bluuebunny/crossref_metadata_2025 huggingface dataset:
Driving restrictions following defibrillator implantation significantly affect recipients' ability to maintain employment
Authors: Bjerre J , Hansen M H , Schou M , Rasmussen T B , Ruwald A C
Published: October 2022

Background

Following defibrillator implantation or in case of ICD therapy, ICD recipients are subject to temporary driving restrictions for private driving. Moreover, the current European recommendations permanently ban professional driving which can significantly alter the recipients' daily life and ability to maintain employment.

Aim and methods

To investigate Danish ICD recipients' perspective on driving restrictions following ICD implantation we distributed a questionnaire to all living ICD patients with a first-time implantation between 2013 and 2016 (n=3913). We linked questionnaire responses with relevant nationwide Danish registers.

Results

Among the 2741 ICD recipients who responded to the questionnaire (response rate 71%, 47% primary prevention, 83% male, median age 67 years), 2513 (92%) held a valid private driver's license at time of implantation and 175 (7%) were actively using a professional driver's license. Almost all (n=2344, 94%) had resumed driving following device implantation. Among those with a driving ban of at least 1 month following either ICD implantation or ICD therapy (n=911), 26% stated the restrictions had severely impeded their daily life, significantly more in the professional drivers group compared with the private drivers (32% vs 24%, p=0.01). Including only patients working prior to implantation (n=465), 27% stated they were very limited and 20% somewhat limited in maintaining employment following implantation due to the driving restrictions. Likewise, 23% were very limited and 19% somewhat limited in getting to their job. Among the active professional drivers (n=175), 58 (33%) stated they had lost their job as a direct consequence of the post-implantation driving restrictions.

Conclusion

Every fourth Danish ICD recipient is severely limited in their daily life due to the driving restrictions. Both professional and private drivers are significantly affected with regards to maintaining employment following implantation, which should be a key focus in rehabilitation programs.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The Danish Heart Foundation and Arvid Nilssons Fond
Strategic management to optimize response to cardiac resynchronization therapy registry
Authors: Garcia Bolao I , Gras D , D'Onofrio A , Mark G , Nair D , Lellouche N , Novak M , Lo R , Chew E , Wright D , Kaplan A , Veraghtert S , Hu Y , Yong P , Gardner R S
Published: October 2022

Background

Cardiac resynchronization therapy (CRT) is guideline-recommended for the treatment of symptomatic heart failure (HF) in patients (pts) with reduced LVEF and prolonged QRS. Clinical trials report Clinical Composite Score (CCS) response rates from 60 to 75%. However, patients with common comorbidities, such as atrial fibrillation, are often under-represented in clinical trials. The Strategic MAnagement to optimize response to cardiac Resynchronization Therapy (SMART) Registry (NCT03075215) was designed to examine outcomes in CRT patients in the real world.

Methods

The SMART Registry was a global, multicenter, prospective, clinical registry that enrolled subjects undergoing a de novo CRT-D implant or upgrade from pacemaker to CRT-D using a quadripolar LV lead. CCS was assessed at 12 months post-implant.

Results

For study design and CCS outcomes see Figure 1. CCS at 12 months showed that 58.8% of pts improved and 20.1% stabilized. Of the 21.1% of pts that worsened, 8.4% were due to death, 7.8% non-fatal heart failure event, and 5% worsening of NYHA or patient global assessment. Notably, this registry had a high prevalence of pts with NYHA I/II (51%), Non-LBBB (50%), AF (37%), diabetes (35%), and bradycardia (31%) at baseline. Age (>65), diabetes, ischemia, non-LBBB, atrial fibrillation (AF) and renal dysfunction correlated with worsened CCS outcomes. NYHA III/IV patients had significantly higher HF hospitalization (HFH) rates than NYHA I/II (P-value <0.001) (Figure 2a) and patients with AF had higher HFH rates than those without (P-value <0.001) (Figure 2b). Similar effects of NYHA score and AF were seen on mortality. The use of ACE/ARB, or ARNI, and MRA correlated with better outcomes, whereas diuretics and anticoagulants correlated with poorer outcomes.

Conclusions

In this large registry, clinical outcomes across important sub-populations are in line with expectations, with older age, ischemia, renal dysfunction, AF, non-LBBB, and diabetes associated with a lower likelihood of response to CRT. By including these patients, this study provides a clearer picture of the effectiveness of CRT in the real world. Future studies should examine optimization approaches to facilitate CRT effectiveness in these under studied patient populations.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): This registry was funded by Boston Scientific (BSC)
A systematic review and meta-analysis of upgrade to biventricular or conduction system pacing approaches
Authors: Kaza N , Htun V , Miyazawa A , Simader F , Porter B , Howard J P , Arnold A , Francis D P , Whinnett Z I , Shun-Shin M J , Keene D
Published: October 2022

Introduction

Chronic RV pacing has been recognised as being harmful to cardiac function. Patients undergoing a de novo pacemaker implant with even mild LV impairment are recommended to instead receive a physiological pacing strategy (biventricular or conduction system pacing [CSP]). No corresponding guideline recommendation exists for patients who already have a pacemaker.

Methods

We undertook a random-effects meta-analysis of all RCTs and observational studies covering device upgrade to biventricular pacing or conduction system pacing.

Results

6 RCTs assessing effect of upgrade to BiV pacing randomising 161 patients were eligible for analysis. Eligible observational studies included 46 of BiV upgrade and 7 of CSP upgrade totalling 2795 patients.

Mean LVEF improved by +8.3% from 34.4% in BiV upgrade RCTs (p=0.001) and +8.3% from 25.7% in BiV upgrade observational studies (p<0.001).

In observational studies of upgrade to CSP, LVEF increased by +10.1% from 38.4% (p=0.001) despite less severe LV impairment at baseline (p=0.004 vs mean EF in BiV RCTs and p<0.0001 vs mean EF in BiV observational studies).

LVESV decreased significantly by −25.4 ml, −23.7 ml, and −19.8 ml in BiV RCTs, BiV observational studies and CSP observational studies. Significant changes were also seen in NYHA class (decreased by −0.4, −0.8 and −1.0 respectively).

Minnesota Heart Failure Score (−6.9 points) and peak oxygen uptake (+1.1 ml/kg/min) increased significantly in RCTs of BiV upgrade. This was also seen in observational studies of BiV upgrade (−21.0 points and +2.63 ml/kg/min respectively).

Conclusions

RCTs and observational studies of upgrade to BiV pacing show significant physiological and symptomatic benefit. Observational studies of CSP upgrade show similar benefit with significant improvements in LVEF, LVESV and NYHA class in patients with an even milder degree of baseline LV impairment.

Funding Acknowledgement

Type of funding sources: None.
Cardiac implantable electronic device infections: prognostic value of the PADIT score and its cost-utility implications for antimicrobial envelope use in the United Kingdom
Authors: Mahtani K , Maclean E , Honarbakhsh S , Bhuva A , Finlay M , Creta A , Earley M J , Zemrak F , Moore P , Muthumala A , Sporton S , Schilling R J , Hunter R J , Monkhouse C , Chow A
Published: October 2022

Background

The incidence of cardiac implantable electronic device (CIED) infections is rising.

Purpose

We examined the factors associated with CIED infection, assessed the prognostic power of the PADIT risk score, and modelled the cost-utility of selective TYRX antimicrobial envelope use for preventing CIED infections.

Methods

Data were extracted from 2016 to 2019, and included all de novo implants, generator changes and lead interventions for transvenous CIEDs at a high-volume UK centre. CIED infection was defined as hospitalisation for device infection within 12 months of a procedure. Cost-utility analysis was informed by standardised tariffs, and quality adjusted life year (QALY) and efficacy data was extrapolated from analysis of the WRAP-IT trial.

Results

6,035 patients underwent 7,383 procedures; CIED infection occurred in 59 individuals (0.8%). In addition to the constituents of the PADIT score, lead extraction (HR 3.3 (1.9–6.1), p<0.0001), C-reactive protein >50mg/l (HR 3.0 (1.4–6.4), p=0.005), re-intervention within two years (HR 10.1 (5.6–17.9), p<0.0001), and procedure duration over two hours (HR 2.6 (1.6–4.1), p=0.001) were independent predictors of infection. Increased PADIT score was strongly associated with infection (AUC: 0.82, HR per point increase: 1.36 (1.27–1.47), p<0.0001). A cost-utility model assigning TYRX envelopes to patients with PADIT scores ≥6 predicted a reduction in infections (number needed to treat: 72) and a cost per QALY gained within the UK's (NICE) cost-effectiveness threshold (£25,107).

Conclusions

The PADIT score was a powerful predictor of CIED infections in a heterogeneous population,and may facilitate cost-effective TYRX envelope allocation in selected high-risk patients.

Funding Acknowledgement

Type of funding sources: None.
Influence of lead extraction on tricuspid valve function
Authors: Polewczyk A , Jachec W , Nowosielecka D , Tomaszewski A , Brzozowsk W , Szczesniak-Stanczyk D , Duda K , Kutarski A
Published: October 2022

Background

Transvenous lead extraction (TLE) is the main part of contemporaneous lead management strategy. Connecting tissue scar surrounding the lead and binding of it to heart structures creates risk venous or cardiac wall injury with severe bleeding or severe damage of tricuspid valve (TV)

Purpose

The aim of the study was to determine circumstances of appearance and risk factors of TV damages (TVD) and the influence of TVD on long term mortality

Methods

This post-hoc analysis used clinical data of 2693 patients who underwent transvenous lead extraction between 2007and 2021 in three high-volume center. Based on the transthoracic (TTE) and transesophageal echocardiography (TEE), the function of the tricuspid valve before and after TLE was compared, and the potential risk factors for TVD as well as the long-term survival of patients after TLE were assessed

Results

In most procedures (82.0%), TLE had no effect on TV function, in 9.5% different severity of tricuspid regurgitation (TR) was noted, significant deterioration occurred in 2.5% patients. The most important risk factors of TV damage were: young age of patient, long implant duration, multiple leads, abnormal heart lead route and procedure complexity. TVD was often seen in patients with normal left ventricular ejection fraction (LVEF >50% in 73,1% patients), strong adhesion of the lead with the heart structures (46,4%), and abnormal loop of the lead irritated TV (28,8%). The long-term mortality of patients with significant worsening of tricuspid valve function during TLE was comparable to that in patients without TVD (6,0% vs 14,4%; p=0,06).

Conclusions

Significant tricuspid valve dysfunction during TLE is relatively rare in an experienced center. The main echocardiographic predictors of significant TVD during TLE is the presence of intense connective tissue adhesions binding the lead to the heart structures related to long lead dwell tome. Significant TLE related TVD has no clear influence on long-term survival after lead extraction.

Funding Acknowledgement

Type of funding sources: None.
Transvenous lead extraction in pediatric patients. Is it the same procedure in children as in adults?
Authors: Kutarski A , Miszczak-Knecht M , Brzezinska M , Birbach M , Polewczyk A M , Jachec W , Tulecki L , Polewczyk A , Tomkow K , Stefanczyk P , Nowosielecka D , Bieganowska K
Published: October 2022

Background

Fibrous tissue encapsulating the lead and causing venous occlusion makes lead removal more difficult.

Purpose

This study sets out to define the differences in transvenous lead extraction (TLE) between pediatric and adult patients.

Methods

We report a retrospective review of prospectively collected data on lead extraction in 63 children aged ≤18 years and 2659 adults ≥40 years of age. The two groups were compared with respect to risk factors, procedure complexity, effectiveness, and complications.

Results

The predominant systems were VVI in children and DDD in the adult group. Lead dysfunction and infection were the main indications for extraction in children and adults respectively. Risk factors: the number of leads extracted in one patient, multiple lead extraction and ICD leads were significantly more common in adults. The mean implant duration before TLE was longer in children (p=0.03). Dwell time of the oldest lead per patient and dwell time of the oldest extracted lead did not differ significantly. The duration (p=0.006) and mean extraction time per lead (p<0.001) were longer in children. Technical difficulties during TLE were more common in the pediatric group (p<0.001). Similarly, additional tools were more frequently used in children (p<0.001). Major complications were more common, albeit not significantly, in children. Complete radiographic and complete procedural success were significantly lower in the children's group (p<0.001).

Conclusions

TLE in children was frequently more complex, time consuming and arduous, and had lower procedural success. Lead removal in children is a different procedure than in adults.

Funding Acknowledgement

Type of funding sources: None.
Exercise ventilation inefficiency and dynamic tricuspid regurgitation in heart failure
Authors: Mondellini G , Rusconi I , Giustiniani A , Torta D , Novello G , Bursi F , Guazzi M
Published: October 2022

Background

Exercise ventilation inefficiency, i.e. increase slope of the relationship of ventilation (VE) vs carbon dioxide (VCO2) slope is a key prognostic indicator in heart failure (HF). Many determinants have been identified primarily related to the left heart and impaired reflexogenic control of VE. In parallel, the severity of tricuspid regurgitation (TR) at rest is increasingly recognized as an important determinant of functional status and prognosis. It is undefined whether VE inefficiency may be related to the dynamic TR during exercise.

Purpose

We tested the role of dynamic TR and its correlates to exercise VE inefficiency by combining cardiopulmonary exercise test (CPET) with echocardiography.

Methods

We prospectively studied stable HF patients with both reduced and preserved left ventricular ejection fraction (LVEF). Patients with severe pulmonary disease and those who underwent valve replacement or cardiac surgery were excluded. Mitral and tricuspid regurgitation degree were adjudicated accordingly to ESC Guidelines criteria.

Demographics and clinical characteristics along with laboratory parameters including electrolytes, biomarkers of congestion (NT-proBNP), renal and liver function, were collected at the time of CPET. Dynamic TR was defined as worsening of TR grade from rest to stress detected by Doppler analysis. VE/VCO2 slope and peak oxygen consumption (pVO2) were compared between patients with dynamic TR (Group 1) vs non-dynamic TR (Group 2).

Results

Among 56 patients (66±13 years, 64% men, mean LVEF of 50±14%, 35% ischemic) 12% showed at least moderate mitral regurgitation and 16% patients had at least moderate TR at rest.

TR jet velocity at rest and at peak exercise were associated with VE/VCO2 slope (r=0.36 and r=0.3 respectively, p value <0.05, Figure 1). A dynamic TR pattern (Group 1) appeared in 28 (50%) patients. No differences in clinical characteristics, laboratory parameters, LV ejection fraction, prevalence and degree of mitral regurgitation at rest and at peak were found between the two groups.

Group 1 compared to Group 2 exhibited a lower right ventricular fractional area change at peak exercise (45% [41–50] vs 52% [44–62] p=0.03), lower median pVO2 (13.3 [10.4–17.5] vs 16.3 [13.9–21.8], respectively (p=0.04)) and higher VE/VCO2 slope (40.3 [33.1–44] vs 34.1 [29.2–38.8], p=0.01; Figure 2A and B).

Conclusions

Patients with a dynamic TR pattern during CPET imaging exhibit a worse VE efficiency that correlates with TR extent. These data prospect, for the first time, an interaction between dynamic TR and ventilatory pattern during exercise in HF whose relevance may translate in targeting the right heart appropriately.

Funding Acknowledgement

Type of funding sources: None.
Potential role of circulating exosome miRNAs in left ventricular remodeling of patients with ST-segment elevation myocardial infarction
Authors: Guan R , Zeng K , Liu Y Q , Liu C Y , Li J W , Zhang B , Jiang H Q , Gao M N , Zhang L U , Li J F , Zhang Q , Yang M O , Yang Y
Published: October 2022

Background

Left ventricular remodeling (LVR) in patients with ST-segment elevation myocardial infarction (STEMI) may lead to poor prognosis in which circulating exosome miRNAs play a critical role. The aim of the present study is to identify specific exosome miRNAs for LVR in patients with STEMI.

Method

Plasma exosome miRNAs were assessed in 20 patients (90% male, mean age of 66.95±1.65 years) 3–6 months after STEMI and 24 healthy individuals (83% male, mean age of 33.2±0.93 years) by using qPCR. Of the 20 patients, 8 had post-STEMI LVR according to echocardiographic evaluation, and the others did not. Clinical biochemical data including total cholesterol, HDL-C, LDL-C, LDH and NT-pro-BNP were collected from the patients with STEMI at same time as exosome miRNAs assessment. Specific exosome miRNAs for LVR were identified by using qPCR. Correlations between the dysregulated exosome miRNAs and the clinical biochemical parameters in patients with STEMI were analyzed using spearman correlation test.

Results

Five exosome miRNAs including hsa-miR-181a-3p (p<0.05, fold change = 0.59), let-7d-3p (p=0.01, fold change = 0.51), hsa-miR-224-5p (p<0.01, fold change = 0.11), hsa-miR-23a-3p (p<0.01, fold change = 1.42) and miR-874-3p (p<0.01, fold change = 0.48) were dysregulated in the post-STEMI patients comparing with the healthy individuals. Among them, the exosome miR-181a-3p (p=0.01, fold change = 0.09) and let-7d-3p (p=0.01, fold change = 0.16) were significantly lower expressed in patients with LVR compared to those without (Figure 1). There was no significant difference in expression of the other three miRNAs between patients with and without LVR. Exosome hsa-miR-874-3p positively associated with LDH (p<0.01, r=0.50) in all the patients with STEMI. In vitro cell culture confirmed that the miR-874-3p mimics upregulated expression of apoptosis related gene BMF (p<0.05, fold change = 1.7) in cardiomyocyte. Exosome hsa-miR-23a-3p and hsa-miR-224-5p positively correlated with both HDL-C (p<0.01, r=0.61; p=0.02, r=0.50) and LDL-C (p=0.02, r=0.50; p<0.05, r=0.52) in all patients with STEMI. No correlation between the dysregulated exosome miRNAs and cholesterol or NT-ProBNP was observed (Figure 2).

Conclusions

Circulating exosome miR-181a-3p and let-7d-3p might play a potential role in LVR in patients 3–6 months after STEMI. Exosome hsa-miR-874-3p might be associated with cardiomyocyte injury. Hsa-miR-23a-3p and hsa-miR-224-5p demonstrated an activity in regulation of lipid metabolism and biosynthesis in patients with STEMI.

Funding Acknowledgement

Type of funding sources: Public hospital(s). Main funding source(s): This work was supported by grants from the 3×3 Clinical Scientist Fund of Sun Yat-sen Memorial Hospital
The utility of splenic imaging parameters in cardiac magnetic resonance for the diagnosis of immunoglobulin light-chain amyloidosis
Authors: Lama N , Briasoulis A , Karavasilis E , Stamatelopoulos K , Kastritis E , Kelekis N
Published: October 2022

Objectives

Cardiac Magnetic Resonance (CMR) Imaging is a key test in the diagnosis of cardiac amyloidosis (CA). Extracardiac involvement is common in light chain (AL) amyloidosis and MRI findings may assist in its diagnosis. We sought to investigate the utility of splenic CMR parameters for the diagnosis of CA.

Methods

Thirty-four patients with AL amyloidosis and 32 patients with severe left ventricular hypertrophy in the setting of aortic stenosis (LVH-AS) who completed 3T cardiac MRI at the time of their diagnosis of AL or LVH-AS were assessed with T1, T2 (modified Look-Locker inversion recovery), Extracellular volume (ECV) mapping, and late gadolinium enhancement (LGE) imaging of the heart and spleen.

Results

Age, left ventricular mass index, wall thickness, ejection fraction, and splenic dimensions did not differ significantly between groups. All AL patients had cardiac involvement. T1 and T2 spleen mapping did not differ significantly between groups but AL patients had higher median ECV in the spleen than in LVH-AS (AL 46.9%, LVH-AS: 31%, p<0.001), and significantly lower short tau inversion recovery (STIR) ratio (AL: 1.7, LVH-AS: 2.7, p<0.001) both with very good diagnostic performance to diagnose AL. We identified 16 AL patients with spleen involvement and 16 without. Spleen ECV and “normalized” spleen ratio, defined as the ratio of spleen LGE to muscle values exhibited strong correlation and had excellent diagnostic performance to discriminate those with spleen involvement.

Conclusion

Our findings show that spleen CMR parameters can identify spleen involvement in AL patients and differentiate them from those without AL amyloidosis.

Funding Acknowledgement

Type of funding sources: None.
Usefulness of right ventricular longitudinal systolic strain to predict the progression to heart failure with preserved ejection fraction in hypertensive patients
Authors: Marketou M , Kampanieris E , Maragkoudakis S , Alifrangie A , Karagounis T , Zervakis S , Anastasiou I , Fragkiadakis K , Plevritaki A , Kassotakis S , Pateromichelakis T , Savva E , Kochiadakis G
Published: October 2022

Background

Accurate assessment of right ventricular (RV) systolic function is important, as it is an established prognostic marker in cardiac diseases. Speckle-tracking echocardiography is a sensitive tool for detection of subclinical left ventricular impairment in essential hypertension.

Purpose

Our aim was to investigate the usefulness of RV longitudinal peak systolic strain (LS) to predict the risk of future development of heart failure with preserved ejection fraction (HFpEF) in patients with essential hypertension

Methods

We performed a retrospective observational study that included 453 patients with essential hypertension (266 males, aged 63±18 years) and 175 normotensives (100 males, aged 66±15 years). Standard echocardiography was performed at the initial visit. 2D speckle tracking echocardiography with evaluation of longitudinal strain in each segment of the RV (basal: RVLS-B; mid: RVLS-M, apical: RVLS-A) and global RV free-wall strain (RVLS-G) were also performed. We studied the cases of new onset HFpEF in hypertensive patients.

Results

The median follow up was 85 months (22–122). RVLS-G, RVLS-B and RVLS-M were significantly impaired in hypertensives compared to controls (RVLS-G: −16.1±9.7 vs −20.0±5.1, RVLS-B: −11.7±3.7 vs −20.6±3.3, RVLS-M:-16.3±5.4 vs −20.7±4.9, p<0.05 for all). No significant difference was detected for the RVLS-A (−20.1±3.8 for hypertensives vs −21.31±6.5 for controls, p=NS). Thirty two hypertensive patients developed HFpEF (7%). A cut-off RVLS-G worse than −17% was significantly associated with new onset HFpEF (p<0.001) in those patients. A multivariate Cox regression analysis showed that RVLS-G had independent significant prognostic value for the risk of HFpEF (HR: 10.5, 95% confidence interval (CI): 7.3–25.4).

Conclusions

Essential hypertension leads to a decrease of RVLS which is strong predictor of a new onset HFpEF. Future studies are needed to assess the significance of these findings and the effect of treatment.

Funding Acknowledgement

Type of funding sources: None.
Impact of aortic regurgitation on long-term outcomes in heart failure with preserved ejection fraction
Authors: De Colle C , Paolisso P , Gallinoro E , Bertolone D T , Mileva N , Fabbricatore D , Valeriano C , Mancusi C , Collet C , Vanderheyden M , De Luca N , Van Camp G , Barbato E , Bartunek J , Penicka M
Published: October 2022

Background

Aortic Regurgitation (AR) may aggravate the clinical course in patients with heart failure and preserved ejection fraction (HFpEF) by increasing filling pressures and triggering LV remodelling.

Objective

To assess AR's prevalence and long-term prognostic implications in patients with HFpEF.

Methods

The study population consisted of 458 consecutive patients (age 77.5±9.2 y, 57.9% females) hospitalized with de novo or worsened HFpEF. Patients with more than moderate aortic and/or mitral valve disease were excluded. Data on cardiovascular death, HF re-hospitalization and their composite (MACE) were collected.

Results

Out of 309 (67.5%) patients with any AR, 156 (34.0%) and 153 (33.5%) had mild-AR and moderate-AR, respectively. The remaining 149 (32.5%) individuals had no-AR. Patients with versus without AR were significantly older with larger LV and LA volumes and a higher prevalence of diastolic dysfunction (all p<0.05). During a median follow-up of 33±25 months, a total of 114 patients (24.9%) died from cardiovascular causes, 126 patients (27.5%) were re-hospitalized for HF, while 272 (59.4%) had the composite endpoint (MACE). In multivariable Cox regression analysis, any AR emerged as an only independent predictor of MACE (HR=1.90, 95% CI 1.26–2.87, p=0.002). Mild-AR and Moderate AR increased the risk of MACE by 77% and 92%, respectively, compared to the No-AR (Figure).

Conclusions

In patients with HFpEF, mild-to-moderate AR is highly prevalent, and it seems to identify individuals with worse long-term outcomes. This suggests that even mild AR should be considered a high-risk prognostic marker in patients with HFpEF.

Funding Acknowledgement

Type of funding sources: None.
The therapeutic potential of relaxin for heart failure with preserved ejection fraction
Authors: Salama G , Palma J , Gabris-Weber B , MacMahon B , Kuhn B , Dschietzig T , Romero G
Published: October 2022

Background and significance

Heart Failure (HF) is the leading cause of cardiovascular deaths and ∼50% of HF patients have HF with preserved ejection Fraction (HFpEF). HFpEF patients typically have co-morbidities such as atrial fibrillation (AF), diabetes, lung edema and hypertension. The latter is a predictor of mortality and is targeted to prolong survival given the lack of a direct therapy for HFpEF. To address this unmet public health problem, we investigate the therapeutic potential of the insulin-like hormone Relaxin (RLX) in a rat model of HFpEF that recapitulates most aspects of clinical HFpEF.

Methods

ZSF1 diabetic rats were placed on a high fat diet (HFD for 11-weeks) and echocardiograms were used to track HFpEF development. At week 20, osmotic mini-pumps were implanted to release vehicle (Na-acetate) or RLX (400μg/kg/day, 2-weeks). Hearts were then perfused with a voltage-sensitive dye (RH237) and a Ca2+ indicator (Rhod-2/AM) to optically map action potentials and Ca2+ transients and analyze arrhythmia phenotype. Left ventricular (LV) tissue sections were used for immune-fluorescence (IF) imaging for changes in fibrosis (collagen 1), connexin 43, Wnt1 and β-catenin in LV myocytes. Blood draws were taken to measure changes in serum NT-pro-ANP, ET-1 and RLX.

Results

ZSF1 rats on a HFD developed HFpEF with E/e' (an echo marker of diastolic dysfunction) decreasing to −24.4 from −17.9 MV (n=12) and was reversed to −18.6 MV by RLX (n=6, p<0.0001). In HFpEF rats that received the vehicle (n=6), a premature stimulus (S1-S2= 40 ms) elicited: a) no arrhythmia b) non-sustained AF or c) sustained AF, with (1/3 of rats in each group). RLX blocked sustained supraventricular (n=0/12) and n=4/12 had non-sustained AF. RLX improved conduction velocity (CV), at short cycle lengths (150 ms) from 0.74 to 0.9 m/s (n=4/group). IF indicated that RLX increased Cx43 (26.8±0.03%, p<0.0001, n=6), and β-catenin (52.8±0.05%, p<0.0001) at intercalated disks. RLX reduced collagen deposition in HFpEF rats (25±0.04%, p<0.04, back to normal) and caused a marked increase of cytosolic Wnt1 (47.3±0.06%, p<0.0001). IF data are given as mean ± SEM.

Conclusions

The ZSF1 diabetic rat on a high-fat diet recapitulates most of the phenotypes associated with human HFpEF, including atrial arrhythmias, fibrosis, and lung edema. RLX treatment post-development of HFpEF reversed the pro-arrhythmic phenotype, increased conduction velocity particularly at fast heart rates, reversed fibrosis, reduced NT-pro-ANP and ET-1 in male rats. Most intriguing, RLX treatment activated Wnt1 and β-catenin indicating that the beneficial actions of RLX occur via genomic remodeling of the heart.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Relaxera Pharmazeutische Gesellschaft mbH & Co. KGStubenwald-Allee 8a, 64625 Bensheim, Germany & Uhlandstraße 4-5, 10623 Berlin, Germany
SGLT2 inhibitors in real-world patients with heart failure with preserved ejection fraction
Authors: Tarantini R , Vecchi A L , Matteo F , De Ponti R , Mortara A
Published: October 2022

Introduction

The diagnosis and management of heart failure with preserved ejection fraction (HFpEF) is challenging since ejection fraction is normal, clinical signs are often lacking and there are few therapeutic options. Two randomized clinical trials have tested SGLT2i for the treatment of HFpEF: DELIVER (pending results) and EMPEROR-PRESERVED; the findings of the latter trial show that empagliflozin, a sodium-glucose cotransporter inhibitor (SGLT2i) reduces the risk of cardiovascular death or hospitalization for HF in patients with HFpEF regardless the presence of diabetes. The results of this clinical trial have allowed European Medicine Agency (EMA) to extend the indication also to the patients with HFpEF, however the characteristics of the trial population don't often correspond to real-word HF population.

Aims

This study aims to investigate the eligibility of the EMPEROR-PRESERVED and DELIVER trial to a real-world heart failure population comparing the baseline characteristics of our patients to the recruited patients of clinical trials.

Material and methods

In this retrospective, observational study, 206 HF outpatients were enrolled from September 2018 to September 2019. The percentages of eligible patients according to EMPEROR PRESERVED and DELIVER inclusion criteria were analyzed, then we analyzed the difference between the characteristics of our HFpEF population and trials population.

Results

72 patients (35% of HF population) had heart failure with preserved ejection fraction. The EMPEROR-PRESERVED criteria and DELIVER trial were applied to these patients: 13 (18.1%) and 12 (16.7%) patients respectively fulfilled all enrolment criteria, whereas considering only EMA label criteria (EF >40% and eGFR >20 ml/min) 71 patients (98.6%) were eligible. The eligible patients according EMA criteria were significantly younger (67.3±14.3) than EMPEROR-PRESERVED population (72±9, p<0.001) and DELIVER population (72±10, p<0.001). The ejection fraction was significantly lower (50.2±5.8 vs 54±8.8; p<0.001) whereas eGFR was no significantly different (64.4±22.7 vs 60.6±19.8; p=0.17).

Conclusion

Only a small percentage of our heart failure with preserved ejection fraction population was eligible for SGLT2 inhibitors according trials criteria, whereas according to EMA label almost all patients are candidate to these drugs. Furthermore, these patients were younger than EMPEROR-PRESERVED and DELIVER population with lower EF. The difference of eligibility between trials and real population is related to inclusion criteria, in particular the trial patients had elevated NT-proBNP levels whereas in the real world this criterion isn't considered. There is a lack of data about real-world patients who are often different from trials population. National and international registries of HF population may resolve this issue.

Funding Acknowledgement

Type of funding sources: None.
Targeted discovery proteomics to identify clinical phenotypes in heart failure with preserved ejection fraction: a proteomics substudy of VITALITY-HFpEF
Authors: Defilippi C , Shah S J , Alemayehu W , Lam C S P , Butler J , Reimann S , O'Connor C M , Shah P , Westerhout C M , Armstrong P W
Published: October 2022

Background

Heart failure with preserved ejection fraction (HFpEF) is a heterogenous syndrome that may emerge from overlapping systemic processes associated with several medical co-morbidities, often within an inflammatory milieu. Identification of unique proteins associated with distinct phenotypes may yield insight into novel therapeutics.

Purpose

Determine if unique clusters of circulating proteins are associated with specific clinical characteristics in patients with HFpEF.

Methods

A targeted discovery proteomics approach with 358 unique proteins associated with cardiovascular disease and inflammation (Olink) was used at baseline in VITALITY-HFpEF among 789 participants with documented left ventricular EF ≥45% and recent decompensation (<6 mos). Proteins were clustered applying the weighted correlation network analysis (WCNA). The associations of the clinical characteristics and frailty and clusters were estimated with linear regression adjusted for age and eGFR. Frailty was characterized as normal, pre-frail, and frail using the Fried criteria. KCCQ was the primary and 6-minute walk distance (6MWD) the secondary endpoint of VITALITY-HFpEF.

Results

Four unique clusters were identified containing 24, 66, 197, and 81 proteins, respectively. Figure 1 shows the adjusted association of the 4 protein clusters, shown with their hub proteins, with the clinical characteristics. The color (red: positive, green: negative relationship) and intensity indicate the magnitude of the standardized difference (relative to the variation [i.e., T-value]); p-value shown in boxes. Cluster 3, with tumor necrosis factor receptor 1 as a hub protein that mediates apoptosis and inflammation, was associated with greater frailty and physical limitation along with shorter 6MWD. In contrast, cluster 4, with protein C as a hub protein that regulates anticoagulation and exerts a protective function on endothelial cells, is associated with less frailty and younger age, and more frequently male sex. Cluster 2 was associated with only younger age and cluster 1 with no clinical characteristics.

Conclusions

Proteomics appear to identify specific clinical phenotypes associated with HFpEF. Further exploration of this approach may provide insight into the diverse pathophysiology characterizing this disorder and a more targeted approach to therapy.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): VITALITY-HFpEF was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Bayer AG, Wuppertal, Germany.
Longitudinal characterization of clinically relevant haemodynamics in conscious Ossabaw pigs with HFpEF
Authors: Balitzki J , Bauersachs J , Thum T , Hueser J , Sandner P , Mondritzki T
Published: October 2022

Background

The constantly growing population of patients suffering from heart failure with preserved ejection fraction (HFpEF) is one of the largest unmet needs in cardiovascular medicine and translational animal models are important for identification and profiling of novel therapeutic approaches. Large animal models have shown that chronic cardiac pressure overload by aortic banding (AoB), when combined with a Western diet leads to left ventricular hypertrophy, diastolic dysfunction and metabolic syndrome in the Ossabaw pig, reflecting important features of human HFpEF characteristics. However, the requirement of invasive diagnostics under anaesthesia often limits the ability to monitor disease development continuously and compromises the results. Therefore, current disease models lack the temporal progression of clinically relevant HFpEF parameters like the left ventricular end diastolic pressure (LVEDP) and time constant of left ventricular relaxation (Tau).

Purpose

We aim to non-invasively investigate disease progression in Ossabaw pigs exhibiting a cardiometabolic HFpEF phenotype. The longitudinal assessment of LVEDP, Tau and heart rate (HR) should identify a time window to test novel therapeutics.

Methods

Naive, female Ossabaw pigs were instrumented with telemetric devices followed by AoB to induce chronic cardiac pressure overload. The wound healing and acclimatization period was followed by the start of a Western diet feeding regime to mimic components of the metabolic syndrome. Disease progression was characterized over 9 months by monthly telemetric recordings of LVEDP, Tau and HR and compared to a control (Ctrl) measurement in healthy animals. All animal studies followed the `Principles of laboratory animal care'.

Results

Compared to Ctrl the LVEDP is significantly elevated already 1 month (+8.90±0.4 mmHg) after AoB and further increases over time until 8 months (+18.80±0.4 mmHg) post AoB. Significant elevations in Tau are evident 4 months (+1.61±0.4 ms) post AoB. After 1 month the HR is significantly elevated (+13.90±0.7 bpm) but tends to normalize between 5 to 7 months post AoB. After AoB a maximal relative increase in LVEDP (+5.12±0.4 mmHg), Tau (+5.04±0.4 ms) and HR (+16.90±0.7 bpm) can be observed after 8 months.

Conclusions

We present long term haemodynamic changes over time in a translational in vivo model for HFpEF in Ossabaw pigs with high temporal resolution. For the first time elevations in key parameters allow to set a time point where HFpEF characteristics are evident, and a drug testing regime could be started. The opportunity to non-invasively and longitudinally follow on LVEDP, Tau and HR will be a clear benefit in the development of novel treatment options for HFpEF.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Bayer AG, Wuppertal
Value of the HFA-PEFF and H2FPEF scores in patients with heart failure and preserved ejection fraction caused by cardiac amyloidosis
Authors: Tomasoni D , Aimo A , Merlo M , Nardi M , Adamo M , Cani D , Lombardi C M , Pancaldi E , Panichella G , Porcari A , Vergaro G , Sinagra G , Rapezzi C , Emdin M , Metra M
Published: October 2022

Aims

The HFA-PEFF and H2FPEF scores have been developed to diagnose heart failure with preserved ejection fraction (HFpEF), and hold prognostic value. Their use in patients with HFpEF caused by cardiac amyloidosis (CA) has never been investigated.

Methods and results

We evaluated the diagnostic and prognostic value of the HFA-PEFF and H2FPEF scores in 304 patients from 3 cohorts with HFpEF caused by transthyretin (ATTR)-CA (n=160, 53%) or immunoglobulin light-chain (AL)-CA (n=144, 47%). A diagnosis of HFpEF was more likely using the HFA-PEFF score with 2 (1%), 71 (23%), and 231 (76%) patients ranked as having a low (0–1), intermediate (2–4) or high (5–6) probability of HFpEF, respectively. Conversely, 36 (12%), 179 (59%) and 89 (29%) of patients ranked as having a low (0–1), intermediate (2–5) or high (6–9) probability of HFpEF using the H2FPEF score. During a median follow-up of 19 months (interquartile range 8–40), 132 (43%) patients died. The HFA-PEFF score, but not the H2FPEF, predicted a high risk of all-cause death which remained significant after adjustment for age, AL-CA diagnosis, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and echocardiographic parameters, including left ventricular (LV) global longitudinal strain, LV diastolic function and right ventricular function (hazard ratio 1.51, 95% confidence interval 1.16–1.95, p=0.002 for every 1-point increase in HFA-PEFF).

Conclusions

The HFA-PEFF score has a high sensitivity to diagnose HFpEF caused by CA and holds independent prognostic value for all-cause mortality, while the H2FPEF score does not.

Funding Acknowledgement

Type of funding sources: None.
Nitro-oxidative stress impairs single cardiomyocyte adrenergic reserve in a murine model of HFpEF
Authors: Semmler L , Jeising T , Huettemeister J , Schiattarella G G , Oeing C U , Heinzel F R
Published: October 2022

Background

Exercise intolerance is the central symptom of patients with heart failure and preserved ejection fraction (HFpEF). Underlying reduced cardiac functional reserve in response to adrenergic stimuli (stress testing) has been suggested but the molecular mechanisms are insufficiently understood. In cardiomyocytes, nitric oxide (NO) modifies contractility and is required to achieve a full adrenergic response. Recently, dysregulation of NO release has been described to contribute to HFpEF. In a murine model of HFpEF, we investigated cardiomyocyte's adrenergic functional reserve and the role of NO in cardiomyocyte contractility, calcium handling and adrenergic reserve.

Methods

Firstly, the effects of NO on sarcomere shortening and calcium handling (Fura-2) were studied in isolated, adult ventricular cardiomyocytes (AMVMs) from 8–10 weeks old, male C57BL/6J mice. Secondly, male C57BL/6J mice (12w) were fed regular CHOW (Sham) or a high fat diet (D12492, Research Diet) and L-NAME (1g/l, via the drinking water) for 15 weeks to induce HFpEF. At week 27, mice underwent echocardiography and exercise testing (treadmill). In AMVMs isolated from HFpEF and Sham mice, we quantified sarcomere shortening, calcium handling (Fura-2), release of NO (CuFL2) and reactive oxygen species (DCF) before and after the addition of isoproterenol (ISO, 1μM), in the absence and presence (40 min preincubation) of an inhibitor of inducible NO Synthase (1400W) or a denitrosylating agent (glutathione).

Results

In AMVMs, addition of the NO donor SNAP (10μM) increased calcium transient amplitude and accelerated relaxation time. Inhibition of NO synthesis with L-NAME (100μM) impaired adrenergic response upon exposure to ISO. HFpEF mice (evident by diastolic dysfunction (e/e' ratio) and lung edema (wet lung weight / TL)) exhibited significantly reduced exercise capacity (running distance). In AMVMs isolated from HFpEF mice, NO and ROS release were increased at baseline, associated with an increased sarcomere shortening amplitude and faster relaxation and calcium removal as compared to Sham. Strikingly, after the addition of ISO, the adrenergic functional reserve (cellular inotropy and lusitropy) was significantly lower in HFpEF vs. Sham AMVMs. Preincubation with the iNOS inhibitor 1400W or glutathione restored adrenergic inotropic and lusitropic reserve in HFpEF AMVMs.

Conclusion

In HFpEF, adrenergic reserve is impaired on a single cardiomyocyte level. This is at least partially related to an increase in NO release. Pharmacologic inhibition of iNOS improved adrenergic reserve in HFpEF.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DFG
Type III collagen formation is significantly associated with risk of outcome in HFpEF patients but loses its significant association with underlying AF
Authors: Angeli E , Reese-Petersen A , Gonzalez A , Lopez B , Ravassa S , Genovese F , Karsdal M , Diaz J
Published: October 2022

Introduction

Heart failure with preserved ejection fraction (HFpEF) is the most common type of heart failure, associated with high morbidity and mortality. Atrial fibrillation (AF) has been associated with structural remodelling and fibrosis and can coexist with HFpEF. Type III collagen is the second most abundant collagen in the heart wall and has been associated with cardiac fibrosis. It has been previously shown that type III collagen formation, measured by PRO-C3, is prognostic for all-cause mortality in HFpEF.

Purpose

In this study, we aimed at investigating if the prognostic power of PRO-C3 in relation to all-cause mortality would be affected by underlying AF in HFpEF patients.

Methods

The analysis included 166 individuals with hypertensive HFpEF. The patients were classified in three groups according to NYHA classification, 43.2% in NYHA Class II, 52.5% NYHA Class III and 2.5% NYHA Class IV. A previous history of AF was present in 53.4% of the patients. Cardiac function was assessed by echocardiography and standard clinical measures. Type III collagen formation was evaluated by means of ELISA with the biomarker PRO-C3, which targets the released N-terminal pro-peptide of type III collagen.

Results

Levels of PRO-C3 were significantly elevated in HFpEF patients with AF (p=0.0063). PRO-C3 was significantly predictive of all-cause mortality in HFpEF patients (AUC=0.643, p=0.0053), but lost its significant association when factoring in AF (AUC=0.581, p=0.235). There was an increased risk of all-cause mortality (p=0.0089) but not statistically significant differences in HFpEF patients with AF (p=0.178) with increasing tertiles of PRO-C3.

Conclusions

Type III collagen formation as measured by PRO-C3, was increased in patients with HFpEF and previously diagnosed AF. However, while PRO-C3 can be predictive of all-cause mortality in HFpEF patients, it lacks predicting ability when AF is considered. The presented data suggest a potential role of increased type III collagen formation in HFpEF patients with adverse outcomes, which is consistent with the presence of increased fibrosis, and can potentially be used as a tool of risk stratification.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Nordic Bioscience A/S
Lung fluid levels estimated by remote dielectric sensingTM values and invasive hemodynamic measurements
Authors: Imamura T , Hori M , Kinugawa K
Published: October 2022

Background

Remote dielectric sensing (ReDSTM) is a recently introduced non-invasive electromagnetic-based technology to quantify lung fluid levels (Figure 1A). The association between ReDS values and invasively measured hemodynamics, particularly among those with small body size, remains uncertain.

Methods

Consecutive patients with chronic heart failure who were admitted to our institute and underwent right heart catheterization as well as simultaneous ReDS measurement at clinically stable conditions between Sep and Nov 2021 were prospectively included. The correlation between ReDS values and PCWP was investigated.

Results

A total of 30 patients (median 79 [73, 84] years old, 13 men) were included. Median ReDS value was 26% (22%, 28%). ReDS values had a moderate correlation with PCWP (r=0.698, p<0.001; Figure 1B), even among those with a height <155 cm. ReDS values with a cutoff 28% predicted a PCWP >15 mmHg with sensitivity 0.70 and specificity 0.75.

Conclusions

A non-invasive electromagnetic-based technology ReDS might be a promising tool to estimate cardiac pressure in patients with heart failure, even among those with smaller body size.

Funding Acknowledgement

Type of funding sources: None.