bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors and outcomes of intracranial hemorrhage in 58,000 patients with atrial fibrillation on oral anticoagulation: insights from COMBINE-AF
Authors: Tannu M , Hua K , Hankey G , Alexander J H , Giugliano R P , Eikelboom J , Lopes R , Wallentin L , Ruff C , Oldgren J , Patel M , Jones W S , Mahaffey K W , Carnicelli A , Granger C B
Published: October 2024

Background

Among anticoagulated patients with atrial fibrillation (AF), intracranial hemorrhage (ICH) is the leading cause of bleeding-related death and disability. The COMBINE-AF database has patient-level data from four major randomized-controlled trials [ROCKET-AF (rivaroxaban), RE-LY (dabigatran), ENGAGE-TIMI 48 (edoxaban), ARISTOTLE (apixaban)] of direct oral anticoagulants (DOACs) versus warfarin in patients with AF.

Purpose/Methods

We investigated the rates, predictors, and mortality of ICH in patients randomized to DOAC (rivaroxaban, dabigatran, edoxaban, apixaban) or warfarin. ICH was subclassified as subdural or non-subdural (intracerebral, intraventricular, subarachnoid, epidural). Multivariable Cox models were used to identify predictors of ICH. Frequencies and fatality rates of ICH were calculated and displayed as Kaplan-Meier curves.

Results

In COMBINE-AF, there were 58,634 patients randomized to either DOAC (n=29,362) or warfarin (n=29,272). The mean age was 70.5 years, 37% were female, and 81% were White. The mean CHA2DS2-VASc score was 2.6, 43% of patients had a history of smoking, 31% had diabetes, and 29% had prior stroke/TIA.

After a mean of 32 months, ICH occurred in 593 patients (1.01%, 0.58 per 100-patient years, 95% CI [0.54, 0.63]). The most significant independent predictors of ICH in order of importance were: treatment with warfarin, older age, prior stroke/TIA, enrollment in Asia, antiplatelet use at randomization, and history/risk of falls (Figure 1).

Mortality after ICH was 48.4% (287/593 participants), with a majority of deaths (82%) occurring within 30 days of ICH event. Non-subdural ICH was more common than subdural ICH (73% vs 25%) and had a higher risk of death (Figure 2). Participants randomized to DOAC had a lower risk of both subdural and non-subdural ICH than those treated with warfarin; however, mortality rates after ICH were similar regardless of anticoagulant type.

Conclusion

ICH is an uncommon but devastating complication of oral anticoagulation in patients with atrial fibrillation. The mortality rate following ICH is high, particularly following non-subdural ICH. To reduce the risk of ICH, clinicians should consider using DOACs over warfarin and carefully evaluate the need for antiplatelet therapy, particularly in patients with other significant predictors of ICH such as prior stroke, advanced age, residence in Asia, and history of falls.Predictors of Intracranial Hemorrhage90-Day Mortality after ICH
Combined PVI and LAAC is feasible using RFA or PFA in a canine model despite acute tissue edema in PFA versus RFA
Authors: Saliba W , Delurgio D , Mikaelian B , Jaber W , Baldo C , Kilvington J , Curtis M A , Shuros A , Hynes E , Natale A
Published: October 2024

Background

Combined procedure with pulmonary vein isolation (PVI) using thermal energy followed by left atrial appendage closure (LAAC) has been used in select patient populations with positive results. Pulsed field ablation (PFA) is a novel non-thermal ablation modality that ablates cardiac tissue by irreversible electroporation. The effect of PFA on cardiac tissue and its interaction with a LAAC device in a single procedure has not been studied.

Purpose

To evaluate using transesophageal echo (TEE) imaging the acute tissue response following ablation by PFA compared to radiofrequency ablation (RFA) and its interaction with the WATCHMAN FLX Pro LAAC device when used in a combined procedure in a healthy canine model.

Methods

Nine mongrel canines underwent PVI using either circumferential PFA (FARAPULSE) energy application (n=6) or RFA energy (n=3). TEE imaging was obtained at the time of the procedure before and immediately after ablation energy application. The general appearance and echogenicity of the left lateral ridge was assessed and the os of the left atrial appendage (LAA) was measured in the four standard TEE views (0, 45, 90, and 135 degrees). Decisions about device sizing were made accordingly. PVI was evaluated by entry and exit block in all veins except the right inferior pulmonary vein (RIPV), which was not ablated. Following ablation, the LAAC device was implanted using TEE and fluoroscopic guidance in all animals and the percentage of compression measured. PASS criteria were assessed before the release of each device. All animals received dual antiplatelet therapy post implant.

Results

PVI was confirmed in all animals (except RIPV which was not targeted for ablation) using PFA and RFA. LAA dimensions (at device landing site) did not change substantially after RF ablation. With PFA, there was evidence of more diffuse edema and decrease in LAA diameter (Table). The LAAC device was implanted successfully after meeting PASS criteria in all animals within 30 minutes post ablation. The device size was decreased following PFA in two (2/6) animals, whereas there was no deviation from baseline measurements in device size for any of the RFA animals. Average LAAC device compression was higher for PFA versus RFA animals (Table). TEE post implant confirmed absence of any peri-device leaks in all animals.

Conclusion

Concomitant PVI using PFA (FARAPULSE) and LAAC (WATCHMAN FLX Pro) is feasible with 100% success and no residual acute peri-device leak. In the canine model, PFA is associated with more diffuse edema compared to RFA, which might affect device sizing. Long term consequences of this acute edema need to be evaluated in serial imaging and future larger clinical trials.Table
Diagnostic yield of actionable arrhythmias in patients referred with syncope and collapse using ePatch extended holter
Authors: Dunn A , Parikh P , Gillstrom G , Wadhwa M
Published: October 2024

Background/Introduction

Cardiac syncope commonly points to a potentially lethal disease process and carries one-year mortality up to 30%. Current guidelines on management of syncope suggest choosing ambulatory monitoring modality based upon the likelihood of symptoms during the monitoring period and is frequently undertaken with short duration (0-2 days) or extended wear Holter (EWH) monitoring (3-14 days).

Purpose

Determine the diagnostic yield (DY) of actionable arrhythmias (AA) in patients referred for syncope and collapse prescribed short or extended ambulatory monitoring.

Methods

A retrospective analysis was conducted for patients wearing the Philips ePatch between July 1st, 2022, and June 30th, 2023, with ICD-10 referral code R55 (Syncope and Collapse). Monitoring duration was grouped by 0-2, 3-7, and 8-14 days of wear time. Wear time was defined as number of hours with analysable ECG data. Arrhythmia detection was defined as either non-AA (did not meet urgent or emergent criteria) or AA (met urgent and/or emergent criteria). Urgent criteria were defined as Atrial Fibrillation/Flutter (>10 seconds), Ventricular Tachycardia (>100 BPM for >3 beats), Severe Tachycardia (>170 BPM for ≥30 seconds), Pause/Asystole (≥3 seconds), Severe Bradycardia (<35 BPM), and 2nd Degree or Higher AV Block. Emergent criteria were defined as VT (>100 BPM for ≥30 beats), Severe Tachycardia (≥220 BPM for ≥30 seconds), Pause/Asystole (≥10 seconds), and Severe Bradycardia (<20 BPM).

Results

The DY for any urgent and/or emergent AA was 6.8%, 11.0%, and 20.4% at 0-2, 3-7 and 8-14 days of wear time, respectively (p<0.00001 for all). For urgent AA, DY increased 1.6X at 3-7 vs 0-2 days, 1.9X at 8-14 vs 3-7 days and 3X at 8-14 vs 0-2 days of wear time (p<0.05 for all); for emergent AA, the DY increased 5X at 3-7 vs 0-2 days, 1.6X at 8-14 vs 3-7 days, and 8.2X at 8-14 vs 0-2 days of wear time (p<0.05 for all) (Graph 1). When examining tachyarrhythmias vs bradyarrhythmias, similar multiplicative yields in AA were noted between short, intermediate, and extended duration monitoring; statistical significance was noted for all arrhythmia subtypes (p<0.01), except for Severe Tachycardia and Bradycardia which were not significant between 0-2 and 3-7 days of wear time (Graph 2).

Conclusion(s)

In patients referred for ambulatory monitoring with syncope and collapse, urgent and emergent actionable arrhythmias increase significantly when extending from short to intermediate to long duration monitoring, with both tachyarrhythmias and bradyarrhythmias demonstrating similar increases in occurrence. Accordingly, EWH monitoring in patients referred with syncope and collapse has greater potential to identify arrhythmic aetiologies than use of standard duration Holter.
Implications of age and sex on the diagnostic yield of sudden arrhythmic death syndrome
Authors: Gray B , Behr E R , Papatheodorou E , Raju H , Wijeyeratne Y , Finocchiaro G , Malhotra A , Cook S , Whiffin N , Ware J , Tome Esteban M , Sheppard M , Sharma S , Papadakis M
Published: October 2024

Introduction

Sudden arrhythmic death syndrome (SADS) refers to an unexplained sudden death with a negative autopsy. An inherited cardiac condition (ICC) may be diagnosed through familial clinical evaluation (FE) or post-mortem genetic testing (molecular autopsy [MA]) or both. We aimed to investigate the impact of age and sex of SADS decedents on the diagnostic yield and aetiology to facilitate a targeted approach to management.

Methods

Consecutive referrals to a single centre for FE only, MA only or both, following a SADS death were included. First-degree family members underwent comprehensive FE. A panel of 36 cardiac genes was sequenced for MA. A post-mortem diagnosis could be obtained by either FE, MA or both. A Bayesian framework for analysis was performed to identify associations.

Results

Seven-hundred-and-sixty SADS decedents (66% male; mean age 31±12 years) were investigated. The overall diagnostic yield for an ICC was 37% (32-42%) and 9% (6-12%) for FE and MA cohorts, respectively. In a subset where both MA and FE were performed the diagnostic yield was 45% (38-61%). For each year increase in age, the relative risk of an FE diagnosis of long QT syndrome (LQTS) or Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) versus remaining unexplained declined by 5.6% (RR 0.94 [0.91-0.98]) and by 11% (RR 0.89 [0.81-0.97]), respectively. Females were more likely to have a diagnosis compared with males by both FE (40% [34-45%] vs 36% [31-41%]) and MA (15% [10-21%] vs 6% [3-8%]). Females (8.1% [4.1-13.4%)], were more likely to be diagnosed with LQTS than males (1.2% [0.2-2.7%]) in the MA cohort.

Conclusions

After a SADS death, the diagnostic yield of comprehensive FE, MA or both in an expert setting can be up to 45%. Younger age of death is associated with greater likelihood of LQTS and CPVT diagnosis with the highest yield in children and adolescents. Female sex in SADS decedents is associated with a higher yield of LQTS in MA. These data highlight the relative utility of FE and MA depending on age and sex for determining underlying diagnoses following SADS deaths.
A sane approach to the high volume of alert transmissions in remote monitoring- turning of clinically non-relevant alerts decreases substantially workload
Authors: Sane M , Jantti T , Marjamaa A , Karvonen J , Raatikainen P
Published: October 2024

Background

Remote monitoring (RM) offers a safe and effective method of monitoring patients with cardiac implantable electronic devices (CIEDs). The downside of RM is the data deluge of various transmissions, the majority of which are non-actionable. It has been suggested that optimizing alert transmissions could partly overcome this problem.

Purpose

The purpose of this study is to evaluate how the workload in RM can be safely decreased by thoroughly assessing the clinical relevance of each alert and deactivating non-relevant alerts.

Methods

Data on the number of alerts, scheduled and patient-initiated transmissions, as well as the causes and actions initiated by the transmissions, were systematically collected from the year 2023, during which the approach of actively deactivating clinically non-relevant alerts was conducted (A sane approach, Figure 1). The trend of alert transmissions and the proportion of actionable scheduled transmissions are presented.

Results

Overall, during the study period, 8182 transmissions were generated from 3732 followed CIEDs. Of these, 2306 were alert transmissions, and the rate of alerts decreased by 56% during the follow-up, from 0.07 to 0.04 per device per month. Additionally, our data shows that new alerts that have not occurred in the previous six months occurred on average at a rate of 0.03 per CIED per month, and this trend remained unchanged during the follow-up. Of the 3335 scheduled transmissions, 11% (364) were actionable, and both the number and proportion of actionable scheduled transmissions remained unchanged during the follow-up period. Interestingly, no alerts were triggered from 1124 (70%) of all patients but 88 (2%) of all CIEDs generated 30% of all alerts.

Conclusions

In this study, we demonstrate that RM workload can be decreased by actively evaluating the clinical relevance of each alert transmission. Our approach, where non-relevant alerts are turned off, likely does not impair patient safety and thus this practise enhance the RM.
A propensity-matched cohort study examining the impact of gentamycin-collagen sponge on the prevention of infections in patients with implantable cardioverter defibrillator undergoing revision surgery
Authors: Kleemann T , Mousavi S B , Kouraki K , Strauss M , Mohammad O , Wenz A , Weisse U , Werling C , Sack F , Zahn R
Published: October 2024

Introduction

Despite the obvious benefits, the use of implantable cardioverter defibrillators (ICDs) is associated with serious complications, including infections. In particular, device replacement or revision procedures are associated with an increased risk of infection. Aim of the study was to compare the cardiac device infection rate with and without the use of the gentamycin-collagen sponge (GCS) in patients undergoing device replacement or revision procedures of implanted ICDs.

Methods

This cohort study analyzed ICD patients from a prospective single-centre ICD-registry who underwent elective device replacement, system upgrade or lead revision between 2014 and 6/2023. From September 2020 onwards, a GCS was inserted into the device pocket (GCS group, n = 204). Each patient of the GCS group was matched to a control without GCS.

Results

The baseline characteristics and the PADIT score were well matched except for the rate of submuscular device pockets which was lower in the GCS group (Table 1). The GCS was well tolerated and there were no complications associated with the GCS. The Kaplan-Meier estimated infection rate after one year was 1.0% in the GCS group and 6.5% in the control group (p < 0.001, Figure 1). Time from revision to infection was 144 + 134 days in the GCS group vs. 334 + 261 days in the control group.

Conclusion

Adjunctive use of a GCS was associated with a lower incidence of device infections than standard-of-care infection-prevention strategies alone.Table 1Figure 1
Latent class analysis reveals a novel phenotype of heart failure that spans the left ventricular ejection fraction range
Authors: Leyba K , Roeder C R , Goerg C , Jhund P , Kao D P
Published: October 2024

Background

It is increasingly evident that heart failure (HF) represents a heterogenous syndrome rather than a single clinical entity. The elusiveness of effective therapies for heart failure with preserved ejection fraction (HFpEF) has led to a consensus that our current, unidimensional construct of HF using only left ventricular ejection fraction (LVEF) does not adequately capture the multiplicity of the disease states. The ability to harmonize echocardiographic data from multiple sources has enabled use of unsupervised cluster-based analysis to identify multidimensional cardiac structural phenotypes.

Purpose

To identify cardiac structural phenotypes of HF across the LVEF spectrum.

Methods

We harmonized echocardiographic data from eight randomized clinical HF trials (ESCAPE, EXACT-HF, FIGHT, I-PRESERVE, NEAT-HFpEF, RELAX, STICH and TOPCAT), which included both HFrEF and HFpEF populations (total n=4223 echocardiograms). These studies collectively spanned the years 2000 through 2015 and represent a balanced LVEF distribution. Latent class analysis (LCA) was performed iteratively to identify predominant structural phenotypes using LVEF, RV function, LV end diastolic volume, LV mass index, eccentricity, mitral valve deceleration time, and lateral E/e’ ratio.

Results

LCA identified 4 echocardiographic phenotypes. Three phenotypes skewed toward either high or low EF, but one phenotype demonstrated a relatively even distribution of patients with HFrEF, heart failure with mildly reduced ejection fraction (HFmrEF) and HFpEF (36.0%, 21.4% and 42.7%, respectively). Patients in this phenotype had preserved RV function and left ventricular hypertrophy (97%), of which 56.8% had concentric and 43.2% eccentric LVH. E/e’ was normal in 63% of subjects. A vast majority (91%) of patients had recent-onset HF (diagnosed within the past year). There were no remarkable distinguishing comorbidities. Notable differences in biomarker profile included higher levels of troponin I, cyclic GMP and lower levels of neurohormones (aldosterone, endothelin-1, dopamine, and norepinephrine) than the other phenotypes.

Conclusions

This is the first cluster-based analysis to identify a quantitative structural HF phenotype of HF that is not distinguished by LVEF. While the underlying pathophysiology is unclear, most patients have recent onset HF and biomarker profiles with relatively low neurohormone activity. These features may reflect a distinct pathophysiology that could indicate a specific, targeted intervention.
Interventricular abnormal septum displacement as contributory mechanism for impaired peak oxygen consumption and exercise cardiac output response in heart failure
Authors: Crisci G , Serrantoni V , Losito M , Bursi F , Zegarra T , Guazzi M
Published: October 2024

Background

In Heart failure (HF), the role of septum position and abnormal right ventricular (RV) geometry in determining exercise performance is unknown. Especially an abnormal interventricular septal (IVS) position is a well-known sign of RV pressure overload which affects left ventricular filling and output due to interdependence.

Aim

We postulated that an abnormal septum displacement during exercise and RV geometry alteration would affect peak exercise oxygen consumption (VO2) and cardiac output (CO) increase.

Methods

17 HF patients with reduced ejection fraction (HFrEF) (mean age 71±12) underwent a cardiopulmonary exercise testing imaging (iCPET) with RV 3D-imaging analysis and were compared with a control population (mean age 67±14).

3D imaging of the RV chamber was examined off-line using the 4D RV TomTec software and obtained 3D mesh of the RV model using custom software to obtain the mean curvature value of IVS in 4 regions of: inflow tract (RVIT), outflow tract (RVOT), apical and body.We acquired measurements of curvature during end-diastole (ED) and at end systole (ES) phases and obtained a parametric curvature map.

Results

HF patients typically exhibited an abnormal of septal curve, with a more leftward configuration either at rest and under exercise (rest =−0.01±0.004 at ED, and −0.01±0.006 at ES; peak exercise= −0.01±0.004 at ED, and −0.01±0.004 at ES, Figure) compared to controls (rest=−0.02±0.003 at ED, and −0.02±0.005 at ES; peak exercise −0.02±0.008 at ED, and −0.03±0.006 at ES, Figure). Notably, the degree of the IVS curvature was found to linearly correlate with an impaired gas exchange performance as lower peak VO2 and a limited CO in HF (respectively r=0.62, p<0.001 and r=0.5, p<0.001 at ED during exercise; r=0.34, p<0.001 at ES during exercise, Figure).

Conclusions

In HF, the RV geometrical alterations reflected by an abnormal IVS displacement appear as novel contributory factors to a reduced exercise performance, impaired oxygen uptake and decreased CO.
Fabry cardiomyopathy: myocardial fibrosis, inflammation and reduced mannose6phosphate receptors cause low accessibility to enzyme therapy
Authors: Frustaci A , Verardo R , Magnocavallo M , Frustaci E , Russo M A , Chimenti C
Published: October 2024

Background

Clinical impact of enzyme replacement therapy (ERT) on advanced Fabry disease cardiomyopathy (FDCM) appears limited.

Purpose

Clarify the pathologic mechanisms responsible of ERT inefficacy in the advanced FDCM.

Methods

Ten male patients with advanced FDCM (echocardiographic maximal wall thickness 19.3 ± 2.1 mm) underwent left ventricular endomyocardial biopsy before and 4 hours after beta-agalsidase infusion. Comparative studies between pre and post infusion samples included: histology and electron microscopy; assessment of myocardial alpha-galactosidase A activity; immunohistochemistry for alpha-galactosidase A and semiquantitative evaluation (from 0 to 3) of its cardiomyocyte content; Ultrastructural immunogold analysis with anti-alpha-galactosidase A ab. Western Blot (WB) quantification of mannose-6-phosphate receptors (M6Pr). Controls were surgical left ventricular biopsies from patients with mitral stenosis.

Results

Histologic and Ultrastructural evaluation showed no removal of storage material while myocardial fibrosis was 9.8 ± 6.8 vs 3.8 ± 2.0 of controls and virus-negative lymphocytic inflammation was observed in 7 out of 10 patients. At Ultrastructural immunogold analysis, Myocardial alpha-galactosidase A activity increased in post infusion samples by overall 1.89-fold.

Alpha-galactosidase A immunostaining in cardiomyocytes was absent at baseline in all patients and did not significantly improve in post-infusion samples. Immunogold particles increased by 1.33-fold remaining far from normal controls (86.9 ± 6.6).

Protein analysis showed M6Pr in advanced FDCM to be 81% lower than in normal heart.

Conclusions

Our study shows a low accessibility to ERT of cardiomyocytes affected by advanced FDCM. It is sustained by myocardial fibrosis, inflammation and severe down-regulation of M6Pr.

Figure Legend

Histologic and ultrastructural and mannose6phosphate receptors characteristics of patients with severe Fabry Disease Cardiomyopathy.

Panel A shows severe cellular glycolipid infiltration associated with diffuse interstitial fibrosis (Masson trichrome, 100x). Panel B reveals an overlapping lymphocytic CD45Ro+ myocardial inflammation with focal necrosis of adjacent cardiomyocytes. Insert(i), Ultrastructural detail showing vacuoles (black arrows) to consist of myelin bodies,( scale bar=3μm). Panel C (upper) Western blot analysis of all 10 patients of Mannose-6-phosphate Receptor, molecular weight 275 Kd. Alpha sarcomeric actin (43 kDa) was used as a loading control. (Panel C -lower)

Panel D: Graphs document western blot of Mannose-6-phosphate Receptor, in all 10 patients with severe FDCM showing 3-fold lower of Mannose-6-phosphate Receptor values in patients versus normal heart (4.830 ± 1116,724 vs 14.737± 1145,386; p < 0.001).
Gender differences in the evolution of echocardiographic HFpEF characteristics through age deciles: is menopause an inflection point?
Authors: George K , Gorcilov J , Hecker T , Eng-Frost J , De Pasquale C
Published: October 2024

Background

Heart failure with preserved ejection fraction (HFpEF) is more prevalent with advancing age and in females. Since sex hormones have trophic effects, menopause may be an inflection point in HFpEF gender characteristics.

Aim

To compare left ventricular (LV) echocardiographic parameters between gender, through age deciles.

Methods

A sequential "normal" outpatient cohort in sinus rhythm with Ejection Fraction (EF) >50%, ≤ mild valvular dysfunction, normal chamber sizes and tricuspid regurgitation (TR) gradient <39mmHg were included. Analysis was performed by Kruskal-Wallis and Mann-Whitney U tests. Results are median (quartiles) and p-values of <0.05 were considered significant.

Results

In 634 patients (65% females), EF tended be larger in females from the fifties decile; females EF 62% (59,65) versus males 60 (56,64) p= 0.013, sixties 62 (58,66) versus 61 (58,64), p=0.07, seventies 63 (59,67) versus 60 (55,64) p=0.009. Mitral inflow characteristics of HFpEF (E:A decreased and E;e’ increased) and TR gradient (increased) progressively evolved throughout the deciles, with no apparent gender difference (males and females all p<0.001). However, while body surface area (BSA) normalised LV diastolic diameters decreased in males (p<0.05) and females (p<0.01), LV systolic diameter (decrease, p<0.01) and left atrial size (increase, p<0.01) only changed in females.

Conclusions

Whilst age progressively alters hemodynamic echocardiographic characteristics of LV diastolic dysfunction in both sexes, females demonstrate larger LVEF from the fifties decade and left sided structural changes (smaller LV systolic diameter and larger left atrial size) not seen in males. This chronology supports a potential role of loss of sex hormones in HFpEF aetiology.
Assessment of cardiopulmonary exercise capacity in suspected heart failure with preserved ejection fraction: impact of coronary flow velocity reserve and body fat
Authors: Kim S , Cho D H , Kim M N , Kim B R , Park S M
Published: October 2024

Background and objectives

Heart failure with preserved ejection fraction (HFpEF) has various pathophysiology including coronary microvascular dysfunction (CMD), obesity, and frailty. In the present study, we aimed to assess the cardiopulmonary exercise capacity according to coronary microvascular function and body composition in patients with suspected HFpEF.

Methods

Patients with chest symptoms with non-obstructive coronary artery disease (<50% stenosis) and preserved left ventricle (LV) ejection fraction (≥50%) were enrolled. LV end-diastolic pressure was measured during coronary angiography. All patients underwent body composition analysis, adenosine stress echocardiography with the evaluation of coronary blood flow, and cardiopulmonary exercise test assessing maximal oxygen consumption (VO2max). Coronary flow velocity reserve (CFvR) was defined as the ratio of peak to baseline mean diastolic velocity of coronary blood flow. Association between VO2max and CFvR as well as body composition was assessed.

Results

Of the 106 patients (mean age 63.5), 54 (50.9%) were women, 52.4% had hypertension, and 28.6% had diabetes. Baseline LV end-diastolic pressure was 15.3 ± 5.5 mmHg. Median Heart Failure Association-PEFF score was 3, while medial e’ velocity was 6.7 ± 2.0 cm/s and E/e’ was 9.6 (7.6 – 12.0). Mean diastolic velocity of coronary blood flow was 0.17 [interquartile range (IQR) 0.13 – 0.23] m/sec at baseline, while it increased to 0.46 [IQR 0.38 – 0.57] m/sec at peak, resulting in CFvR of 2.75 [IQR 2.10 – 3.67]. Eighteen (17.1%) patients had CMD (CFvR <2.0). VO2max was 23.1 ± 5.4 mL/kg/min with lower value in women (21.7 ± 4.8 vs. 24.5 ± 5.6 mL/kg/min, p = 0.007). CFvR was directly related to VO2max (r = 0.350, p <0.001). In body composition, skeletal muscle mass index, percent body fat, and visceral fat area were associated with VO2max. In multivariable analysis, age, visceral fat area or percent body fat, and CFvR were linearly correlated with VO2max, and estimated VO2max was well correlated with measured VO2max.

Conclusions

Cardiopulmonary exercise capacity represented by VO2max was correlated with CFvR and body composition including skeletal muscle mass index, percent body fat, and visceral fat area in patients with suspected HFpEF. VO2max could be estimated by CFvR and fat component in the body.
cardioprotective effects of nicorandil on mitochondrial apoptosis signaling in the failing heart of cardiac-specific Bcl-2-associated athanogene (BAG) 3 knockout mice
Authors: Sanbe A , Obara M , Sato S , Hanasaka T , Hirose M , Taira E
Published: October 2024

Background

Bcl-2-associated athanogene (BAG) 3 is a known regulator of mitochondrial apoptotic cell death and autophagic protein degradation in the heart. Disruption of the BAG3 gene in a cardiac-specific manner can lead to cardiac failure in mice. However, therapeutic approaches for cardiac failure induced by BAG3 gene disruption remain poorly understood.

Method and results

We characterized mice with the ablated BAG3 gene using the Cre-recombinase-loxp site system in a cardiac-specific manner (BAG3f/f crossbred with cardiac specific Cre transgenic mice; BAG3 cKO) and examined the therapeutic effect of nicorandil, an antianginal drug, in BAG3 cKO mice. Cardiac BAG3 levels were markedly reduced in the cytoplasmic and mitochondrial fractions from the hearts of BAG3 cKO mice compared to BAG3f/f mice. BAG3cKO mice exhibited cardiac disease such as a reduction in fractional shortening detected by echocardiography, cardiac fibrosis at 6 months of age, and approximately 40% premature death by 6 months of age. Electron microscopy analysis confirmed cardiomyocyte loss and mitochondrial abnormalities in some areas of the heart section from BAG3cKO mice at 4.5 months of age. A marked decrease in the level of cytochrome C in the mitochondrial fraction and a slight increase in the cytoplasmic fraction, along with apoptotic cell death, were observed in hearts from BAG3 cKO mice at 4.5 months. Mitochondrial levels of anti-apoptotic factors, such as Bcl-2 and Bcl-xl, were reduced, while there was a marked increase in Bak1, an apoptotic inducible factor, in hearts from BAG3 cKO mice at 4.5 months of age. These results suggest that cardiac mitochondrial impairment and subsequent apoptotic cell death occurred in BAG3cKO mice. Nicorandil treatment (81 mg/L drinking water) initiated at 2 months of age prevented the reduction of fractional shortening, cardiac fibrosis, ultrastructural cardiac abnormalities, and premature death. Furthermore, nicorandil treatment prevented the decrease in mitochondrial cytochrome C and the increase in cytoplasmic cytochrome C in hearts from BAG3 cKO mice at 4.5 months of age. Nicorandil treatment also inhibited the elevation of mitochondrial Bak1 levels, reduction in Bcl-2 levels, and occurrence of apoptotic cell death in hearts from BAG3 cKO mice at 4.5 months of age.

Conclusion

Long-term treatment with nicorandil can inhibit cardiac disease induced by cardiac- specific BAG3 ablation through mitochondrial protection via the prevention of activation of mitochondrial apoptosis signaling.
Obesity plays a key role in inducing myocardial and vascular dysfunction in a translational model of heart failure with preserved ejection fraction in rats
Authors: Simoes M , Oliveira-Neto P , Sapalo A T , Tanaka D M , Carvalho E E V , Rodrigues K P , Souza H C D , Tostes R , Fazan R , Romano M M
Published: October 2024

Background

Exploring experimental models of heart failure with preserved ejection fraction (HFpEF) may help to understand the mechanisms leading to this challenging condition.

Purpose

In a translational model, we aimed to assess the relative contribution of hypertension and obesity in inducing structural, functional and hemodynamic changes associated to the HFpEF phenotype.

Methods

We investigated 3 groups of male 40 weeks old rats: control Wistar Kyoto (WKY, n=10), Spontaneous Hypertensive Rats (SHR, n=10) and SHR with obesity induced by consumption of cafeteria diet during 28 weeks (Ob-SHR, n=9). Animals were submitted to assessment of: body weight, systolic (SBP) and diastolic (DBP) blood pressure; in vivo structural and functional changes evaluated by high resolution Echocardiography including left atrial dimension (LA), left ventricle (LV) diastolic dimension (LVDD), LV posterior wall thickness (LVPW), LV wall relative thickness (LVWRT), LV ejection fraction (LVEF). Invasive hemodynamic evaluation assessed the intraventricular pressure curves obtaining LV end diastolic pressure (LVEDP) and calculation of LV diastolic time constant (Tau). After euthanasia, thoracic aorta was used for vascular function assessment by measuring the maximal cumulative concentration-effect curves of contraction to phenylephrine (PE), expressed as Emax (%). Protein expression of Intercellular Adhesion Molecule 1 (ICAM-1) was determined in myocardial tissue (% in relation to WKY). Results were expressed as mean ± SEM and effects of groups vs time were compared with mixed ANOVA.

Results

The results are shown in the table. We observed higher levels of SBP and DBP in SHR and Ob-SHR when compared to WKY, but with similar values between SHR and Ob-SHR groups. Regarding the structural LV changes, we observed LV remodeling and LA dilation in both SHR and Ob-SHR groups, but with no difference between both hypertensive groups. The Ob-SHR was the only group showing increased LVEDP in comparison to other groups. The Tau was also increased in the Ob-SHR animals. Concordantly, the Ob-SHR group showed increased expression of ICAM-1 (figure - A) that was concomitant to abnormal vascular response with increased contraction to PE (figure - B) as compared to SHR and WK groups.

Conclusions

In this translational model of HFpEF in rats, the structural changes related to LV remodeling were similar in SHR and Ob-SHR, probably reflecting comparable higher levels of blood pressure observed in both groups. In contrast, elevated EDP, a hallmark of HFpEF, was only seen in the Ob-SHR group and this was concomitant to diastolic dysfunction, endothelial inflammatory activation and altered vascular function. Our results indicate that obesity is a key factor inducing vascular and myocardial changes that triggers HFpEF phenotype in this model.
Association of epicardial adipose tissue with cardiac geometry alternation and diastolic dysfunction in the early stage of diabetic cardiomyopathy
Authors: Hsu J , Huang K C , Lin T T , Lee J K , Juang J M , Wu C K , Lin L Y
Published: October 2024

Background

Diastolic dysfunction and alterations in cardiac geometry are early indicators of diabetic cardiomyopathy. However, the association between cardiac changes across the glucose continuum and the contribution of epicardial adipose tissue (EAT) to these changes has not yet been investigated.

Purpose

In this study, we aim to investigated the EAT on cardiac diastolic function and structural alterations along the diabetic continuum using cardiac magnetic resonance imaging (CMR).

Methods

We enrolled individuals who were categorized into groups based on glucose tolerance status. Left ventricular structure and diastolic function were assessed using echocardiography and CMR to determine the EAT, intramyocardial fat, and associated parameters. Multivariate logistic regression models were also used.

Results

In a study of 370 patients (209 normal glucose tolerance, 82 prediabetes, 79 diabetes), those with prediabetes and diabetes showed increased heart dimensions and diastolic dysfunction, including E/E' (7.9±0.51 vs. 8.5±0.64 vs. 10.0±0.93, p=0.010), left atrial volume index (28.21±14.7 vs. 33.2±12.8 vs. 37.4±8.2 mL/m2, p<0.001), and left ventricular peak filling rate (4.46±1.75 vs. 3.61±1.55 vs. 3.20±1.30 mL/s, p<0.001). EAT significantly increased in prediabetes and diabetes (26.3±1.16 vs. 31.3±1.83 vs. 33.9±1.9 gm, p=0.001), while intramyocardial fat did not differ significantly. Prediabetes altered heart geometry, but not diastolic function (OR 1.22 [1.02–1.83], p=0.012; and 1.70 [0.79–3.68], p=0.135). Diabetes significantly affected both heart structure and diastolic function (OR 1.42 [1.11–1.97], p=0.032; and 2.56 [1.03–5.40], p=0.034) after adjusting for covariates.

Conclusions

Elevated EAT was observed in patients with prediabetes and is associated with adverse alterations in cardiac structure and diastolic function, potentially serving as an underlying mechanism for the early onset of diabetic cardiomyopathy.
Association of left ventricular ejection fraction improvement with prognosis in patients with cardiac sarcoidosis: insights from the ILLUMINATE-CS study
Authors: Maeda D , Matsue Y , Dotare T , Sunayama T , Yoshioka K , Nabeta T , Naruse Y , Kitai T , Taniguchi T , Tanaka H , Okumura T , Baba Y , Minamino T
Published: October 2024

Introduction

While the beneficial impact of enhancing left ventricular ejection fraction (LVEF) is well-documented in patients with heart failure with reduced LVEF, its relevance in cardiac sarcoidosis (CS) remains unclear.

Purpose

This study aimed to identify predictive factors for LVEF improvement and explore its association with prognosis in patients with CS.

Methods

A post-hoc analysis of the ILLUMINATE-CS registry, a retrospective observational study across multiple centers, was conducted. CS diagnosis adhered to either the 2016 Japanese Circulation Society guidelines or the 2014 Heart Rhythm Society expert consensus statement. Patients with baseline LVEF ≥50% were excluded in the current analysis. LVEF improvement was quantified as the variance between baseline and follow-up echocardiography. Patients were categorized into tertiles based on LVEF improvement: 1st tertile (≤0%, least improved), 2nd tertile (0–9%), and 3rd tertile (>9%, most improved) groups. The primary outcome was all-cause mortality after follow-up echocardiography.

Results

Among 188 enrolled patients (mean age 62.1±10.7 years; 42.6% male), 65, 60, and 63 were allocated to the 1st, 2nd, and 3rd tertile groups, respectively. Multivariate linear regression analysis revealed that narrower QRS duration, lower baseline LVEF, and absence of beta-blocker prescription at baseline were independently associated with greater LVEF improvement. Over a median follow-up of 407 days, 26 all-cause deaths occurred. Kaplan–Meier curves exhibited significant difference among the tertile groups (log-rank, P=0.002). Cox proportional hazard analysis, adjusted for possible prognostic factors including LVEF, demonstrated significantly higher mortality in the 1st and 2nd tertile groups compared to the 3rd tertile group (vs. 1st tertile: hazard ratio [HR] 22.14, 95% confidence interval [CI] 2.73–179.50, P=0.004; vs. 2nd tertile: HR 8.17, 95% CI 1.02–65.71, P=0.048). Additionally, treating LVEF improvement as a continuous variable revealed an independent association with increased mortality (LVEF improvement per 5%: HR 0.69, 95% CI 0.54–0.87, P=0.002).

Conclusions

Improvement LVEF in patients with CS is significantly associated with improved outcomes, highlighting its clinical importance in managing CS.Kaplan–Meier curves for all-cause death
Predicting progression from coronary artery disease to heart failure in community cohorts
Authors: Pilbrow A P , Tragante V , Cameron V A , Jones G T , Helgadottir A , Troughton R W , Richards A M , Doughty R N , Patel R S , Asselbergs F W , Gudbjartsson D , Sulem P , Holm H , Stefansson K , Poppe K K
Published: October 2024

Background

Approximately 10% of people develop heart failure (HF) within 5 years after an acute coronary event. Once ischaemic damage has occurred, the heart undergoes remodeling, which can lead to subclinical dysfunction and HF. However, remodeling varies considerably between patients and is difficult to predict.

Purpose

To assess whether adding genetic information to clinical factors improves the accuracy of predicting incident non-fatal/fatal HF within 5 years in people with coronary artery disease (CAD).

Methods

In the UK Biobank (UKB) [1], we developed a clinical risk model (predictors age, sex, ethnicity, body mass index, social deprivation, smoking, personal medical history, time since most recent CAD admission, lipids, HbA1C, creatinine, medications). Separately, we performed a genome-wide association meta-analysis of 13,360 (6,315 + 7,045) cases and 58,126 (37,245 + 20,881) non-cases from the UKB and deCODE [2] cohorts, relating common genetic variants to non-fatal/fatal HF or cardiomyopathy in people with CAD. For the current analysis of the UKB cohort, we derived a polygenic risk score using summary statistics from deCODE alone. We then compared risk estimates and assessed reclassification of 5-year risk using the clinical risk model with and without polygenic risk score, in UKB. Risk groups were <5%, 5-9.9%, 10-14.9%, ≥15%.

Results

Among people with CAD in the 5 years prior to assessment in UKB (n=8,880, mean age 61y, 27% women) or deCODE (n=10,113, mean age 66y, 34% women), 377 (4%) and 915 (9%) developed non-fatal/fatal HF over 5 years follow-up, respectively. In the UKB cohort, median 5-year risk with the clinical model was 3.2% (IQR 2-5.4%, C-statistic 0.72, 95% CI 0.70–0.74, Table 1) and plots of predicted versus observed risk showed very good calibration across deciles. The polygenic risk score was predictive of non-fatal/fatal HF in the UKB (hazard ratio 1.03, 95% CI 1.00 to 1.05 per standard deviation) with significance decreasing after adjusting for the prognostic index of the clinical risk model (hazard ratio 1.02, 95% CI 0.99 to 1.05 per standard deviation). Median 5-year risk by the clinical+polygenic model was 3.0% (IQR 1.9-5.0%). Net reclassification with the addition of the polygenic score improved accuracy of risk prediction for 3.6% of non-cases but deteriorated accuracy of risk prediction for 6% of cases. Overall net reclassification was deterioration of -0.025.

Conclusion

Our data suggest that common genetic variants may be associated with progression from CAD to HF, but that adding genetic data did not improve the accuracy of predicting progression from CAD to HF beyond established clinical predictors in the UKB cohort. Confirmation of these findings in deCODE and other large cohorts is warranted.
20 year picture of a heart failure clinic: changes in the patients profiles' and 2-year mortality
Authors: Carrete A , Codina P , Ruiz-Cueto M , Santiago-Vacas E , Borrellas A , Camblor A , Domingo M , Gonzalez B , Rivas C , Diez C , Troya M I , Boldo M , Julian M T , Lupon J , Bayes-Genis A
Published: October 2024

Background

Heart failure (HF) is one of the most prevalent diseases. Improvements in cardiac disease management in the last two decades and in HF itself might have influenced the referral of patients with HF to a specialised HF clinic.

Purpose

To evaluate changes in the profile of patients referred to an outpatient HF clinic over the span of 20 years, and to analyse trends in 2-year mortality.

Methods

A retrospective analysis of a prospective registry of HF patients in a specialised ambulatory HF clinic was conducted, from January 1st 2002 to December 31st 2021. We divided the 20 years of the study into five periods of four years each, in order to compare the clinical characteristics of patients at admission. The variables analysed include age, sex, aetiology, HF type (preserved - HFpEF, reduced - HFrEF, mildly-reduced - HFmrEF), NYHA class, left ventricle ejection fraction (LVEF), NT-proBNP level, number of previous hospitalizations, and treatment at referral (first visit). Two-year mortality was also analysed.

Results

A total of 2973 patients were included (mean age 67.1± 12,9, 69.7% men). Age remained stable across the five periods, p=0.43), while the referral of women increased throughout the study period (27.7% in 2002-2005 vs 32.9% in 2018-2021, p-for-trend=0.037). Patients with HFpEF were also increasingly referred (12.3% first period vs. 27.6% last period, p-for-trend<0.001) and LVEF tended to be higher (33.09% vs. 40,9%, p<0.001). The main aetiology of the referred patients was ischaemic heart disease, although it progressively decreased in favour of other aetiologies (Table 1) (p<0.001). NYHA class tended to improve (NYHA 3-4 40.3% vs. 21.3%, p-for-trend <0.001) and NT-proBNP levels tended to decrease, predominantly in the last period (p-for-trend=0.025), as well as hospitalisation rates in the previous year (p-for-trend<0.001). Treatment with ACEi/ARB was progressively less frequent (p<0.001), at least partially due to replacement by ARNi (p<0.001). Treatment with digoxin and loop diuretics also diminished (p<0.001 and p=0.04 respectively), whereas treatment with betablockers, ARM, ivabradine and SGLT-2i increased during the study periods (all p<0.001) (Table 2); Patients carrying ICD and CRT also increased (p=0.014 and p<0.001 respectively). Adjusted 2-year mortality significantly decreased, mainly in the last period (p<0.001) (Figure 1).

Conclusion

The profile of HF patients referred to a tertiary HF ambulatory Clinic changed along 20 years of study. HFrEF remained the most common, but is declining in favour of HFpEF. Ischaemic aetiology also remained the most frequent but, again, showed a decreasing trend. Two-year mortality has globally decreased, markedly in the last period.Figure 1
Increased cancer incidence in patients with pre-existing heart failure: results from a French Nationwide Cohort study
Authors: Hulot J , Mirabel M , Nevoret C , Domenge O , Empana J P
Published: October 2024

Background

It is unclear whether patients with a history of heart failure (HF) have an increased risk of developing cancer.

Purpose

To assess the incidence of cancer (all types) in patients with pre-existing HF compared with patients without known HF at a nationwide level. Secondary objectives include analysis by cancer site and impact on all-cause mortality.

Methods

We used the French National Administrative Health Data System (SNDS), a comprehensive database containing all health care information (outpatient and hospital) for 99% of the French population, to identify adult patients with a first diagnosis of HF (ICD-10 diagnosis code I50) between 2010 and 2019 and without a personal history of cancer before HF diagnosis. HF patients were matched for sex and age to HF-free and cancer-free individuals (3:1 ratio), randomly identified in the SNDS. Incident cancers were identified by corresponding ICD 10th codes.

Results

We found 330,867 adult patients with a first diagnosis of HF between 2010 and 2019, and 992,601 matched controls (54.7% women, mean age 77.7±13.5 years in both groups). There was an increased risk of a first cancer in HF patients as compared to controls: 28,151 (8.5%) in HF patients over a mean follow-up of 4.3±2.8 years vs. 77,325(7.8%) in controls over a mean follow-up of 4.9±2.8 years (unadjusted HR: 1.12 [1.11-1.13], P<0.001). The higher risk of new cancer in HF patients remained after adjustment for major comorbidities (i.e., ischemic heart disease, diabetes, arterial hypertension, renal dysfunction, morbid obesity), age, sex, year of diagnosis, region of residence, tobacco use and alcohol consumption (adjusted HR=1.06, [1.04-1.07]; P<0.0001). Overall, the estimated attributable risk of new cancer after HF was 16.53% (9.88-16.76%). This increased risk was observed for most solid malignancies (especially colorectal and lung cancer), and for multiple myeloma. We finally observed that the risk of all-cause mortality after cancer diagnosis was significantly higher in patients with pre-existing HF compared to controls (adjusted HR: 1.36 [1.33-1.39], P<0.001).

Conclusions

People with a history of HF have a higher risk of developing cancer than the general population. These findings suggest that cancer screening strategies should be encouraged in patients with HF.