bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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 &lt; 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

Abstract

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

Abstract

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&lt;0.001 and r=0.5, p&lt;0.001 at ED during exercise; r=0.34, p&lt;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

Abstract

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 &lt; 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

Abstract

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) &gt;50%, ≤ mild valvular dysfunction, normal chamber sizes and tricuspid regurgitation (TR) gradient &lt;39mmHg were included. Analysis was performed by Kruskal-Wallis and Mann-Whitney U tests. Results are median (quartiles) and p-values of &lt;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&lt;0.001). However, while body surface area (BSA) normalised LV diastolic diameters decreased in males (p&lt;0.05) and females (p&lt;0.01), LV systolic diameter (decrease, p&lt;0.01) and left atrial size (increase, p&lt;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

Abstract

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 (&lt;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 &lt;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 &lt;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

Abstract

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.