bluuebunny/crossref_metadata_2025 huggingface dataset:
An online international survey study into the incidence and potential reasons of therapy non-adherence in catecholaminergic polymorphic ventricular tachycardia: preliminary results
Authors: Peltenburg P , Van Den Heuvel L M , Kallas D , Probst V , Blom N A , Wilde A A M , Clur S A , Van Der Werf C
Published: November 2023

Background

Since the first description of catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited cardiac arrhythmia, effective medical therapy to prevent the arrhythmic events – syncope, sudden cardiac arrest, sudden cardiac death – have been described. However, a significant proportion of patients experience breakthrough events despite optimal medical therapy, which are regularly associated with therapy non-adherence.

Purpose

To investigate the incidence of and potential reasons for therapy non-adherence in a large cohort of patients with CPVT.

Methods

An online survey was created in Dutch, English, and French and shared with CPVT patients at the outpatient clinic, through peer-recruitment, and on social media from November 1, 2022 onwards. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS, contains five 5-Point Likert scale questions, non-adherence was defined as a score <22). The Beliefs about Medication Questionnaire (BMQ, eleven 5-Point Likert scale statements regarding concern and necessity of CPVT medication and eight 5-Point Likert scale questions regarding overuse and harm of medication in general) and Illness Perception Questionnaire (IPQ, statements rated with a scale from 0 to 10) were used to explore associations between patient beliefs and non-adherence.

Results

After three months, 85 patients had completed the survey, of whom 77 (91%) used medication (32 [42%] used a beta-blocker, 5 [6%] flecainide, and 40 [52%] beta-blocker and flecainide dual therapy). Of the patients using medication, current median age was 37 (interquartile range [IQR]: 26-55) years, 56 (73%) were female, and 15 (20%) suffered from syncope, aborted cardiac arrest or appropriate ICD shock after diagnosis. Ten (13%) of the patients were non-adherent. Clinical characteristics of non-adherent patients did not differ from adherent patients (Table). Non-adherent patients reported a significantly higher agreement with statements regarding concern about CPVT-related medication (17.5 [15.2-20.8] vs. 14.0 [12.0-18.0], p=0.039), specifically the statement about unpleasant adverse effects (4.0 [3.2-4.8] vs. 3.0 [2.0-4.0], p=0.008, Figure). The IPQ statements did not differ between non-adherent and adherent patients (Figure).

Conclusion

Preliminary data of this survey study shows that the rate of self-reported non-adherence is significant and is associated with concern regarding CPVT-related medication. This knowledge could assist in improving patient education aimed at therapy adherence. In addition, this preliminary data show that it is feasible and useful to study non-adherence in a CPVT population using online surveys.TableFigure
Long-term outcomes in carriers of the familial idiopathic ventricular fibrillation linked to the DPP6 locus
Authors: Bergeman A , Hoeksema W F , Van Der Ree M H , Postema P G , Wilde A A M , Van Der Werf C
Published: November 2023

Background

Idiopathic ventricular fibrillation (IVF) is a malignant condition with no clinical sequelae except for ventricular fibrillation. The genetic basis is ill-defined but in 2009 a Dutch founder variant - the DPP6 risk haplotype - was linked to a familial form of IVF characterized by a very high incidence of sudden cardiac arrest (SCA) and sudden cardiac death (SCD). Consequently, for more than a decade asymptomatic haplotype-carriers from the ages of 18 (male) and 25 (female) have had an implantable cardioverter-defibrillator (ICD) inserted. However, the associated long-term outcomes in these individuals is unknown.

Purpose

To assess the long-term outcomes of DPP6 risk haplotype-carriers who presented to our tertiary referral center and qualified for ICD insertion.

Methods

Clinical follow-up information of DPP6 risk haplotype-carriers, including the occurrence of SCD, SCA, appropriate ICD shocks, and ICD-related complications, was collected through February 2023. ICD-carriers were classified as either asymptomatic (primary prevention), or with previous sudden cardiac arrest (secondary prevention). Survival rates are presented using a survival curve and were compared with the log-rank test.

Results

A total of 118 haplotype-carriers (62 males) were included. One-hundred nine (92%) carriers had an ICD inserted, for primary (n=85) or secondary prevention (n=24), and 9 patients refused a primary prevention ICD. Among primary prevention ICD-carriers and those who refused implantation (n=94), 9 (10%) patients experienced a total of 28 appropriate shocks, there was 1 SCA and no deaths, during a median follow-up of 11 years (IQR 7-13; Figure). Of these, 9 patients were ever treated with quinidine and 5 still used quinidine at last follow-up. Among secondary prevention ICD carriers, 20 (83%) patients experienced a total of 225 appropriate shocks and one patient died, during a median follow-up of 13 years (IQR 10-16). Of these patients, 11 were ever treated with quinidine, of whom one patient discontinued quinidine due to adverse effects. Overall, 14 (13%) patients experienced inappropriate shocks and 16 (15%) experienced other ICD-related complications.

Conclusion

Predictive genetic testing of the DPP6 haplotype provides the unique opportunity to identify asymptomatic family members at risk for SCD and insert prophylactic ICDs just on the basis of carrying the risk haplotype. Approximately 10% of DPP6 haplotype-carriers who qualified for ICD insertion for primary prevention, predominantly males, experienced appropriate ICD shocks or SCA during 11 years of follow-up, indicating that our approach to ICD implantation has presumably saved several lives. In those with an ICD for secondary prevention the incidence of appropriate ICD shocks was high, often despite quinidine therapy.Survival until appropriate shock or SCA
Asthma and the risk of cardiac events among patients with long QT Syndrome after age 40
Authors: Golovchiner G , Goldenberg I , Buturlin K , Erez A , Goldenberg G , Chen A Y , Polonsky B , Mcnitt S , Aktas M , Zareba W , Barsheshet A
Published: November 2023

Background

The effect of asthma on the clinical course of long QT syndrome (LQTS) in the middle and old age population has not been studied.

Purpose

The present study was designed to investigate the association between asthma comorbidity, β2-agonist treatment and cardiac events among LQTS subjects after age 40 years.

Methods

The risk of cardiac events (comprising syncope, aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from age 40 through 75 years, by the presence of asthma and time-dependent β2-agonist use was assessed among 1020 LQTS patients from the LQTS Registry.

Results

Asthma was identified in 162 (16%) study patients and 63% of asthma patients received β2-agonist inhalers. Patients with asthma vs. no asthma had a higher cumulative rate of cardiac events during follow-up (44% vs. 26%, respectively; p<0.001 [Figure: left panel]). Consistently, multivariate analysis demonstrated that asthma was a powerful predictor of cardiac events with an associated 2-fold (HR=1.97, p=0.001) increased risk for cardiac events as compared to patients with no asthma. β2-agonist inhalers use was associated with a similar increased risk for cardiac events (HR =1.90, p=0.035) among all study patients (Figure: right panel]). Subgroup analysis did not show a statistically significant difference in the association of asthma with cardiac events by risk subsets of LQTS patients, including QTc duration, syncope prior to age 40 years, beta-blocker use, sex, and the LQTS genotype (all p-values for risk subset-by-asthma interaction >0.10).

Conclusion

The presence of asthma and β2-agonist treatment are associated with an increased risk of cardiac events among middle and old age patients with LQTS.
The added value of abnormal regional myocardial function for risk prediction in arrhythmogenic right ventricular cardiomyopathy
Authors: Kirkels F P , Rootwelt-Norberg C , Bosman L P , Aabel E W , Muller S , Taha K , Van Osta N , Lie Ø H , Asselbergs F W , Lumens J , Te Riele A S J M , Hasselberg N E , Cramer M J , Haugaa K H , Teske A J
Published: November 2023

Background & aims

A risk calculator for individualized prediction of first-time sustained ventricular arrhythmia (VA) in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients has recently been developed and validated. This study aimed to investigate whether regional functional abnormalities, measured by echocardiographic deformation imaging, can provide additional prognostic value.

Methods & results

From two referral centres, 150 consecutive patients with a definite ARVC diagnosis, no prior sustained VA and an echocardiogram suitable for deformation analysis were included (aged 41 ± 17 years, 50% female). During a median follow-up of 6.3 (IQR 3.1-9.8) years, 37 (25%) experienced a first-time sustained VA. All tested left and right ventricular (LV, RV) deformation parameters were univariate predictors for first-time VA. While LV function did not add predictive value in multivariate analysis, two RV deformation parameters did; RV free wall longitudinal strain and regional RV deformation patterns remained independent predictors after adjusting for the calculator-predicted risk (HR 1.07 [1.02-1.11]; p = 0.004 and 4.45 [1.07-18.57]; p = 0.040, respectively) and improved its discriminative value (from C-statistic 0.78 to 0.82 in both. Akaike information criterion change >2). Importantly, all patients who experienced VA within 5 years from the echocardiographic assessment had abnormal regional RV deformation patterns at baseline.

Conclusions

This study showed that regional functional abnormalities measured by echocardiographic deformation imaging can further refine personalized arrhythmic risk prediction when added to the ARVC risk calculator. The excellent negative predictive value of normal RV deformation could support a watchful waiting strategy regarding ICD implantation in intermediate risk patients.Added value of functional abnormalities
Arrhythmic risk stratification of filamin C truncating variants carriers
Authors: Gigli M , Stolfo D , Barbati G , Sinagra G , Mestroni L
Published: November 2023

Background

Truncating variants in Filamin C (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentation and high incidence of life-threatening ventricular arrhythmias, including sudden cardiac death (SCD). Nevertheless, there is a residual gap in the definition of solid risk markers for the stratification of arrhythmic risk and the significance of conventional predictors (i.e. left ventricular ejection fraction [LVEF]) remains extremely controversial.

Purpose

The aim of this study was to analyze the risk profile and to identify the factors associated with increased risk of life-threatening arrhythmias in an international multicenter cohort of FLNCtv carriers.

Methods

Patients were retrospectively collected from 19 international tertiary care centers for genetic cardiomyopathies. Primary endpoint was SCD/major ventricular arrhythmias (MVA, i.e. sustained ventricular tachycardia and appropriate implantable cardioverter defibrillator [ICD] shocks). Multivariate Cox regression analysis was performed to identify the predictors of SCD/MVA, taking into account non-sudden cardiac death/heart transplant/destination left ventricle assist device as competing event and including family clusters in the model as clustering factor.

Results

Among the 326 included carriers (median age 45 years, IQR 33-57; 51% males), 120 (37%) were probands. 100 (31%) carriers had no clinical signs of overt disease; for the others, phenotypic presentation was heterogeneous (36% dilated cardiomyopathy, 17% arrhythmogenic left dominant cardiomyopathy, 4% arrhythmogenic right or biventricular cardiomyopathy, 11% minor phenotype). Median LVEF was 51% (IQR 35%-59%, 41% had LVEF<50%), 16% had right ventricle dysfunction. During a median follow-up of 32 months (IQR 8-63), 60 carriers (18%) experienced SCD/MVA (65% probands, 97% with overt disease, median age at event 48 years, IQR 38-64, min-max 18-78). Among variables associated with the risk of SCD/MVA at univariable analysis, male sex, previous syncope and non-sustained ventricular tachycardia maintained a significant association with the primary outcome at multivariable analysis (Table), whereas there was no significant association between LVEF and the risk of SCD/MVA neither as a continuous nor categorical (i.e. LVEF<50%) variable. In the subgroup of 175 patients with available cardiac magnetic resonance, 57% had late gadolinium enhancement with no significant association with the outcome.

Conclusions

In the largest worldwide cohort of FLNCtv carriers the high risk of SCD/MVA was confirmed. Three important factors emerged to be associated with higher arrhythmic risk and should be considered for decisions on ICD implantation. Remarkably, LVEF was not significantly associated with SCD/MVA risk. The higher risk observed in males compared with females advocates for prompt investigations on the influence of sex-related factors on the disease expression in genetic cardiomyopathies.
No association between COVID-19 vaccination and sudden cardiac death
Authors: Paratz E , Stub D , La Gerche A
Published: November 2023

Background

Global concerns regarding potential cardiac side effects of COVID-19 vaccination have been raised, particularly with regards to sudden cardiac death (SCD) in young people.

Methods

Data from April 2019 to March 2022 was obtained from a state-wide registry investigating all OHCAs aged 1-50 years old. Vaccination and COVID-19 rates for people aged 1-50 years old were derived from publicly-available data. The primary outcome was comparison of vaccination availability against young OHCA rates, unascertained causes of arrest or myocarditis. The secondary outcome was causes of young sudden death within thirty days of COVID-19 vaccination, with reference to age-matched normative data.

Results

2,242 people experienced OHCA during the study period (unascertained causes = 223, myocarditis = 13). No variation was seen in monthly rates of OHCA (p=0.7481), rates of myocarditis (p=0.7378) or unascertained cause of arrest (p=0.2323) according to vaccine availability. 38 people experienced sudden death within thirty days of vaccination and were referred for forensic assessment (vaccine types: BNT162b2=22, ChAdOx1 nCoV-19= 9, mRNA-1273=2, vaccination type not documented =5). No difference was seen in underlying causes of the sudden death compared to previously-published age-matched data (p=0.235).

Conclusion

A state-wide analysis of OHCA in the young did not show any increase in rates of overall OHCA, myocarditis causing OHCA or unascertained OHCA during the COVID pandemic or following the introduction of COVID-19 vaccination. Causes of death in young people experiencing fatal OHCA within 30 days of their COVID-19 vaccination were consistent with pre-pandemic causative profiles.
Risk factors and prognostic implications for new-onset heart failure with ventricular pacing - a nationwide study
Authors: Maiwand F , Rorsman C , Marinko S , Mortsell D , Chaudhry U , Wang L , Platonov P , Borgquist R
Published: November 2023

Background

Studies have shown that the incidence of new-onset heart failure (HF) is higher for patients receiving pacemaker therapy with traditional right ventricular pacing, compared to age matched controls. Conduction system pacing may overcome this, but is more expensive and technically challenging.

Objectives

To investigate risk factors and implications for long-term prognosis of new-onset HF in patients after pacemaker-implant, with the aim of identifying patients at high risk already prior to device implant.

Methods

All patients without preexisting HF, who received a pacemaker with a right ventricular lead in Sweden during the period 2005-2020, were identified via the nationwide Pacemaker Registry. Data was crossmatched with the population registry and national disease registries. Outcome was new-onset HF within 5 years post-implant, HF hospitalization and all-cause mortality.

Results

In all, 65579 patients met the inclusion criteria (10351 single chamber ventricular and 55228 dual chamber pacemakers). 13792 (21.0%) patients were diagnosed with HF within five years post-implant. Of these, 6244 (45.3%) were hospitalized for HF (see Figure 1). Patients with heart failure were older (80.6 vs. 76.7 years, p<0.001), had a higher burden of comorbidities, and were more likely to die within five years compared to those without HF (41.2% vs. 19.7%, p<0.001). Independent risk factors with more than 25% increased odds ratio for developing heart failure within 5 years included increasing age, diabetes, atrial fibrillation, chronic lung- and kidney disease, ischemic heart disease, and AV block. A combined score using these variables was strongly associated with increased risk of both HF-hospitalization (OR 1.48 [1.46-1.51], p<0.0001) and 5-year mortality (OR 1.81[1.77-1.98], p<0.0001). There was a progressively increasing risk proportional to the summed score. Patients with at least five points on the score had >25% risk of new-onset heart failure within five years, and patients with at least seven points had >25% risk of new-onset heart failure within two years. In figure 2 we present a suggested score model, based on the results.

Conclusions

Pacemaker therapy with a lead in the right ventricle was associated with >20% risk of new-onset HF within five years. This in turn was associated with higher risk of death. Based on clinical risk factors, our proposed score can be used to identify patients at high risk for new-onset heart failure. These patients may be eligible for conduction system pacing or resynchronisation therapy. Randomized trials are needed to determine if a score-based pacing strategy (right ventricular or conduction system pacing) approach results in better clinical outcome, and if it is cost-effective.Included patients and risk of HF hosp.Decision algorithm based on results
Leadless vs. transvenous single-chamber pacing - propensity-matched comparison of outcomes
Authors: Amador R , Presume J , Carmo P , Carmo J , Santos A R R , Matos D , Rodrigues G , Santos P G , Costa F M , Carvalho M S , Cavaco D , Morgado F , Adragao P
Published: November 2023

Background

Clinical Trials have demonstrated the safety and efficacy of the leadless pacemaker. However, real-world outcome comparisons between patients receiving conventional VVI and leadless pacemakers are still scarce. The aim of this study was to evaluate short and long-term complications of patients receiving leadless pacemakers in comparison to a population of conventional VVI.

Methods

We conducted a single-centre retrospective study of patients receiving the leadless or a conventional VVI between 2014 and 2022. Propensity score matching was performed on 725 patients (156 leadless and 569 conventional) and according to age, sex, coronary artery disease (CAD), chronic kidney disease (CKD), haemodialysis and AF, with a 1:1 matching protocol without replacement (matching tolerance 5%).

Complications that occurred up to one month after implantation were considered acute and included access site BARC ≥ 3 bleeding events, pacemaker pocket hematoma requiring medical intervention (either drainage o antibiotic therapy), femoral access infection, pneumothorax, pericardial effusion, cardiac tamponade, and dysfunction of the implanted device. Long-term complications were defined as those occurring at least one month after implantation and included device infection, need for reintervention, and device upgrades due to left ventricular dysfunction. The primary outcome was a composite of acute and long-term complications.

Results

A total of 312 patients (80 [73 - 86] years, 63% male, 79% with AF and 7% on dialysis) were included, 156 within each group. The main indication for PM implantation was AF with low ventricular rate (48%), followed by atrioventricular block (31%) and sick sinus syndrome (13%). In total, 19 patients (16%) had a previously implanted device, and 14 (4%) had previously been submitted to lead extraction, of which 10 (71%) were due to device-related infection. All of these were more frequent in patients receiving the leadless pacemaker (p = 0.001).

During a median follow-up of 26 [11 - 47] months, a total of 32 patients (10%) had a complication related to the implantation of the device – table 1. While intra-hospital complications showed only a tendency towards higher incidence in the VVI group (5% vs 3%; p = 0.124), overall complications (16% vs 5%) and long-term complications (12% vs 2%) were higher in the VVI group (p < 0.001 for both).

The Kaplan-Meier curves for the primary outcome showed a significantly lower event-rate for patients receiving the leadless pacemaker – Figure 1.

Conclusions

In this propensity-matched study, leadless pacemaker implantation was associated with a lower incidence of complications during follow-up, in comparison to conventional VVI pacemaker.
Mortality and appropriate therapies in ischaemic ICD recipients according to the electrophysiological study
Authors: Teodorovich N , Swissa M S , Diamante R , Jaber M , Cuciuc V , George J , Swissa M
Published: November 2023

Aims

Current guidelines recommend ICD implantation for primary prevention in patients with ischaemic heart disease and LVEF ≤35%. We aimed to access the value of the EP study in prediction of the arrhythmic events in ischaemic patients with reduced EF (≤35%) who underwent EPS and ICD implantation and do address the impact of ICD implantation on the all-cause mortality.

Methods

We compared the risk for all-cause mortality in ischaemic patients with negative and positive EPS with and without ICD implantation and compared the risk for appropriate therapy according to the results of the EP study of patients who underwent ICD implantation in our institution. The median follow-up was 84 months.

Results

Of 235 patients, who underwent EPS, 115 were negative (noninducible to VT). These patients were more likely to be female and did not differ in age, presence of diabetes, hypertension, atrial fibrillation or ejection fraction.

Kaplan-Meier survival analysis showed that there was no difference in mortality between the 2 groups (49.6% vs 44.2%, p=0.419). ICD was implanted in 168 patients: there was no difference in mortality between them (47%) and patients without implanted ICD (46.6%), p=0.861. This was true for patients with negative and positive EPS (p=0.136 and p=0.554, respectively)

Of 167 patients who underwent ICD implantation, 66 had negative EPS. Kaplan-Meier analysis showed that these patients were significantly less likely to receive appropriate therapy (7.6% vs 25.7%, p=0.003) and appropriate shock (0% vs 10.9%, p=0.004. The time to first appropriate ICD therapy was significantly longer in EPS negative patients (112 vs 93 months, p<0.001). The incidence of inappropriate therapies was similar in both groups (2.6% vs 5.8%, p=0.221).

Conclusion

ICD implantation does not reduce mortality in ischaemic patients with reduced EF and both positive and negative EPS. Patients with negative EPS and implanted ICD had much lower incidence of appropriate ICD therapies and no appropriate shocks. The policy of implanting ICDs to all ischaemic patients with EF<35% should be reconsidered.ICD shocks according to the EPS resultsMortality with and without ICD
Lead extraction of very old leads using the PISA technique - experience of a portuguese tertiary care center
Authors: Ferreira A , Valente B T , Cunha P S , Portugal G , Lousinha A , Ferreira R C , Oliveira M
Published: November 2023

Background

The "Pisa Technique" (PT) is an increasingly used method of lead extraction (LE) that is associated with the lowest rate of complications reported in the ELECTRa Registry. Lead dwell time has been recognized as the highest risk factor for extraction failure and procedure-related complications.

Purpose

To investigate the safety and efficacy of LE, using the PISA technique, of very old cardiac implantable electronic devices (CIED) leads.

Methods

Patients submitted to LE of very old leads (with an implant duration of more than 10 years) between February 2013 and October 2022 (Old group), were compared with a contemporary cohort of patients subjected to LE of leads with a shorter implant duration (New group). The PT was used in all patients. Demographic, clinical, and patient-related variables, complications, mortality, and reimplantation data were assessed.

Results

A total of 150 very old leads were removed from 86 patients in the Old group, and a total of 305 leads were removed from 171 patients in the New group during the study period. Regarding the baseline characteristics, patient mean age was 69.5±16.9 years, 82.6% were male. Nine patients (10.5%) had cardiac resynchronization devices, 11 (12.8%) implantable cardioverter-defibrillator devices, and 66 (76.4%) pacemaker systems (mostly DDD). Of the total LE in the Old group, 88.4% were due to CIED infection (44.1% with valvular or lead endocarditis) vs 75.9% (p=0.464) vs the New group. The mean "age" of the extracted leads was 163.7±53.4 vs 46.6±34.9 months, and there were more of active fixation in the New group 35.2% vs 58.9%, p<0.01. A previous attempt of LE had been done in 5.8% vs 11.1% (p=0.172) of the patients, there were more previous generator replacements in the Old group 67.4% vs 23.7% (p<0.01). The radiographic success rate of the attempted lead extractions was similar between both groups 90.7% vs 96.5% (p=0.063). The clinical success rate was slightly lower in the Old group 95.3% vs 99.4% (p=0.031). The procedure major complications rate in the Old group was 2.3% (there were 2 cases of cardiac tamponade that required sternotomy with no laceration of the SVC observed) vs 1.2% (p=0.294) in the New group. Minor complications occurred in 11.6% vs 8.8% (p=0.466) of the LE (mostly comprised of infected pocket hematomas). No deaths occurred during the procedures, and there was no extraction-related mortality in both groups.

Conclusion

Our center’s experience with the PISA technique confirms the method’s safety and feasibility for the percutaneous extraction of very old CIED leads.
Complications according to intrathoracic versus extrathoracic venous access for cardiac device implantation: results from the PLACE (Planning Lead Access for Cardiac Electrostimulation) study
Authors: Dell'era G , Ghiglieno C , Palmisano P , Floris R , Pimpini L , Coluccia G , Fais L M , Colombo C , Malacrida M , D'amico A , Mazzoleni F , Antonicelli R , Delogu G , Accogli M , Patti G
Published: November 2023

Background and Aims

The choice of the vascular access for cardiac pacing devices (CIED) implant may impact on patients outcome. Recent studies and consensus documents encourage the use of an extra-thoracic access to prevent adverse events. In this large, multicenter, retrospective study we report the impact of leads access on post-procedural outcome.

Methods

Consecutive patients receiving a CIED from 2008 to 2019 in 4 high-volume Italian hospitals were enrolled. Short- and long-term complications (i.e. pneumothorax, cardiac tamponade, pocket decubitus, pocket hematoma, lead dislodgement, lead failure) were collected and their relationship with the type of vascular access (extra- vs intra-thoracic, i.e. cephalic vein/extra-thoracic axillary vein vs subclavian vein puncture) was analyzed. Primary endpoint was the occurrence of at least one complication during follow-up.

Results

A total of 4,443 patients were enrolled; 3,374 (75.9%) received a pacemaker (PM) and 1,069 (24.1%) an implantable cardioverter defibrillator (ICD). Mean follow-up was 1,630±1,010 days. At least one complication occurred in 7.6% of patients. At multivariate Cox regression analysis, adjusted for baseline confounders, the presence of structural heart disease (HR 1.59, 95%CI 1.21-2.10; p=0.001), anticoagulant therapy at implantation [HR 1.31, 95%CI 1.0004-1.71; p=0.05) and female gender (HR 0.78, 95%CI 0.63-0.98; p=0.03) were associated with the primary outcome measure. Extra-thoracic access did not reduce the risk of complications compared to intra-thoracic access (HR 0.97, 95%CI 0.76-1.25 p=0.81). The use of both accesses in the same patient conferred a significant increase in the risk of complications (HR vs single approach:1.95, 95%CI 1.41-2.69; p <0.001).

Conclusions

The choice of a different vascular access (intra- vs extra-thoracic) does not impact on post-procedural complications in patients receiving CIED. In particular, the intra-thoracic subclavian vein puncture by experienced operators is not related to a poorer outcome. The need for both types of access in the same patient (i.e. increased procedure complexity) increases the risk of post-procedural complications.Graphical abstract
Social and clinical predictors of 90-day readmission after hospitalization for pacemaker implantation in patients with dementia: insight from the National Readmissions Database
Authors: Kodali M , Atluri R , Vallabaneni M , Yalamanchili S , Shoura S , Vardar U
Published: November 2023

Background

Patients with dementia are one of the most common subpopulations that are at risk for readmission and are responsible for a significant burden on American healthcare resources. In addition to this, many studies have shown poor outcomes with dementia patients undergoing invasive procedures. Nonetheless, dementia patients presenting with conditions such as high degree heart block and sinus node dysfunction still require pacemaker implantation (PMI).

Purpose

We aimed to analyze social and clinical predictors of readmission in those with Dementia who were admitted for PMI.

Methods

We utilized the National Readmission Database (NRD) from 2018 to identify adults hospitalized for pacemaker implantation (PMI) who also had dementia. We included those who were readmitted within 90 days after the index admission. We excluded elective and traumatic admissions. A multivariate cox regression model was used to identify independent predictors of readmission.

Results

In our study, 7,529 patients with dementia who were hospitalized for pacemaker implantation (PMI) were discharged alive. Within 90-days from discharge, 1,250 (16.6%) were readmitted. The top three causes of readmission were heart failure (12.2%), sepsis (8%), and acute kidney injury (5%). Readmitted patients had more comorbidities (≥3; 64.4% vs 57.3%; p<0.001), higher rates of intubation (4.9% vs 1.59%; p<0.001) and annual income < $44,000 (29.39% vs 25.7%; p=0.03). In-hospital mortality (3.9% vs 1.27%; p<0.001) was higher during readmission. Figure 1 shows the Forrest plot of multivariate analysis of independent factors associated with readmissions.

Conclusion

We identified predictors of readmission after hospitalization for PMI in dementia patients such as household income, leaving against medical advice, federal insurance, heart failure, atrial flutter, and liver disease during their index admission. Healthcare systems should use this data to have an open discussion with caregivers and family members to weigh the prognosis on a case by case basis prior to pacemaker implantation in this population.
Multiplex screening for biomarkers associated with subsequent heart failure hospitalisation in patients with atrial fibrillation: insights from the ARISTOTLE trial
Authors: Pol T , Lindback J , Alexander J H , Granger C B , Lopes R D , Siegbahn A , Wallentin L , Hijazi Z
Published: November 2023

Background

Atrial fibrillation (AF) is associated with heart failure (HF) with a complex cause and effect relationship. We performed multiplex screening of plasma proteins in order to identify biomarkers and pathways associated with subsequent HF hospitalisation in patients with AF.

Methods

Using a case-cohort design of patients with AF from the ARISTOTLE trial, the study cohort consisted of 596 cases of HF hospitalisations during follow-up and 4029 randomly selected controls without HF hospitalization. The median follow-up time was 1.9 years. Plasma obtained at randomisation was analysed with conventional immunoassays and three OLINK proximity extension assay panels; CVDII, CVDIII and the inflammation panel. Biomarker associations with subsequent HF hospitalisation was evaluated using Random Survival Forest (RF), Boruta and Cox-regression analyses adjusted for baseline characteristics, renal function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) as well as cardiac troponin-T (cTnT-hs).

Results

The biomarkers most associated with HF hospitalisation, using all three statistical methods (Table), were (hazard ratio for inter-quartile comparison [95% CI]), NT-proBNP (2.07 [1.76 - 2.4]), cTnT-hs (1.35 [1.15 - 1.58]), fibroblast growth factor 23 (FGF-23; 1.26 [1.15 - 1.39]), spondin-1 (SPON-1; 1.21 [1.10, 1.33]), TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2; 1.19 [1.07 - 1.32]), insulin Growth Factor Binding Protein 7 (IGFBP7; 1.25 [1.13 - 1.39]), urokinase receptor (uPAR) 1.4 [1.19 - 1.66]), vascular Endothelial Growth Factor D (VEGF-D; 1.28 [1.08 - 1.53]), pro-adrenomedullin (ADM; 1.20 [1.03 - 1.40]), and C-C motif chemokine 3 (CCL3; 1.15 [1.06 - 1.24]).

Conclusions

Out of 269 evaluated biomarkers, this comprehensive screening study identified biomarkers representing cardiorenal dysfunction (NT-proBNP, cTnT-hs, FGF-23), cell adhesion (SPON-1), apoptosis (TRAILR2), growth factors (IGFBP7, VEGF-D), fibrinolysis (uPAR), vasodilation (ADM) and inflammation (CCL3) as being the most strongly associated with subsequent HF hospitalisation in patients with AF. These findings highlight the most important pathophysiological pathways involved in new or worsening HF in patients with AF.Biomarkers associated with HF hospitalis
Genome-wide association study of heart failure in a multiethnic south-east asian cohort
Authors: Loong S , Hong P , Goh V J L , Lee S S G , Loh S Y , Soon D , Chin C W L , Maurer-Stroh S , Amikeng F , Loh M , Wang D , Lam C S P , Richards M , Foo R
Published: November 2023

NMRC

Heart failure (HF) is a leading cause of morbidity and mortality worldwide (1). While existing genome-wide association studies (GWAS) have yielded many different loci and causal genes, most of such studies has been conducted in European populations (2). There has been little insight into the genetic architecture of complex diseases, especially HF among Asians, despite up to 60% of the world population consisting of Asians. Through this study, we aim to uncover the genomic basis of heart failure in a South-East Asian cohort, with deep phenotyping of cardiovascular, metabolic, immune, and inflammatory traits.

We conducted the largest multi-ancestry South-east Asian all-cause HF GWAS (n=2310, 1305 cases and 1005 controls), utilizing whole genome sequencing (WGS) data. Eleven independent loci were found to be associated with HF (P-value = 5e10-8). In-silico and functional studies were interrogated, allowing us to map most of the loci (n=9) to various genes implicated in various metabolic diseases - hypertension (HTN), diabetes mellitus (DM), and coronary artery disease (CAD). We further conducted a phenome-wide association study (PWAS) of significant loci, which revealed that they augment signals related to CAD, atrial fibrillation, DM and HTN, suggesting a shared genetic etiology between these metabolic risk factors and Asian HF. Of note, this the first HF GWAS to implicate the PDE9A gene, which was previously discovered as a potential biomarker for HF with preserved ejection fraction (HFpEF) through its involvement in the cGMP signaling pathways, and is currently being explored as a therapeutic target in the treatment of HFpEF (3).

Polygenic risk scores (PRS) were calculated for heart failure in this Asian cohort, which identified that the most optimized model (HF PRS), included 19,431 of the most significant genetic variants (p=0.073). The prediction power of the HF PRS on HF risk was tested in UKB Asian subjects (N=10,016; 413 cases and 9,603 controls). Our results showed that the highest 10% percentile HF PRS risk subjects in UKB Asian were at 1.56-fold risks (95% CI: 1.16-2.08) for HF.

This study provides a comprehensive understanding of the genetic architecture, and sheds light on novel biological pathways underlying HF in a south-east Asian population, indicating a highly metabolic underpinnings of this disease. It provides a step towards developing a precision-medicine based approach for risk stratification, prevention, and management of HF among Asians. Furthermore, this study provides evidence for the use of WGS in GWAS, to expand the discovery of novel targets for downstream interrogation, biomarker and drug development for complex diseases.
Analysis of the snoRNA profile in ischemic and dilated cardiomyopathy
Authors: Tarazon E , Perez Carrillo L , Alvarez I , Gimenez Escamilla I , Delgado Arija M , Gonzalez I , Portoles M , Rosello-Lleti E
Published: November 2023

Introduction

In last decade, knowledge of how non-coding RNAs (ncRNAs) contribute to the pathogenesis of cardiovascular disease has increased exponentially. However, other than miRNAs, relatively little is known about how other small RNAs specifically contribute to heart failure. snoRNAs have been known for decades, mainly for their role in biogenesis and ribosomal modification. Moreover, recent studies have provided fundamental information on how snoRNA regulated non-coding RNA expression. However, the contribution of these non-coding RNAs to human disease is a relatively new area of research, with heart failure being relatively unknown and understudied.

Purpose

We aimed to investigate whether snoRNA expression is regulated during heart failure from dilated (DCM) and ischemic (ICM) origin, and how its biogenesis is affected by the pathophysiology of the disease.

Methods

Heart tissue samples from ICM (n=22) and DCM (n=20) patients and control (CNT, n=8) subjects were analyzed by non-coding RNA-Sequencing (ncRNA-Seq) to evaluate transcriptome changes in snoRNA/scaRNA. In addition, through mRNA sequencing we analyzed the biogenesis pathway of these ncRNA in ICM (n=13) and DCM (n=13) patients compared to CNT (n=10). Microarray analysis was used to validate the alterations found in the snoRNA/scaRNA expression (ICM, n=24; DCM, n=20; CNT, n=10).

Results

A generalized alteration of the snoRNA biogenesis pathway was not observed, we only found NOLC1 underexpression in ICM patients (FC=-1.42, p<0.05). NOLC1 encodes a nucleolar protein that acts as a regulator of RNA polymerase I and connects RNA polymerase I with enzymes responsible for ribosomal processing and modification. However, ncRNA-Seq data showed altered profiles of snoRNA/scaRNA in ICM and DCM patients. We identified 24 differentially expressed snoRNAs in ICM and 35 in DCM, while only 3 scaRNAs in DCM patients. We highlight SNORD14C that was upregulated in DCM patients (FC=2.37, p<0.01) and we confirmed in the microarray analysis (FC=1.10, p<0.05). Moreover, SNORD116-18 was related to ejection fraction in ICM patients (r=0.460, p<0.05).

Conclusion

Our data indicate that there are changes in the expression of snoRNA and scaRNA with a specific profile for each etiology, ICM and DCM. However, a marked alteration in its biogenesis is not observed. Taken together and given the relationship of SNORD116-18 to ventricular function, our results offer a novel and promising insight into the differential involvement of these molecules in the pathophysiology of ICM and DCM.
Modeling cardiac injury using human cardiac slices to test therapeutic approaches for cardiac regeneration and repair
Authors: Lodrini A M , Meijboom E M , Bezhaeva T , Bogunovic N , Kruithof B P T , De Vries A A F , Quax P H A , Smits A M , Goumans M J
Published: November 2023

Background

Due to limited regenerative capacity of the adult human heart, myocardial infarction causes irreversible damage by inducing the death of cardiomyocytes and the formation of a fibrotic scar. These remodeling mechanisms cause loss of contractility and eventually heart failure ensues in a significant proportion of patients.

Purpose

There is a need for a reliable model that can replicate the adult cardiac pathophysiology in order to test treatments against cardiac remodeling. Here, we developed a cardiac tissue culture model that can simulate in vitro the molecular changes occurring after cardiac injury using human cultured cardiac slices.

Methods

We obtained cardiac slices by sectioning ventricular myocardium from the surgical waste material of adult patients undergoing valve surgery or Morrow myectomy. Cardiac slices were cultured at a liquid-air interface and were viable up to 7 days of culture, even in the absence of stimulation. During this time cardiac slices underwent mechanical and chemical treatments to induce ischemia and/or local injury.

Results

We found that following these treatments we were able to simulate cardiac remodeling in terms of cardiomyocyte death, activation of cardiac fibroblasts and induction of inflammation and oxidative stress. Following small molecule screening, we discovered that addition of compounds with anti-inflammatory properties (e.g. dexamethasone) or targeting the TGF-β pathway (e.g. SB-431542) into our culture medium helped in preserving the microscopic structure of the slices. Additionally, we found that treatment with these compounds protected cardiac slices against remodeling following ischemic injury.

Conclusions

In conclusion, our model can emulate cardiac pathophysiology in culture, providing us a reliable platform to test therapies for cardiac regeneration and repair in an adult, multicellular, 3-D environment.
Plasma levels of intact parathyroid hormone and congestion burden in heart failure: clinical correlations and prognostic role
Authors: Ciccone M M , Capriati G , Gambacorta S , Antonica C , De Palo M , Massari F , Scicchitano P
Published: November 2023

Circulating parathyroid hormone (PTH) concentrations increase in heart failure (HF) and are related to disease severity. The relationship between PTH and congestion is still a matter of debate. The objective of this analysis was to evaluate the role of PTH as a marker of congestion and prognosis in HF. We enrolled 228 patients with HF. Intact PTH concentrations and HYDRA score (constituted by: B-type natriuretic peptide, blood urea nitrogen-creatinine ratio, estimated plasma volume status, and hydration status) were evaluated. The study endpoint was all-cause mortality. PTH levels were higher in acute compared with chronic HF and in patients with clinical signs of congestion (i.e., peripheral oedema and orthopnea). PTH concentrations significantly correlated with NYHA class and HYDRA score. At multivariate analysis of HYDRA score, estimated glomerular filtration rate (eGFR), and corrected serum calcium were independently determinants of PTH variability. Fifty patients (22%) died after a median follow-up of 408 days (interquartile range: 283-573). Using univariate Cox regression analysis, PTH concentrations were associated with mortality (hazard ratio [HR]: 1.003, optimal cut-off: >249 pg/mL-area under-the-curve = 0.64). Using multivariate Cox regression analysis, PTH was no longer associated with death, whereas HYDRA score, left ventricular ejection fraction, and eGFR acted as independent predictors for mortality (HR: 1.96, 0.97, and 0.98, respectively). Our study demonstrated that intact PTH was related to clinical and subclinical markers of congestion. However, intact PTH did not act as an independent determinant of all-cause death in HF patients.
The SGLT2I Dapagliflozin reverses metabolic stress driving myocardial inflammation in a mouse model of heart failure with preserved ejection fraction: insights from single-cell RNA sequencing
Authors: Panico C , Felicetta F , Kunderfranco P , Salvarani N , Carullo P , Rubino M , Cremonesi M , Peano C , Colombo F , Passaretti M , Doro R , Villaschi A , Kallikourdis M , Greco C M , Condorelli G
Published: November 2023

Background

Heart failure with preserved ejection fraction (HFpEF) is often associated with metabolic distress and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes impact myocardial inflammation in the context of HFpEF is not known.

Methods

We generated a model of metabolic HFpEF by feeding ApoE knockout (ApoE KO) mice a high-fat diet (HFD), and used single-cell expression analysis (scRNA-seq) on CD45+ cardiac cells to evaluate the involvement of inflammation. By focusing our analysis on macrophages, we obtained high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and identify a macrophage-to-cardiomyocyte (CMC) regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor (SGLT2i) could ameliorate the cardiac immune infiltrate profile in our model, ApoE KO-HDF mice were randomized to receive the SGLT2i dapagliflozin (DAPA) or vehicle for 8 weeks.

Results

We describe a new metabolic HFpEF model: mice present with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 sub-populations of resident and monocyte-derived macrophages displaying a pro-inflammatory profile exclusively in ApoE KO-HFD mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic-reticulum stress pathways. Investigation of the macrophage-to-CMC regulatory axis revealed the potential effects on CMCs of multiple inflammatory cytokines secreted by macrophages, impacting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe the anti-inflammatory effect of SGLT2i.

Conclusions

Through a newly described model of HFpEF based on metabolic stress, and using scRNA-seq, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest SGLT2i as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.