneous circulation (ROSC). There is minimal evidence regarding its role in predicting survival from OHCA, and the evidence that exists is limited to survival at discharge.

Purpose

To test the hypothesis that the first, the maximum, the minimum and the average values of AMSA are associated with one-year survival with good neurological outcome in OHCA patients.

Methods

All the OHCAs with at least one shockable rhythm, that occurred from January 2015 to December 2020 and collected from an Utstein-style database, were considered. AMSA values were calculated by retrospectively analyzing the data collected by the monitors/defibrillators used and by using a 2-second pre-shock ECG interval. The first, the maximum, the minimum and the average AMSA values during resuscitation were computed. Data were analyzed by using Cox regression analysis.

Results

250 patients (84% male, median age 67 [57-77] years) with at least one computable AMSA value were included; 12% achieved ROSC and 9.4% survived at one year with good neurological outcome, defined as Cerebral Performance Category (CPC) ≤ 2. The first, the maximum, the minimum and the average values of AMSA were higher in patients alive one year after OHCA with CPC≤2 (first: 11.6 [9.9-14.7] vs 7.8 [5.1-11.8]; max: 15.4 [12-20] vs 9.9 [6.2-14.4]; min: 9.9 [8.5-12.2] vs 6.1 [4.3-9.6]; avg: 12.5 [10.7-15.2] vs 8.3 [5.5-12]; all p <0.01). These values showed similar areas under the curve of the receiver operating characteristic (ROC) curve for one-year survival with good neurological outcome (first: 0.77; max: 0.76; min: 0.78; avg: 0.78, p=ns). In univariable model, the survival probability with good neurological outcome was significantly lower in the first tertile (T1) of AMSA compared to the third one (T3; p<0.05; figure). In multivariable analysis, after correction for sex, presence of bystander CPR, age, EMS arrival time, witnessed status, OHCA location, the use of mechanical CPR and the total amount of epinephrine administrated, AMSA was significantly associated with probability of death or poor neurologic outcome [HR 0.5 (95%CI 0.3-0.9), p=0.03].

Conclusions

This is the first study to evaluate the association between AMSA values and one-year survival with good neurological outcome. We found that AMSA is independently associated with one-year survival with­ good neurological outcome in OHCA patients and that the first, the maximum, the minimum and the average of AMSA values all have similar prediction power in survival rate with CPC≤2.
High-intensity interval training in patients with an implantable cardioverter defibrillator: a randomized controlled study
Authors: Nyman M , Mjolstad O C , Dale A C , Amundsen B , Rossvoll O , Wisloff U , Loennechen J P
Published: November 2023

Background

Exercise is an effective treatment in a broad spectrum of cardiovascular diseases. High-intensity interval training (HIIT) has shown superior effect on cardiorespiratory fitness and equal or superior effect on morbidity and quality of life (QoL) compared to moderate continuous exercise training. However, evidence of the efficacy and risks of HIIT in patients with increased risk of ventricular arrhythmia remains limited.

Purpose

To evaluate the effects of HIIT on exercise capacity, QoL and burden of ventricular arrhythmias in patients with an implantable cardioverter defibrillator (ICD) with or without cardiac resynchronization therapy.

Methods

Patients with ischemic or dilated cardiomyopathy and ICD were randomized to a supervised 12-week HIIT program or to a control group continuing their usual exercise routines. HIIT consisted of four 4-minute intervals aiming at 85-95% of maximum heart rate (HRmax), and 3-minute active recovery aiming at 60-70 % of HRmax in between intervals, 3 times a week for 12 weeks. Primary outcomes were exercise capacity measured as peak oxygen uptake (VO2 peak) and QoL assessed with the Short Form 36 (SF-36) questionnaire. Main secondary outcome was the burden of ventricular arrhythmias analysed from remote patient monitoring data.

Results

Fifty-six patients were included (table 1). Three patients in the HIIT group did not complete the intervention. Two withdrew due to a knee injury and due to fear of SARS-CoV-2 exposure, respectively. One experienced an appropriate shock during exercise and was excluded from further training after clinical consideration. Fifty-three patients completed all follow-up examinations. HIIT significantly increased VO2 peak with 7.0 %, with no changes in the control group (p=0.001) (figure 1A). There was a significant increase in the SF-36 subscale scores on physical functioning (p<0.05), general health (p<0.05) and health change (p=0.001) in the HIIT group compared to the control group (figure 1B). There were no significant differences between groups in number of non-sustained or sustained ventricular tachycardias, anti-tachycardia pacing therapy or ICD shocks.

Conclusions

In patients with ICD due to ischemic or dilated cardiomyopathy, a supervised 12-week HIIT-program significantly increased VO2 peak and QoL without increasing the burden of ventricular arrhythmias.Table 1:Patient characteristicsFigure 1:Peak oxygen uptake and QoL
Incidence of sustained ventricular tachyarrhythmias in patients with non-ischemic cardiomyopathy in a multicenter multinational WCD cohort
Authors: Erath J W , Koepsel K K , Kovacs B K , Dreher T D , Blockhaus C B , Grotzmann M G , Klein N K , Hijazi M H , Saguner A S , Kowitz J K , Duru F D , Beiert T B , Aweimer A A , Akin I A , El-Battrawy I B
Published: November 2023

Background

Defibrillator use in patients with non-ischemic cardiomyopathy (NICM) and HFrEF remains controversial after the DANISH study. The new ESC guidelines recommend individualized risk stratification in these patients. The wearable cardioverter-defibrillator (WCD) seems to be appropriate to both protect and screen patients with HFrEF at risk for sudden cardiac death (SCD).

Puropose: To evaluate the rate of ventricular tachyarrhythmias (VT/VF) in NICM vs. ICM patients receiving a WCD for temporary SCD protection.

Methods

1157 patients were included in a multicenter registry from eight European centers. Among these patients, 602 patients received a WCD due to ischemic cardiomyopathy (ICM) and 555 patients for non-ischemic cardiomyopathy (NICM). Incidence of VT/VF and/or appropriate WCD shock discharge during WCD use were evaluated. The mean follow-up (FU) time of the whole cohort was 620.2±607.8 days.

Results

NICM patients were younger (mean 56.5±14.8a vs 63.9±11.6a; p<0.001) and less often male (75% vs. 87.2%; p<0.001) compared to ICM patients. Heart failure medication at hospital discharge did not differ between the two groups except for a higher prescription rate of aldosterone-antagonists in NICM compared to ICM patients (73.8% vs. 66.7%; p=0.02). The index left ventricular ejection fraction (LVEF) was significantly lower in NICM compared to ICM patients (mean 26.1±9.1% versus 29.5±9.2%; p<0.001). A larger extent of LVEF recovery was detected in NICM patients compared to ICM patients up to the end of WCD use (mean LVEF post WCD: 45.7±35.4% vs. 40.2±11.8%; p=0.02). Average daily WCD wear-time was significantly lower in NICM patients compared to ICM patients (mean 20.7±4.9h vs. 21.6±3.7h; p=0.01). NICM patients had a significantly lower incidence of sustained ventricular tachyarrhythmia (VT/VF) compared to ICM patients (3.4% vs. 6.6%; p=0.02). Consistently, rate of appropriate WCD shock was significantly lower in NICM vs. ICM patients (0.7% vs. 3.7%; p< 0.001), as was rate of re-hospitalization (30.2% vs. 46.1%; p<0.001). Both groups showed a similar mortality rate during FU.

Conclusions

Patients at risk for SCD with NICM showed a more pronounced LVEF recovery, significantly lower incidence of VT/VF with concomitant shocks and hospitalization, while overall mortality was unchanged compared to ICM patients. These results indicate that WCD use might facilitate individual SCD risk stratification in NICM patients.
Integration of electro-anatomical maps in the planning phase of stereotactic arrhythmia radioablation for refractory ventricular tachycardia
Authors: Solana Munoz J , Luca A , Herrera-Siklody C , Van Der Ree M H , Postema P , Le Bloa M , Teres C , Porreta A P , Domenichini G , Pascale P , Schiappacasse L , Pruvot E
Published: November 2023

Introduction

Despite the efficacy of stereotactic arrhythmia radioablation (STAR) for the treatment of refractory ventricular tachycardia (VT), the planning phase to precisely delineate the arrhythmogenic substrate still suffers from limitations due to the incompatibility of data formats between 3D electro-anatomical mapping systems (EAM) and STAR planning software (CyberKnife).

Purpose

Within the STOPSTORM European consortium, we present a workflow to integrate all 3D EAM data (e.g. voltage, activation time, anatomical tags) into the STAR planning software using the open source software Slicer3D to improve targeting of the arrhythmogenic substrate.

Method

Two protocols were compared retrospectively.

Protocol 1 (STAR gold-standard) comprised the manual contouring of the clinical target volume (CTV) on planning 4D-CAT SCAN drawn side-by-side using EAM (Carto3, Biosense Webster) screen-shots and diagnostic reports.

Protocol 2 comprised semiautomatic segmentation of CTV on planning 4D-CAT SCAN using imported EAMs annotated with landmarks for VT target delimitation. The semiautomatic segmentation of CTVs included three steps: (1) semiautomatic segmentation of ventricular myocardium (VM), the blood-pool of the concerned ventricle and at least two additional cardiac cavities; (2) 3D alignment of EAM with the segmented cavities; and (3), 3D delineation of CTV identified as the transmural section of VM segment surrounding the EAM’s VT target delimited by the annotated landmarks.

The volume overlap (Dice coefficient) and the absolute difference of the CTVs obtained with the two protocols were compared. Both measurements were expressed in percentage as follows: Dice coefficient 0% means no overlap and 100% complete overlap; absolute difference of volumes 0% means no difference and 100% means that one CTV was twice the size of the CTV generated by the other protocol.

Results

Both protocols were applied to four patients (65.5 ± 8.5 yo) with refractory VT successfully treated with STAR. Figure 1 shows an example (Patient 1) of the CTV contouring using the CARTO EAMs aligned with the CT images in Slicer3D. Figure 2 illustrates significant mismatch between the segmented CTVs of the two protocols. The median volume overlap of the CTVs was 44%, while the median volume absolute difference was 35%. Table 1 reports detailed results.

Conclusion

Our study reveals a high variability of CTV delineation for STAR using two different protocols. The intraprocedural assignment of anatomical landmarks for VT target delimitation on EAM appears promising to improve CTV delineation. Further research is needed to evaluate the correlation between STAR outcome and CTV delineation accuracy.
Risk prediction of inappropriate implantable cardioverter-defibrillator therapy using machine learning
Authors: Tateishi R , Suzuki M , Shimizu M , Shimada H , Tsunoda T , Miyazaki H , Misu Y , Yamakami Y , Yamaguchi M , Kato N , Isshiki A , Kimura S , Fujii H , Nishizaki M , Sasano T
Published: November 2023

Background

Inappropriate shock from implantable cardioverter-defibrillators (ICDs) undermines quality of life and increases all-cause mortality risk. Various predictors of inappropriate ICD shock have also been indicated in previous studies. Nevertheless, no prediction model by machine learning has been reported.

Purpose

We developed ML models for evaluating the risk of inappropriate ICD therapy, and proposed easily calculable risk scoring.

Methods

In total, 182 consecutive cases implanted with ICD were enrolled. The predictive models were based on 16 statistically significant factors out of 189 items including electrocardiogram parameters and clinical features after ICD implantation. Statistical analysis and 14 ensemble learning methods were performed. Shapley additive explanation (SHAP) method was performed to extract important features in the best ML model, and easily calculable score was established from the features.

Results

Twenty-five patients (13.7%) underwent inappropriate therapy. The extra-trees classifier demonstrated the highest area under the receiver operating characteristic curve (AUROC; 0.839). The top six features were history of atrial arrhythmia, ischemic cardiomyopathy (ICM), no diabetes mellitus (DM), cardiac resynchronization therapy (CRT), and V4- and V5 R-wave amplitudes. From the six features, the Cardi45 score was developed (+6.5 points for history of atrial arrhythmia, -2.0 points for ICM, -1.0 points for DM, -0.5 points for CRT, and +0.5 points for V4 T-wave amplitude ≥1200 μV and V5 R-wave amplitude ≥1400 μV). The AUROC for the Cardi45 score was 0.886, which was higher than that of extra-trees classifier.

Conclusion

Our study demonstrates that the ML approach can provide a good prediction model and Cardi45 score was powerful predictors for inappropriate ICD therapy. Cardi45 score, derived from this model, may be used to judge whether an aggressive rhythm control strategy should be implemented or ICD implantation should be avoided in some patients.Picture 1Picture 2
Remote monitoring of cardiac implantable devices in children: characteristics and outcome in a retrospective single centre contemporary study. TelePaedia study
Authors: Jouen R , Delsarte L , Placide L , Favrot C , Di Giacomo G , Massin F , Granier M , Vicenti M , Pasquie J L
Published: November 2023

Introduction

Remote monitoring (RM) has revolutionized implantable cardiac device care in adults. It has demonstrated its safety on hard criteria, a reduction in the number of hospitalizations and emergency room visits, early detection of events and a reduction in inappropriate therapies. However, while pediatric population is becoming emerging, particularly considering congenital heart diseases, there is no contemporary study.

Objective

The aim of our study was to characterize in our cohort of RM patients the population of children (below 18 yo) implanted with a pacemaker or an ICD and under RM for more than 1 year.

Method

The data collection was carried out retrospectively within the cohort of RM patients at our university hospital. The outcome combined occurrence of ventricular (VT)/supraventricular (SVT) arrhythmias, appropriate or inappropriate therapies, lead dysfunction/fracture and ERI.

Results

The study population included 34 patients (17F/17M) with a mean age of 9.4+/-5.8 years (range 0-18 yo) and a mean remote follow-up of 4.6+/-3.9 years (range 1-13 y). The indications for pacing were postoperative atrioventricular block (AVB, n = 9) for operated congenital heart disease or hypertrophic cardiomyopathy (n=1), congenital AVB (n= 5), muscular dystrophy (n = 1) and genetic sinus node dysfunction (n = 1). Indications for an ICD were resuscitated sudden death in hypertrophic cardiomyopathy (n = 4), LQTS (n = 5), CPVT (n = 2), arrhythmogenic right ventricular dysplasia (n = 2), Brugada syndrome (n = 1) and congenital heart disease (n = 2). Pacing devices (n = 17) were mostly implanted with epicardial leads and abdominal box (n = 12). ICDs (n = 18) were implanted in primary (n = 4) or in secondary prevention with epicardial (n = 2)/ endovascular (n=9) /subcutaneous (n = 2) leads depending on children weight and anatomy. One 12 yo-boy had an S-ICD in addition to a previous pacemaker. There were a total of 13 patients with device-triggered alerts: VT in 8 including appropriate therapies in 6 and inappropriate shocks in 2, supraventricular tachycardia in 2, RV lead dysfunction in 2, RV lead fracture in 1 and no alert for ERI. All alerts were treated within 24h.

Conclusion

This is the first report of cardiac device remote monitoring in a pediatric population. In our population 13/34 patients experienced alerts necessitating intervention over a mean 4.6 year-follow-up. Remote monitoring through device-triggered alerts allowed efficient treatment of an arrhythmic event or a lead dysfunction. This is a preliminary study suggesting the need for further studies on a larger population. Remote monitoring should be considered in all eligible-device children and should be considered as standard of care.
Vascular access in cardiac implantable electronic devices: a systematic review and network meta-analysis
Authors: Castagno D , Saglietto A , Peddis M , Falasconi G , Millesimo M , Ferraris F , Anselmino M , Matta M , De Ferrari G M
Published: November 2023

Background

Despite the increasing number of cardiac implantable electronic devices (CIED) implantations worldwide, gaps in the evidence base on the optimal venous access to perform the procedure still exist and direct comparisons of different techniques are lacking.

Purpose

The aim of this study was to compare the acute and long-term safety and efficacy of the three main vascular access modalities (i.e. subclavian vein puncture [SVP], cephalic vein cut-down [CVC], axillary vein puncture [AVP]) used during CIEDs implantations.

Methods

A systematic review of the literature and network meta-analysis were performed searching Pubmed/MEDLINE databases for relevant articles using the following search strategy, without language restrictions: ((cardiac implantable device) OR (pacemaker) OR (ppm) OR (defibrillator) OR (icd) OR (resynchronization) OR (crt)) AND ((venous access) OR (subclavian) OR (axillary) OR (cephalic)). Randomized and non-randomized studies comparing one or more of the outcomes of interest, between at least two discernible groups (SVP, CVC and AVP), were included in the present analysis and SVP competitive arm was used as the reference group. The primary endpoints were safety outcomes, which included: 1) pneumothorax, 2) pocket haematoma, 3) lead failure, including both acute (dislodgment) and chronic (fracture, subclavian crush syndrome) events, 4) infective complications. Success rate, defined either by successful cannulation of the vein or by successful lead placement was a secondary outcome.

Results

Forty studies (33, 83% non-randomized) were selected and a total of 166782 patients (median age 69.2 years, 65.2% males) followed up for a median of 18 months (IQR 11-51) were included. Both AVP and CVC showed a significant reduction in the risk of pneumothorax compared to SVP (AVP: OR 0.12, 95% CI 0.05-0.28; CVC: OR 0.18, 95% CI 0.15-0.22) but no significant differences between treatment arms concerning bleedings (AVP: OR 1.11, 95% CI 0.52; 2.37; CVC OR 1.16, 95% CI 0.60; 1.88) or infective complications (AVP: OR 1.00, 95% CI 0.47- 2.14; CVC OR 0.67, 95% CI 0.31-1.44) were observed. Compared to SVP, AVP was significantly superior concerning the risk of lead failure (OR 0.42, 95% CI 0.27-0.67) while CVC showed a nearly statistically significant reduction in risk of lead complications (OR 0.73, 95% CI 0.52-1.02), see figure 1. Success rate did not differ significantly between treatments arms albeit CVC showed a trend towards a higher risk of need for alternate venous access compared to AVP (3.56, 95% CI 0.89-14.21).

Conclusions

Considering the lower risk of pneumothorax and lead failure, AVP and CVC should be preferred over SVP to achieve venous access during CIEDs implantation taking into account the higher success rates associated with AVP.Figure 1
Thoracic ultrasound versus chest X-ray for early detection of mechanical early complications of cardiac device implantation procedures
Authors: Floris R , Dell'era G , Pimpini L , Ghiglieno C , Fais L M , Cucco A , Faggioni A , Claretti C , Orru F , Demontis M V , Casella M , Dello Russo A , Delogu G , Guerra F
Published: November 2023

Background

In the immediate postoperative of cardiac implantable electronic devices (CIED) implantation, the use of chest radiography (CXR) is the gold standard diagnostic tool for early complications, accompanied by electrical parameters testing for diagnostic of early catheter dislodgement. However, the ability to detect thoracic complications using CXR is limited, and it requires radiation exposure. Thoracic ultrasound (TUS) is an easy and highly appropriate technique to detect thoracic pathologies, although its use in cardiac stimulation is not yet widespread.

Purpose

To compare the diagnostic power of the CXR and TUS alone and in association with electrical parameters testing in detecting early complications after CIED implantation.

Methods

397 patients who underwent CIED implantation or upgrade at four large arrhythmia referral centres were prospectively enrolled from November 1, 2021, to September 30, 2022. Following surgery, all patients underwent CXR and TUS at the bedside and the electrical parameters were tested with the device programmer. The primary endpoint was the rate of mechanical complications, defined as a composite or pneumothorax, haemothorax and pericardial effusion. The secondary endpoint was the composite of mechanical complications + electrical complications (lead macro- and micro-dislodgments).

Results

Total mechanical complications were 21 (5.3%), of which the most common were pneumothorax (3.3%) and pericardial effusion (2%). No cases of hemothorax were observed. The diagnosis of mechanical complication was made by TUS alone in 18 cases (86%), by CXR alone in 2 (9.5%) and in 1 case (4.8%) by both. TUS demonstrated a diagnostic sensitivity for mechanical complications of 90% and for total complications of 87% (associated with electrical control) compared to CXR which had a sensitivity of 20% and 57% respectively. Both methods did not differ in terms of specificity (100%).

Conclusions

In our experience, TUS has a diagnostic power superior to CXR to detect early mechanical complications. Our results suggest TUS may be used as the primary technique in association with standard electrical control to search for postoperative complications after CIED implantation.
Mutual effect modification between insulin-resistance and endothelial dysfunction in predicting incident heart failure in hypertensives
Authors: Toscani A F , Maio R , Sciacqua A , Gigliotti S , Fabiani G , Capomolla A , Perticone F , Perticone M
Published: November 2023

Both type-2 diabetes mellitus and endothelial dysfunction are associated with heart failure (HF); in addition, a strong interplay between endothelial dysfunction and insulin-resistance status that precedes of many years the clinical appearance of type-2 diabetes mellitus, has been well-demonstrated. Thus, the aim of this study was to investigate whether endothelial dysfunction and insulin-resistance are independent predictors of incident HF and if exists a possible interaction between them.

For this study we selected 705 white never-treated hypertensive outpatients free from HF, type-2 diabetes mellitus, chronic kidney disease, previous cardiovascular events and other chronic diseases potentially impacting on HF development. Endothelium-dependent vasodilation was investigated by intra-arterial infusion of acetylcholine, and laboratory determinations were obtained by standard procedures. Insulin-resistance was evaluated by the homeostasis model assessment (HOMA). During the follow-up [median 117 months (range 31–211)], there were 223 new cases of HF (3.3 events/100 patient-years). Stratifying the study population in progressors and non-progressors, we observed that progressors were older and had a higher prevalence of females, baseline glucose, insulin, HOMA, creatinine, and hs-CRP mean values, while estimated glomerular filtration rate and endothelium-dependent vasodilation were lower. In the multiple Cox regression analysis, serum hs-CRP (HR=1.362,(95% CI=1.208-1.536), HOMA (HR=1.293, 95% CI=1.142-1.465), maximal ACh-stimulated FBF (100% of increase, HR=0.807,(95% CI=0.697-0.934) and e-GFR (10 ml/min/1.73m2 increase, HR=0.552, 95% CI=0.483-0.603) maintained an independent association with incident HF. The subsequent analysis demonstrated that HOMA and endothelial dysfunction interact between them in a competitive manner (HR = 6.548, 95% CI = 4.034-10.629), showing also a mutual effect modification. These interaction analyses revealed that, in crude and adjusted models, HOMA significantly modified the effect of acetylcholine-stimulated FBF on incident HF and, given the mutualistic nature of the effect modification, also acetylcholine-stimulated FBF significantly modified the effect of HOMA on HF development.

Our findings demonstrate that both endothelial dysfunction and HOMA are independent and strong predictors of incident HF in hypertensives; we also demonstrated that these two risk factors interact between them with a competitive mechanism.Figure 1Figure 2
Longitudinal modeling of cardiac function to identify trajectories with differential risk of heart failure
Authors: Reimer Jensen A , Ross J C , Arthur V , Hall M E , Matsushita K , Lutsey P L , Biering-Soerensen T , Shah A M
Published: November 2023

Background

Impairments in left ventricular (LV) systolic and diastolic function are common precursors of clinical heart failure (HF) and underlie HF risk. Little data exist regarding trajectories of cardiac function in mid- to late-life, when HF risk is greatest, and the extent to which such trajectories may differentially relate to risk of HF with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF).

Purpose

To (1) identify multidimensional trajectories of cardiac function from mid- to late-life using serial echocardiographic data, (2) apply the resulting models to predict trajectory membership in a separate sample, and (3) determine associations between assigned trajectory and incident HFpEF and HFrEF.

Methods

We used a Bayesian nonparametric trajectory approach to jointly model longitudinal measures of LV ejection fraction (LVEF) and E/A ratio among 747 participants in two longitudinal cohort studies (the Atherosclerosis Risk in Communities [ARIC] study and Jackson Heart Study [JHS]) who underwent ≥2 echocardiograms in 2000-04 (mean age 65±5 years), 2011-2013 (age 75±5 years), and 2018-19 (age 81±5 years).

Using the trajectories inferred from this modeling, we applied Bayes theorem to assign 4,419 ARIC-only participants to their most likely trajectory using single time-point measures of LVEF and E/A ratio acquired in 2011-2013 (age 75±5 years). These assignments were treated as a categorical variable in subsequent analysis. In ARIC-only participants, we used Cox proportional hazards models adjusted for age, sex, obesity, hypertension, diabetes, chronic kidney disease, and coronary heart disease to assess the relationship between assigned trajectory and incident HF.

Results

In the discovery set (n=747), we identified six trajectories of cardiac function based jointly on longitudinal changes in LVEF and E/A ratio (Figure 1). The pink (prevalence 50%) and light green (17%) trajectories showed increasing LVEF and decreasing E/A ratio with increasing age, while the red trajectory (22%) demonstrated a lack of increase in LVEF. The dark green trajectory (4%) demonstrated progressive LVEF decline, the orange trajectory (2%) steep LVEF decline and rise in E/A ratio, and the blue trajectory (4%) rising E/A ratio despite increasing in LVEF. Analysis of the ARIC-only participants (n=4,419) showed that trajectory membership was differentially associated with risk of incident HFpEF and HFrEF (Figure 2). Compared to the pink trajectory, membership in the orange trajectory was associated with incident HFpEF and HFrEF, the red and the dark green trajectory associated with HFrEF alone, and the blue trajectory with HFpEF alone.

Conclusion(s)

These results demonstrate the feasibility of identifying trajectories of cardiac function with multidimensional longitudinal data and may have implications for HF risk prediction.
Comparing indices of systemic inflammation and cardiac phenotype between hypertensive and non-hypertensive hypertrophic cardiomyopathy
Authors: Zach D , Schwegel N , Hoeller V , Kolesnik E , Gollmer J , Reiter U , Seggewiss H , Batzner A , Zirlik A , Rainer P , Ablasser K , Verheyen N
Published: November 2023

Background

Arterial hypertension (HTN) is associated with excess mortality in hypertrophic cardiomyopathy (HCM), but underlying mechanisms are largely elusive.

Purpose

The purpose of this study was to investigate the association between HTN and indices of systemic inflammation and cardiac function in a HCM cohort.

Methods

This was a single-center cross-sectional case-control study comparing 30 adult HCM patients with HTN (HTN+) and 30 sex- and age-matched HCM patients without HTN (HTN-). Echocardiographic measures were assessed using post-processing analyses by a blinded investigator.

Results

Mean age of the total sample was 54.6±10.1 years, 30% were women. Mean end-diastolic interventricular septum (IVSd) thickness was 2.1±0.4 cm, 18% previously underwent septal reduction therapy, and 47% had left ventricular outflow tract obstruction. HTN+ portrayed more severe IVSd thickness than HTN- [2.2±0.3 cm vs. 2.0±0.4 cm; p = 0.017], while echocardiographic measures of systolic and diastolic function, including speckle-tracking derived parameters, did not differ between groups. Moreover, levels of N-terminal pro B-type natriuretic peptide were balanced between groups. Compared with HTN-, HTN+ patients exhibited higher circulating plasma levels of interleukin-6 [2.8 pg/ml (2.0, 5.4) vs. 2.1 pg/ml (1.5, 3.4); p = 0.008] and high-sensitivity C-reactive protein [2.6 mg/l (1.4, 6.5) vs. 1.1 mg/l (0.9, 2.4); p = 0.004]

Conclusion

This study demonstrates that HTN is associated with low-grade systemic inflammation among HCM patients. Moreover, this analysis indicates that HTN+ do not exhibit an altered systolic and diastolic function compared to HTN-. Accordingly, the adverse impact of HTN in HCM patients may be a consequence of systemic effects rather than alterations of cardiac function.TableFigure
GFPT1 deficiency is a novel cause of a dilated cardiomyopathy and is required for myocardial adaptation to chronic pressure-overload stress-induced heart failure
Authors: Nabeebaccus A A , Verma S , Catibog N , Thompson R , Shah A M
Published: November 2023

Background

GFPT1 is the rate-limiting enzyme of a pathway called the hexosamine biosynthesis pathway (HBP) that turns fructose 6-phosphate derived from glucose into another monosaccharide called N-acetylglucosamine (GlcNAc). GlcNAc is an important substrate for modifying diverse cellular proteins on their serine and threonine residues termed O-GlcNAcylation often competing with phosphorylation and altering their activity or stability (Bond & Hanover; 2015). Increased GFPT1 activity is known to stimulate the cellular integrated stress response improving protein quality control and cell survival (Denzel et al 2014). In the heart, GFPT1 expression and O-GlcNAcylation increases in the early stages of chronic cardiac stress but the physiological role of GFPT1 in regulating heart function including its role during chronic stress remains unclear. Identifying molecular pathways that promote adaptive cardiac remodelling is a promising approach to discover novel therapies for heart failure.

Methods

Cardiomyocyte-specific GFPT1 knockout mice were generated to study the effects of GFPT1 deletion in hearts. Heart function was examined by echocardiography. HBP activity was quantified using Western blotting of O-GlcNAc-modified proteins. Abdominal aortic banding (AAB) was used to induce chronic pressure-overload heart failure.

Results

Homozygous GFPT1 KO mice spontaneously develop a dilated cardiomyopathy (DCM) with a 30% mortality rate (ejection fraction 32% compared with 62% for floxed controls and end diastolic volume 125 microL versus 60 microL; n=5-6 per group; p <0.05). Hearts showed reduced levels of total protein O-GlcNAcylation suggesting impaired hexosamine biosynthesis pathway activity. Heart function could be rescued by supplementing their diets with oral glucosamine bypassing GFPT1 to provide metabolites required for hexosamine biosynthesis and normalising O-GlcNAcylation (ejection fraction improved to 40% in KO with supplementation versus KO without; n=4-6 per group; p <0.05). Heterozygous KO mice do not develop a DCM but when subject to pressure-overload cardiac stress, develop worse heart failure with a 50% mortality rate over 9 weeks of pressure-overload (ejection fraction 43% in het KO versus 53% in floxed control; n= 3-6 per group; p = 0.0025).

Conclusion

Deficiency of GFPT1 is a novel cause of a spontaneous dilated cardiomyopathy. GFPT1 is required for physiological growth of the heart that may in part involve the O-GlcNAcylation of proteins. Partial GFPT1 deficiency is associated with adverse cardiac remodelling following pressure-overload stress. Increasing GFPT1 activity may be a key therapeutic target in developing novel heart failure treatments.
Intravenous iron administration in patients with heart failure alters endothelial homeostasis with early release of endothelial microvesicles and subsequent mobilization of endothelial progenitor cell
Authors: Mause S , Berger M , Lim H Y , Vogt F , Marx N , Brandenburg V , Stoehr R
Published: November 2023

Background

Intravenous iron supplementation is an established therapy for patients with heart failure (HF) with reduced ejection fraction (LV-EF<50%) and iron deficiency, resulting in reduced risk of HF hospitalization. Since iron may induce oxidative stress, inflammation and apoptosis in endothelial cells, concerns persist regarding potential adverse vascular effects of iron therapy. To evaluate endothelial health following ferric carboxymaltose (FCM) administration, we assessed the profile of circulating endothelial microvesicles (EMVs) and endothelial progenitor cells (EPCs) in a cohort of 23 HF patients using flow cytometry.

Results

Compared to healthy control subjects (HC; n=15), baseline levels of CD31+/CD41- EMVs were significantly higher and EMVs featured a more apoptotic phenotype in HF patients. Following administration of 1000mg FCM, EMV levels showed an early but transient increase (Fig. 1) and displayed an altered phenotype profile with dominant augmentation of EMVs expressing the inducible markers CD62E and CD54, indicating endothelial activation and injury. Levels of circulating vasoregenerative CD45lowCD34+KDR+ EPCs were lower in HF patients and FCM application resulted in an early decrease of EPCs followed by substantial mobilization into the circulation after one week (Fig. 2). Levels of EMVs and EPCs returned to baseline values within two and four weeks, respectively. Compared to HF patients with preserved renal function, the EMV/EPC ratio was higher in HF patients whereas EPC mobilization was diminished with additional chronic kidney disease, suggesting impaired vascular repair capacity. In vitro experiments with cultured endothelial cells revealed that FCM at therapeutic concentrations dose-dependently promotes endothelial apoptosis, increases expression of adhesion molecules and CXCL12, and triggers the generation of EMVs.

Conclusion

Intravenous iron supplementation with FCM in HF patients provokes a biphasic response with early release of CD62E+ and CD54+ enriched EMVs and subsequent mobilization of EPCs, suggesting temporary aggravation of endothelial dysfunction upon FCM supplementation and consecutive engagement of a vascular defense program.
The central role of FAP dysregulation and cardiac fibroblast activation in heart failure patients
Authors: Rosello-Lleti E , Delgado Arija M , Genoves Martinez P , Perez Carrillo L , Gimenez Escamilla I , Gonzalez I , Portoles M , Tarazon E
Published: November 2023

Background

Excessive cardiac fibrosis is an important factor in the progression of heart failure (HF). Fibroblast activation protein (FAP) is a type-II transmembrane serine protease expressed almost exclusively to pathological conditions, being robustly expressed by activated fibroblasts of scarring tissue. Previously different studies have reported alterations of fibrillar and non-fibrillar collagen expression in heart failure linked to fibrosis. However, despite its relevance, the role of FAP in cardiac fibrosis is not fully elucidated.

Purpose

We hypothesized that FAP expression level was altered in heart tissue of heart failure (HF) patients. Furthermore, given the central role of FAP in fibroblast activation, we also studied the expression levels of profibrotic genes and microRNAs associated with fibrosis process, and the relationships between FAP and these altered molecules.

Methods

We analysed transcriptome-level differences in genes involved in fibrosis between HF (n=26) and controls (n=10) in human hearts by RNA-sequencing, and a total of 50 samples were also analysed (HF, n=42; and controls, n=8) by ncRNA sequencing to study the expressions of microRNAs.

Results

We found an overexpression of FAP gene (FC=1.98, p<0.05), and observed that the expression of other molecules, whose activity is also relevant in the activation of fibroblasts, were overexpressed, such as POSTN (FC=3.05, p<0.05), THY1 (FC=4.33, p<0.001) and VIM (FC=1.33, p<0.05). On the other hand, we found several fibrosis-associated genes whose expression was also altered in HF patients. Specifically, THBS4 (FC=3.03, p<0.001), AEBP1 (FC=1.9, p<0.01), ELN (FC=2.1, p<0.01), COL1A1 (FC=1.72, p<0.01), COL1A2 (FC=1.97, p<0.01), COL3A1 (FC=2.1, p<0.01), and MFAP5 (FC=2.34, p<0.001). Interestingly, most of these overexpressed genes showed a correlation (p<0.05) with FAP mRNA expression. We highlight the positive correlations between COL1A2 (r=0.643, p<0.001) and COL3A1 (r=0.651, p<0.001) with FAP expression. Furthermore, we observed dysregulation in several microRNAs related with an antifibrotic or profibrotic function. Specifically, we showed underexpression of a microRNA with antifibrotic function, miR-29c-3p (FC=-1.2, p<0.01), which has COL1A1, COL1A2, COL3A1 as target genes.

Conclusions

In this study, we showed significant alterations in FAP and other specific genes involved in fibroblast activation in HF. We also identified correlations between FAP and key fibrosis markers, giving FAP a central role in cardiac fibrosis process. Fibroblast activation molecules could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases.
Alterations of mitochondrial bioenergetics in human hearts with ischemic and dilated cardiomyopathy
Authors: Tarazon E , Perez Carrillo L , Benedicto C , Gimenez Escamilla I , Delgado Arija M , Gonzalez I , Portoles M , Rosello-Lleti E
Published: November 2023

Background

Heart failure (HF) is a complex multifactorial syndrome characterized by mechanical dysfunction of the myocardium and the inability of the heart to provide adequate blood supply to meet the body's metabolic needs. Defects in mechanisms such as bioenergetics are important pathogenic factors in myocardial dysfunction, since the heart needs a continuous energy supply, which is fulfilled by ATP synthesis through mitochondrial oxidative phosphorylation, a process that takes place in the inner membrane of the mitochondria, whose structure is also affected during the development of HF.

Purpose

The aim of this study was to analyze the alterations in the expression level of mRNAs and proteins involved in mitochondrial function, focusing on bioenergetics and formation of cristae formation in patients with ischemic and dilated cardiomyopathy.

Methods

Transcriptome-level differences between HF and controls (CNT) were investigated in 36 heart samples with RNA-sequencing technology (mRNA-seq; ICM, n=13; DCM, n=13; CNT, n=10). In addition, ATP5I and ATPIF1 protein levels were determined in 30 heart samples (ICM, n=24; CNT, n=6) by Western Blot assay. The miRNAs implicated in the mRNA posttranscriptional regulation were studied through non-coding RNA-seq (ICM, n=22; DCM, n=20; CNT, n=8).

Results

11 mitochondria genes were detected as altered in bioenergetics and mitochondrial cristae formation in HF. Specifically, we found an overexpression of ATP5I (ICM, FC=2.04, p<0.001) and ATPIF1 (ICM, FC=1.81, p<0.01) mRNA levels that correlated with both diastolic (r=-0.577 and r=-0.562, respectively; p<0.01) and systolic diameter (r=-0.574 and r=-0.563, respectively; p<0.01) and with ejection fraction (r=0.442 and r=0.410, respectively; p<0.05). The analysis of ATP5I and ATPIF1 protein expression showed that only ATPIF1 presented differences in expression when comparing patients with ischemic HF with the control group (FC=, 1.75, p<0.01). Furthermore, we observed alterations in ATP5I target miRNA, miR-483-3p (FC=1.37, p<0.01), which can induce dysregulation in its protein level.

Conclusions

The alterations of mitochondrial bioenergetics and cristae formation related molecules could reflect damage of the cardiac mitochondria function in HF, interfering in the critical activities of the cardiomyocyte and showing a significant relationship with the ventricular function.
DNA methylation profiling of circulating CD4+ T cells and network analysis reveal that JUNB, SETD7, and MEF2D genes predict patients with heart failure preserved vs. reduced ejection fraction
Authors: Benincasa G , Pepin M E , Cacciatore F , Russo V , D'alto M , Argiento P , Romeo E , Chiappetti R , Laezza N , Coscioni E , Golino P , Napoli C
Published: November 2023

Background

Heart failure (HF) with preserved ejection fraction (HFpEF) represents about 50% of new HF diagnosis but still lacks specific biomarkers and effective therapy. Epigenetic-sensitive changes accumulated over time, mainly guided by DNA methylation and demethylation, can lead to chromatin remodelling and affect transcriptional molecular networks underlying microvascular inflammation, oxidative stress, and maladaptive cardiac remodelling which predispose synergistically to HFpEF.

Purpose

We hypothesize that circulating genome-wide DNA methylation profiles may identify novel biomarkers for discriminating HFpEF vs. HF with reduced EF (HFrEF) and provide insight into the underlying pathophysiology of disease.

Methods

A total of n=47 subjects were enrolled including patients with HFpEF (n=22) and HFrEF (n=13) as well as healthy subjects (n=12) serving as control group (CON). Starting from pheripheral blood biospecimens, we isolated CD4+ T cells and extracted genomic DNA for genome-wide methylome analysis and total RNA for experimental validation set.

Results

The reduced representation bisulfite sequencing (RRBS) revealed that patients with HFpEF had unique variations in DNA methylation profiles as compared to HFrEF and CON groups and reflected distinct pathogenic mechanisms. Using the list of differentially methylated CpG sites in HFpEF, we performed a complex network analysis to indentify the "HFpEF interactome" (Fig.1 A-B). Then, using the DisGeNET database we extracted n=12 candidate genes which were already associated with diastolic dysfunction, cardiac hypertrophy, cardiac fibrosis, inflammation, obesity, and hypertension, as key pathophenotypes of HFpEF (Fig.1 C). The hub genes included the ACTB, VAV2, JUNB, HOOK2, SETD7, PNKP, ASAP1, PAICS, DNM1L, HIF1AN, MEF2D, and NRG1. Validation experiment set by qRT-PCR revealed that elevated mRNA levels of the JUNB, SETD7, and MEF2D hypermethylated genes significantly discriminated HFpEF patients vs. CON (p<0.01, p<0.01, p<0.001, respectively) and vs. HFrEF patients (p<0.05, p<0.01, p<0.001, respectively) (Fig. 2A). Receiver operating characteristic (ROC) curve showed that network-oriented JUNB (AUC: 1, p<0.001), SETD7 (AUC: 0.97, p<0.01), and MEF2D (AUC: 1, p<0.001) genes have a high diagnostic accuracy in discriminating HFpEF vs. CON as well as HFpEF vs. HFrEF (AUC: 1, p<0.01, AUC: 0.97, p<0.01, AUC: 1, p<0.001, respectively) (Fig. 2B).

Conclusions

Circulating CD4+ T cell-derived hypermethylation of JUNB, SETD7, and MEF2D may reveal novel molecular drivers of HFpEF and suggest possible biomarkers to optimize patient phenotyping.
Hypoxemia in patients with heart failure and preserved ejection fraction
Authors: Omar M , Omote K , Sorimachi H , Popovic D , Kanwar A , Alogna A , Reddy Y N , Lim K G , Shah S , Borlaug B B
Published: November 2023

Background

Pulmonary abnormalities are common in patients with prevalent heart failure (HF). Arterial hypoxemia is considered rare in HF, but this has not been rigorously evaluated in patients with HF and preserved EF (HFpEF).

Methods

Results

Patients with HFpEF (n=539) and no clinically-relevant lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxemia was defined by oxyhaeemoglobin saturation <94%. As compared to those without hypoxemia (n=403), patients with hypoxemia (n=136, 25%) were slightly older, heavier, and had higher NT-proBNP levels. They had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar-arterial O2 difference compared to those without hypoxemia. These differences were replicated in a sensitivity analysis where patients with any spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and capillary pressures were related to lower PaO2. The presence of exertional hypoxemia was associated with two-fold increased risk for death over 2.8 (IQR 0.7-5.5) years of follow up, (Adjusted:HR 2.00 (95%CI: 1.01−3.96), p=0.046).

Conclusion

One quarter of HFpEF patients displayed arterial desaturation during exercise. Patients with hypoxemia display more severely abnormal hemodynamics and increased mortality. Further study is required to better understand the mechanisms in patients with HFpEF.Hemodynamic changes at rest/exerciseRisk of death in HFpEF with hypoxemia
Contribution of reduced skeletal muscle perfusion reserve to exercise intolerance in HFpEF
Authors: Serafin A , Jasic-Szpak E , Przewlocka-Kosmala M , Ponikowski P , Kosmala W
Published: November 2023

Methods

Transthoracic echocardiography and skeletal muscle microvascular perfusion by contrast-enhanced ultrasound were performed at rest and immediately post exercise test in 77 HFpEF patients in NYHA class II and III, and in 20 age- and sex-matched individuals with a similar profile of comorbidities, but normal exercise tolerance. Exercise reserve of cardiac function parameters and skeletal muscle perfusion was calculated by subtracting resting value from exercise value.

Results

HFpEF patients demonstrated impairment of left ventricular (LV) and left atrial (LA) function reserve as reflected by lower exercise-induced increases in LV global longitudinal strain, LA reservoir strain, cardiac output and e’ mitral annular velocity, and higher increase in E/e’ ratio (Table). Similarly, skeletal muscle microvascular blood flow (MBF) reserve was lower in HFpEF patients than in the referents. There was no significant difference between the study group and the control group in resting MBF. MBF reserve was significantly associated with exercise capacity (r = 0.34; p = 0.004) and cardiac output reserve (r = 0.24; p = 0.04). In multivariable analysis including clinical and demographic variables, LV and LA components of cardiac functional reserve (LV global longitudinal strain, LA reservoir strain, cardiac output, e’ and E/e’) and MBF reserve, change from rest to exercise in MBF (beta 0.32, SE 0.10, p = 0.003) was in addition to patient age, sex and LV strain reserve among the independent correlates of exercise capacity.

Conclusions

Skeletal muscle perfusion reserve is impaired in HFpEF, and is associated with reduced exercise capacity independent of clinical, demographic and "central" cardiac factors. Accordingly, our results provide a rationale for extending the spectrum of pathophysiological milieu to be considered when planning patient management strategies in HFpEF over skeletal muscle-associated contributors to exercise intolerance.