bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibroblast activation protein-specific inhibitor imaging in heart failure
Authors: Joshi S , Loganath K , Barton A K , Dweck M R , Newby D E
Published: November 2023

Background

Although myocardial fibrosis can be quantified by magnetic resonance (MR), assessment of fibrosis activity is important as this will inform disease activity and the presence of ongoing adverse cardiac remodelling. Fibroblast activation protein (FAP) is expressed on the surface of activated myofibroblasts and is a marker of ongoing fibrosis activity. Radiolabelled FAP-specific ligands, such as 68-Gallium (68Ga)-FAP inhibitor (FAPI), represent a promising new approach to quantify fibrosis activity in the myocardium.

Purpose

To investigate whether 68Ga-FAPI positron emission tomography (PET)/MR can detect myocardial fibrosis activity in patients with heart failure with reduced ejection fraction.

Methods

In a prospective cross-sectional study, patients with heart failure with reduced ejection fraction and healthy volunteers underwent 68Ga-FAPI PET/MR. 10 patients had repeat imaging at 6 months. Standardised uptake values (SUVmax) and tissue to background ratios (TBR) were calculated within the left ventricular (LV) wall.

Results

Participants were predominantly middle-aged men: patients with heart failure (n=45; median age 65 [60-74] years, 76% male) and healthy volunteers (59 [56-62] years,70% male). LV ejection fraction was reduced in patients with heart failure (40±8%) but was normal in healthy volunteers (60±6%; P<0.001). Within the heart failure cohort, 22 patients had ischaemic cardiomyopathy and 23 patients had non-ischaemic cardiomyopathy. Compared with healthy volunteers, patients with heart failure had higher myocardial uptake of 68Ga-FAPI (SUVmax 3.2±1.5 versus 1.5±0.3, p<0.001; TBR 1.9±0.8 versus 1.1±0.2, p<0.001; Figure 1). Myocardial 68Ga-FAPI uptake was higher in patients with either ischaemic or non-ischaemic cardiomyopathy compared to healthy volunteers (SUVmax 4.0±1.7 and 2.3±0.5 versus 1.5±0.3 respectively; p<0.001 for both) and was higher in patients with ischaemic compared to non-ischaemic cardiomyopathy (p<0.001). Differential patterns of 68Ga-FAPI uptake were also observed with increased LV uptake seen particularly in the basal septum of patients with non-ischaemic cardiomyopathy and in the infarct zone of patients with ischaemic cardiomyopathy (Figure 2). Based on the Youden’s index of the receiver-operator curves, the optimal threshold for identifying myocardial fibrosis in patients with heart failure was SUVmax of 1.9 with a specificity of 90%, sensitivity of 89% and area under the curve of 0.94. At 6 months, 68Ga-FAPI uptake was unchanged in the 10 patients with chronic heart failure that underwent repeat scanning (p=0.91).

Conclusion

Increased myocardial fibrosis activity can be detected with 68Ga-FAPI PET/MR in patients with heart failure. Differential patterns of 68Ga-FAPI uptake are seen in patients with non-ischaemic cardiomyopathy or ischaemic cardiomyopathy. This may help characterise and prognosticate patients with heart failure and inform the future development of novel heart failure therapies.Figure 1Figure 2
Association of microvascular dysfunction with cardiovascular outcomes in heart failure with preserved ejection fraction
Authors: Tao M , Radakrishnan A , Liu Y , Dhaliwal S , Despotidis G , Rahman T
Published: November 2023

Background

Heart failure with preserved ejection fraction (HFpEF) is a disease that portends an increased risk of morbidity and mortality. Studies have reported an association between HFpEF and microvascular dysfunction, however this association and its prognostic significance remain unclear. The purpose of this meta-analysis is to evaluated the association of microvascular dysfunction with cardiovascular outcomes in patients with HFpEF.

Methods

A literature search was conducted for studies evaluating the association between microvascular dysfunction measured with global myocardial flow reserve (GMFR) and coronary flow reserve (CFR) and major adverse cardiovascular events (MACE) in patients with HFpEF. The search included the following databases: Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar. The search was not restricted to time or publication status. The minimum follow up duration was one year.

Results

A total of 5 studies with 448 patients (252 with HFpEF, 196 healthy controls) met inclusion criteria for evaluation of the association of GMPR with HFpEF. Patients with HFpEF had a significantly lower GMPR compared to healthy controls (SMD -0.83, 95% CI -1.03,-0.63; p<0.01). Heterogeneity was moderate: Chi2=9.5, df=4, I2 = 58%. Only 2 studies were identified that reported on the evaluation of CFR in patients with HFpEF so meta-analysis could not be reliably performed.

A total of 4 studies with 591 HFpEF patients (284 with reduced CFR and 307 with normal CFR) met inclusion for evaluating the association with MACE. Mean follow-up was 36 months. Patients with impaired CFR <2.0 had significantly higher risk of MACE compared to patients with normal CFR (OR 8.89, 95% CI 3.77-20.92; P<0.01). Heterogeneity was low: Chi2=4.77, df=3, I2=37%.

Conclusion

Patients with HFpEF have significant microvascular disease compared to patients without HFpEF, which is associated with an increased risk of MACE. Additional high-quality studies are required to further elucidate this association and determine the utility of targeted medical therapy.
Exercise gas exchange and echo-derived analysis in HFpEF based on patterns of oxygen peripheral utilization
Authors: Pina M , Rusconi I , Mondelli G , Giustiniani A , Guazzi M
Published: November 2023

Background

Exercise limitation is a key signature of heart failure with preserved ejection fraction (HFpEF) syndrome evolution with studies highlighting a significant cardiac reserve limitation and others identifying a predominant limit in the peripheral VO2 kinetics and utilization.

Aims

To clarify the cardiopulmonary and hemodynamic response in HFpEF according to the high or low peripheral O2 utilization patterns during maximal exercise.

Materials and Method

38 patients with a HFpEF diagnosis based on the ESC HFpEFF criteria underwent cardiopulmonary exercise test (CPET) combined with stress echocardiography. Patients were divided in two groups according to the median peak c(A-V) O2 difference (Group 1: < 11 mL/dL and Group 2: > 11 mL/dL). Cardiac output (CO) was calculated by echocardiography according to the formula LVOT velocity integral x LVOT area. Data were obtained after a familiarization CPET session.

Results

Group 1 and 2 presented similar rest demographic, left and right hemodynamic data (table). The relationship between CO and c (A-V) O2 in terms of VO2 isopleths at peak exercise were not related to any difference in CO (figure)

Conclusions

In HFpEF, an impairment in O2 utilization during exercise appears independent of the cardiac reserve response (similar peak CO increase) but rather peripheral mechanisms implicated in O2 diffusion/release seem to play a dominant role, emerging as selective therapeutic targets for improving functional capacity and symptoms.
Ablation for atrial fibrillation improves the outcomes in patients with heart failure with preserved ejection fraction: a single-center cohort study
Authors: Xie Z , Qi B Z , Zhou J M
Published: November 2023

Introduction

Patients with heart failure and preserved ejection fraction (HFpEF) are frequently associated with atrial fibrillation (AF), and such clinical condition has worse clinical status than those with sinus rhythm. Whether the use of a strategy to maintain sinus rhythm in patients with HFpEF would affect outcomes remains uncertain.

Purpose

To investigate whether the strategy of AF ablation to maintain sinus rhythm compared to no ablation is associated with improvement of all-cause death and rehospitalization for worsening heart failure in patients with AF and HFpEF.

Methods

In this retrospective cohort study, a total of 1034 patients with HFpEF and AF (69 [63, 76] years, 478 [46.2%] female) were analyzed, 392 patients who received first-time AF ablation were assigned to the ablation group, and the remaining 642 patients with merely medical therapy were assigned to the no ablation group. The primary end point was a composite of all-cause mortality or rehospitalization for worsening heart failure and was assessed by the Kaplan-Meier method and Cox proportional hazard model. Baseline differences were adjusted by multivariable-adjustment analysis, propensity score-matched analysis, and inverse probability of treatment weighting analysis. Atrial tachycardia/AF recurrence was assessed in a multivariable-adjusted Fine & Gray model, with death treated as a competing risk factor.

Results

After a median follow-up period of 39 months, the cumulative incidence of the primary end point was significantly lower in the ablation group compared to the no ablation group after multivariable adjustment in the overall cohort (adjusted hazard ratio [HR], 0.65 [95% CI, 0.45-0.94], P = 0.02; incidence rate difference [IRD], -0.39 [95% CI, -0.54 to -0.25]). Analyses for secondary outcomes revealed that clinical benefit produced by AF ablation was mainly driven by rehospitalization for worsening heart failure (adjusted HR, 0.65 [95% CI, 0.44-0.96], P = 0.03) with an estimated IRD of -0.31 (95% CI, -0.45 to -0.18). Results were consistent in the propensity score-matched analysis and inverse probability of treatment weighting analysis. In addition, patients in the ablation group had a 34% relative decrease in the atrial tachycardia/AF recurrence (adjusted HR, 0.66 [95% CI, 0.55-0.81], P < 0.001) relative to no ablation group in the multivariate-adjusted Fine & Gray model. Patients who received AF ablation and maintained sinus rhythm during the follow-up period had a lower risk of the primary end point (P < 0.001 by log-rank test).

Conclusion(s)

Among HFpEF and AF patients, the strategy of AF ablation to maintain sinus rhythm led to a lower risk of the composite of death from any cause or hospitalization for worsening heart failure.Figure 1.Kaplan–Meier curvesTable 1.Incidence rate and hazard ratio
Empagliflozin improves diastolic function in obese ZSF1 rats by restoring the cardiac mitochondrial respiratory capacity
Authors: Schauer A , Langner E , Augstein A , Winzer E , Fabig G , Linke A , Adams V
Published: November 2023

Background

Clinical studies demonstrated beneficial effects of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) on the combined risk of cardiovascular death or heart failure hospitalization in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes leading to cardioprotection remain unclear.

Purpose

The present study aimed to elucidate the impact of Empagliflozin on myocardial function and metabolism in a rat model (ZSF1 rat) with established HFpEF and to analyze underlying mechanisms.

Methods

24 week old, obese ZSF1 rats were randomized either receiving standard care (obese) or Empagliflozin (Empa, 30 mg/kg/d p.o.). ZSF1 lean rats (lean) served as healthy controls. All animals underwent a baseline, intermediate and final echocardiography. After 8 weeks of treatment, hemodynamics were measured invasively, blood samples were taken, cardiac mitochondrial function was assessed and left ventricular tissue was collected for molecular and histological analyses or for transmission electron microscopy (TEM).

Results

Compared to the obese control Empa treated obese rats demonstrated a significantly improved diastolic function already at 4 weeks of treatment (E/é: lean: 17.9 ± 0.8; obese: 23.7 ± 0.7, p<0.001 vs. lean; Empa: 21.0 ± 1.1, p<0.05 vs. lean; p<0.05 vs. obese), which reached the level of healthy controls after 8 weeks of treatment (E/é: lean: 17.5 ± 0.7; obese: 24.4 ± 1.1, p<0.001 vs. lean; Empa: 19.4 ± 0.8, p<0.001 vs. obese). This was accompanied by reduced hypertrophy, fibrosis, left ventricular stiffness and inflammation as well as by improved hemodynamics. Except for a slightly improved myocardial ketone body utilization in Empa treated rats, there was no shift in metabolic substrate preference between groups. Cardiac mitochondrial respiratory function observed in untreated obese rats was significantly impaired compared to healthy controls but restored by Empa treatment (Vmax of complex II: lean: 0.15 ± 0.007 nmol O2/s/mg, obese: 0.12 ± 0.004 nmol O2/s/mg, p<0.01 vs. lean; Empa: 0.17 ± 0.006 nmol O2/s/mg, p<0.05 vs. lean, p<0.001 vs. obese). Moreover, mitochondrial respiratory capacity correlated with diastolic function, suggesting a pivotal role of restored respiratory function for improved diastolic relaxation. TEM revealed reduced size of cardiac mitochondria in obese rats, which was significantly restored by Empa. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation and antioxidant metabolism.

Conclusions

The present study demonstrates for the first time beneficial effects of Empaglifozin on cardiac remodeling, diastolic function and hemodynamics in an obese rat model of HFpEF. These effects were accompanied by improved mitochondrial respiratory function, enhanced ketone body utilization and improved antioxidant capacity.
A shortened electrocardiographic diastolic interval is involved in diastolic dysfunction and HFpEF
Authors: Van Ommen A M L , Bear L R , Carlos Sampedrano C , Onland-Moret N C , Cramer M J , Rutten F H , Dal Canto E , Tulevski I I , Somsen G A , Den Ruijter H M , Coronel R
Published: November 2023

Background

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by left ventricular diastolic dysfunction (LVDD). We hypothesized that a short electrocardiographic diastolic time predisposes to LVDD and HFpEF by deteriorating diastolic function. This effect may be more pronounced in women than men, given longer QT interval in women.

Methods

To experimentally test if incremental shortening of the diastolic interval indeed worsens the diastolic function, we shortened electrical diastole using right atrial (RA) pacing and QT-prolonging medication (sotalol) in six pigs. We used 12-lead ECG and echocardiography to assess electrical diastole (TQ interval) and diastolic function. We next analyzed electrocardiograms and corresponding information on LVDD and HF in electronic health record data from 85,145 patients that visited one of 13 Cardiology Centers of the Netherlands. We sex-specifically assessed the association between TQ interval on the one hand and LVDD or HFpEF on the other.

Results

In pigs, baseline TQ interval was 257 (±SD 66) ms, which decreased to 232 (±SD 36) ms during RA pacing (100 bpm), and further to 193 (±SD 52) ms with concomitant sotalol administration (2 mg/kg iv, bolus). These changes in TQ interval resulted in reversal of E/A ratio, with a significant correlation between TQ interval and decreasing e’/a’ ratio (r=0.382, p=0.024) (Figure 1). In patients who underwent cardiac evaluation with ECG and echocardiography, diastolic abnormalities were documented as LVDD (n=26,009 (30%)) and HFpEF (n=2,551 (3%)). TQ intervals were significantly shorter in patients with LVDD and HFpEF (479 (±SD 128) and 485 ms (±SD 138), respectively) compared to the ones without LVDD or HFpEF (523 (±SD 137) ms). A shorter TQ interval increased the risk for having LVDD and HFpEF when adjusted for confounders (LVDD; ORadjusted= 1.37 (95% CI: 1.28, 1.45), HFpEF; ORadjusted= and 1.16 (95% CI: 1.01, 1.35) (Table 1). There was significant sex-interaction (p= 0.039) for TQ and LVDD risk, with stronger associations in women (ORadjusted= 1.43 (95% CI: 1.32, 1.56) compared to men (ORadjusted= 1.35 (95% CI: 1.10, 1.64) (Table 1).

Conclusion

Experimentally decreasing the electrical diastolic interval leads to diastolic function abnormalities in pigs. In humans, a shorter diastolic interval is associated with a higher risk of having either LVDD or HFpEF. Our findings imply that a shortened electrical diastolic interval may precede diastolic dysfunction and HFpEF. Therefore, prolonging or preserving electrical diastole may be effective in preventing or treating HFpEF, especially in women.Figure 1Table 1
Ventricular arterial coupling in patients with ischemia but no obstructive coronary artery disease: novel insight into heart failure progression
Authors: Iribarren A , Nelson M D , Oneglia A P , Palmero-Canton A , Obrutu O , Maughan J , Lauzon M , Pepine C J , Handberg E M , Bairey Merz C N , Wei J
Published: November 2023

Background

Ischemia with no obstructive coronary artery disease (INOCA) is prevalent in women and is associated with increased risk of developing heart failure with preserved ejection fraction (HFpEF). While the exact mechanism contributing to heart failure progression remains incompletely understood, we hypothesize that impaired ventricular-arterial coupling (VAC) plays a key role.

Purpose

To evaluate VAC across the INOCA-HFpEF continuum.

Methods

To accomplish our research objective, we leveraged cardiac magnetic resonance images from individuals with INOCA and HFpEF from the WISE Pre-HFpEF (NCT03876223) and WISE HFpEF (NCT02582021) studies, along with reference controls. Aortic pulse wave velocity (aPWV) was measured using velocity-encoded MRI, from the proximal ascending to distal descending aorta. Global longitudinal strain (GLS) was measured by feature tracking of horizontal and vertical long axis cine images. VAC was defined as the ratio between aPWV and GLS. To test for potential mediators, we assessed the relationship between VAC and age, risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP), myocardial perfusion reserve index (MPRI), LV end diastolic pressure (LVEDP), cardiac structure/function, and Kansas City Cardiomyopathy questionnaire (KCCQ).

Results

The baseline characteristics of the three study groups are described in the Table. Patients with INOCA had similar KCCQ scores as HFpEF patients, suggesting INOCA patients may have subclinical HFpEF. Consistent with our hypothesis, we observed a progressive impairment in VAC across the three groups (Controls vs INOCA vs HFpEF), being significantly worst in HFpEF(Figure). Importantly, VAC was inversely related with age, systolic/diastolic blood pressure, and LV mass index (R=-0.6, R=-0.4, R=-0.4, R=-0.3 respectively, all p <0.001).

Conclusion

The data herein support the hypothesis that VAC contributes to heart failure progression, with age, arterial blood pressure and LV mass being key determinants. That VAC was not yet significantly different between INOCA, and reference controls highlights an important opportunity for intervention to prevent heart failure progression.
CPET as a prognosis assessing tool in patients with heart failure with preserved ejection fraction
Authors: Rozados Da Conceicao C , Krannich A , Zach V , Pinto R , Deichl A , Feuerstein A , Schleussner L , Edelmann F
Published: November 2023

Introduction

Patients with heart failure with preserved ejection fraction represent half of the heart failure patients nowadays, an at least steady trend due to the aging of the population. We investigated whether the parameters obtained from cardiopulmonary exercise testing (CPET) correlated with the prognosis of these patients. This prospective observational cohort study looks into the relationship between the CPET parameters peak VO2 and VE/VCO2 slope and the heart failure hospitalizations or cardiovascular death of these patients.

Methods

From August 2016 until May 2019, 99 patients of our outpatient clinic with newly diagnosed with heart failure with preserved ejection fraction underwent cardiopulmonary exercise testing. Median follow-up was 30 months (interquartile range, 24-38.5). We selected peak VO2 <14 ml/min/kg and a VE/VCO2 slope > 34 as threshold values for our primary endpoint, a composite of hospitalization for heart failure or cardiovascular death.

Results

The mean age was 75.07 ± 7.31 years, 48.5% were women, 24.2% were at NYHA class III and mean NTproBNP was 511 pg/mL. Mean peakVO2 was 15.09 ± 4.75 and mean VE/VCO2 was 36.05 ± 6.60. During follow-up, they were 67 hospitalizations, 53 cardiovascular hospitalizations, 24 heart failure hospitalizations and 4 deaths. Over a median follow-up of 30 months, the primary outcome event occurred in 5 of 40 patients (12.5%) with a VE/VCO2 Slope ≤ 34 and in 19 of 59 patients (32.2%) with a VE/VCO2 Slope > 34 (hazard ratio, 2.688; 95% confidence interval (CI); P 0.04). On multivariate analysis, accounting for heart failure hospitalization or cardiovascular death as a terminal event, VE/VCO2 slope was independently associated with the risk of admission due to heart failure worsening.

Conclusion

In patients with heart failure with preserved ejection fraction, a VE/VCO2 Slope > 34 predicts heart failure hospitalizations and cardiovascular death.Primary Endpoint
AAV.Cas9 and AAV.SERCA2a strategies to mitigate heart failure in DMD pigs
Authors: Baehr A , Hornaschewitz N , Stirm M , Hoppmann P , Bozoglu T , Klymiuk N , Laugwitz K L , Moretti A , Wolf E , Hajjar R , Kupatt C
Published: November 2023

Aims

Duchenne muscular dystrophy is a devastating disease affecting skeletal muscle and heart, which is caused by loss-of-function mutations in the dystrophin (DMD) gene. Since pharmacologic treatment is ineffective over time, gene therapy including gene editing is rapidly evolving. In DMDdelta52 pigs, we have previously demonstrated efficacy of an AAV9-Cas9-gRNA approach, which by excision of exon 51 provided a shortened, but stable dystrophin D51-52. Here, we set out to compare this approach to germline excision of exon 51 in the DMDdelta52 pig, resulting in ubiquitous dystrophin D51-52 expression, a porcine model of Becker muscle dystrophy (BMD). Alternately, we provided locoregional AAV.SERCA2a gene therapy to the DMDdelta52 pigs.

Methods and results

We generated pigs lacking exon 52 of the DMD gene. Male offspring are characterized by heart failure (EF33±3%), arrhythmogenesis due to distinct regions of low or no-amplitude action potentials and by sudden cardiac death before 4 months of age. Germline correction of the loss of function mutation by additional excision of neighbouring exon 51 induced a Becker phenotype (BMD), with a mildly reduced ejection cardiac function (EF 45±3%) a reduction of vulnerable areas in electrophysiology mapping and a prolonged lifespan. Postnatal AAV9.Cas9-gE51 also improved EF (40±2%) and reduced electrophysiological vulnerability, increasing survival significantly. Using intracoronary delivery of AAV1.SERCA2a at a dose of 3x1013 virus genomes (vg) per pig by slow antegrade infusion of LAD & LCx improved left ventricular ejection fraction (EF 46±5% +AAV1.SERCA2a), but did not alter the amount of no-amplitude areas per LV.

Conclusions

Compared to ubiquitous excision of exon 51 (DMDdelta51-52) or postnatal AAV.Cas9-gE51 treatment of a DMDdelta52 pig model, which both improved ejection fraction EF and almost normalized action potential amplitudes, a moderate dose of AAV1.SERCA2a sufficed to normalize left ventricular function, but did not affect electrical vulnerability of the heart. Hence, AAV.SERCA2a combined with antitachycardic pacemaker protection may serve as a safe treatment option for DMD cardiomyopathy, whereas Cas9-mediated gene editing may provide additional therapy of electrical vulnerability. Further translational studies will establish novel gene therapeutic options for DMD patients.
Transcriptional regulation of macrophage inflammation in the heart failure with preserved ejection fraction: a translational study
Authors: Gorica E , Mohammed S A , Mengozzi A , Ambrosini S , Wenzl F A , Mongelli A , Ruschitzka F , Hamdani N , Costantino S , Paneni F
Published: November 2023

Background/Introduction

Inflammatory response is a key player in heart failure with preserved ejection fraction (HFpEF) but the underlying mechanisms are poorly understood (1). Recent studies have shown a critical involvement of cardiac macrophage recruitment and activation in myocardial remodelling (2,3).

Purpose

here we sought to determine the role of macrophage inflammation in experimental and human HFpEF.

Methods

We employed a translational approach combining human and murine LV myocardial tissue, FACS analysis of cardiac immune cells, in vitro experiments in primary macrophages and cardiac cells as well as ex vivo functional analyses in LV tissues. Human LV myocardial samples were used to evaluate the pro-inflammatory activity of macrophages in the HFpEF myocardium. Induction of HFpEF in mice was done through a validated mouse model combining metabolic (high-fat diet) and hemodynamic stress (L-NAME). Cardiac function was investigated by high resolution ultrasound imaging (Vevo3100) and the LV myocardial samples were used to study the macrophage polarization and their inflammatory activity. Based on interrogation of available RNA-seq datasets –showing the transcriptional repressor NCOR1 as a relevant signature in macrophages during cardiac inflammation, we generated myeloid cell-specific NCOR1 knockout (Ncor1-KO) transgenic mice to investigate the in vivo effects of NCOR1 deletion on the HFpEF phenotype. In vitro experiments included RAW 264.7 cells polarization through a metabolic stress model via palmitic acid (PA) and the assessment of macrophage phenotype switching in the presence or the absence of NCOR1. To study the crosstalk of macrophages with the surrounding cardiac cells, cardiomyocytes (H9c2) and endothelial cells (HAECS) were exposed to conditioned media from cultured RAW. Afterwards, cellular function and the pro-inflammatory cytokine levels were investigated.

Results

The expression of macrophage markers in human LV specimens showed an increase in pro-inflammatory macrophages (M1) and a decrease in regulatory macrophages (M2) as compared to age-matched control mice. HFpEF mice showed increased expression of vascular adhesion molecules (ICAM1, ICAM2, E-selectin) and a significant recruitment of M1 macrophages to the myocardium. Of interest, cardiac function and myocardial inflammation (TNF-a, IL6, IL-1b) were significantly reduced in Ncor1-KO mice. In vitro assays showed that stimulation of macrophages with PA induced M1 type switch and increased NCOR1, TNF-a, IL-6, and IL-1b levels, whereas NCOR1 depletion prevented detrimental changes of macrophage secretome (Fig.2).

Conclusion

NCOR1 is a crucial co-regulator of immune response and macrophage inflammation in the heart. Our findings pave the way for mechanism-based therapies to prevent HFpEF development.
Mitochondrial dynamics and myocardial metabolism alterations during anthracycline-cardiotoxicity
Authors: Diaz-Guerra Priego A , Villena-Gutierrez R , Cadiz L , Gomez M , Oliver E , Ibanez B
Published: November 2023

Background

Despite the increased effectiveness of chemotherapeutic agents, cancer represents a lethal illness worldwide and anticancer strategies still present severe adverse effects. Cardiac dysfunction is a dose-dependent common affliction of anthracyclines treatment. Anthracycline-induced cardiotoxicity (AIC) and consequent heart failure has recently been suggested to be mediated by mitochondrial dysfunction; however, the molecular mechanisms driving this connection are incompletely understood.

Purpose

To study the early molecular changes (before onset of overt heart failure phenotype) related to mitochondrial biology and cardiac metabolism in a mouse model of AIC.

Methods

CD1 mice underwent 5 weekly i.p. injections (5 mg/kg) of doxorubicin. Cardiac anatomic and functional changes were evaluated by echocardiography at 1, 9 and 15 weeks-after last doxorubicin injection. At each time-point, some animals were sacrificed and hearts were collected for characterisation of mitochondrial dynamics and metabolic substrate utilization by western blot, PCR, immunocytochemistry, high-resolution respirometry, transmission electron microscopy and PET/CT.

Results

Doxorubicin administration resulted in an early reduction in left ventricle (LV) mass which was the result of marked cardiomyocyte atrophy as early as 1 week after doxorubicin completion. Cardiac atrophy preceded functional abnormalities, which were apparent in the form of reduction in LV ejection fraction at 9 weeks. Mitochondrial dynamics (fusion/fission) and membranes were altered as early as 1 week after doxorubicin completion (i.e. long before changes in LV function). Moreover, mitochondrial respiratory rate was decreased in these animals, together with a decrease in mitochondrial DNA content and biogenesis at early timepoints. Early (1 week) mitochondrial molecular changes were accompanied by altered cardiac metabolism (i.e. switch in substrate utilization to glucose).

Conclusions

Here we have characterized the dynamics of molecular, anatomical and functional changes during AIC. LV systolic dysfunction is a late phenomenon happening long after molecular and metabolic changes in the heart. Cardiomyocyte atrophy, altered mitochondrial dynamics and respiration, and metabolic switching occur long before overt heart failure phenotype. These early changes appear as promising therapeutic targets to prevent overt AIC and heart failure.
Anthracycline therapy induces an early decline of cardiac contractility with transient edema in low risk patients with breast cancer
Authors: Voss F , Nienhaus F , Pietrucha S , Melz T , Cramer M , Haberkorn S M , Ruckhaeberle E , Fehm T , Floegel U , Westenfeld W , Scheiber D , Jung C , Kelm M , Polzin A , Boenner F
Published: November 2023

Background

Cancer therapy-related cardiac dysfunction (CTRCD) is a dreaded complication of anthracycline therapy in the treatment of breast cancer. CTRCD most frequently appears in patients with cardiovascular risk factors or known cardiovascular disease. There is limited evidence of incidence and prospective course of anthracycline-induced CTRCD in young patients without common risk factors for CTRCD.

Purpose

To longitudinally investigate a cohort of young women on anthracycline treatment due to breast cancer without cardiovascular risk factors or known cardiovascular disease.

Methods

59 women with first-diagnosed breast cancer and planned anthracycline regime-based therapy were enrolled. Exclusion criteria were cardiovascular risk factors or known cardiovascular disease. We conducted a longitudinal assessment before, immediately after- and 12 months after cancer therapy with general laboratory, electrocardiograms, echocardiography and cardiovascular magnetic resonance (CMR), including myocardial relaxometry with T1, T2 and extracellular volume mapping.

Results

Every single patient experienced a drop in CMR-measured left ventricular ejection fraction (LVEF) of 6 ± 3 % immediately after cancer therapy. According to the novel definition 32 patients (54.2%) developed CTRCD after 12 months defined by reduction in LVEF, global longitudinal strain (GLS) and/or biomarkers elevation (Figure 1). LVEF reduction was accompanied by a decrease in stroke volume and cardiac power index while enddiastolic volume index remained stable. Global myocardial T2 relaxation times as well as myocardial mass increased coincidently with a decline in wall-thickening. While T2 values and myocardial mass normalized after 12 months, LVEF and GLS remained impaired.

Conclusion

Among breast cancer patients without pre-existing risk factors for CTRCD anthracyclines induce a decline of myocardial contractility in every single patient, which may lead to an increased risk of future cardiovascular diseases in these patients.

Figure 1: Patients with diagnosed CTRCD directly after CT and after 12 months follow up stratified by underlying CTRCD criteria. Boldness of arrows proportionally represents the number of patients changing between the criteria. Some patients fulfilled more than one criterium for CTRCD.Graphical Abstract  Figure 1
Pre-diabetes is associated with increased cardiac events in cancer patients prescribed anthracyclines
Authors: Cheang I F , Zhu X , Huang J Y , Tse Y K , Yiu K H , Li X L
Published: November 2023

Background

Pre-diabetes, a precedent of overt diabetes and metabolic disorder, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in cancer patients prescribed anthracycline-containing chemotherapy (ACT) is uncertain.

Objective

To evaluate the association of pre-diabetes with cardiovascular events in cancer patients prescribed ACT.

Methods

We included cancer patients treated with ACT from 2000-2019, drawn from a previously validated territory-wide database. Patients were subsequently divided into diabetes, pre-diabetes, and normoglycaemia groups based on their baseline glycaemic profile. The primary outcome, major adverse cardiovascular events (MACE), was defined as a composite of hospitalization for heart failure and cardiovascular death.

Results

Among 12649 patients treated with ACT (55.5% male, median age 62 years), 3997 had pre-diabetes at baseline and 5622 had diabetes. Over a median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycaemia group, 358 (9.0%) in the pre-diabetes group, and 728 (12.9%) in the diabetes group. Compared with the normoglycaemia group, both pre-diabetes (adjusted hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01-1.43) and diabetes (adjusted HR = 1.46, 95% CI 1.24-1.70) were associated with an increased risk of MACE. In the pre-diabetes group, 475 (18%) patients progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR = 1.76, 95% CI 1.31-2.36) than those who remained prediabetic.

Conclusions

In cancer patients treated with ACT, pre-diabetes at baseline, and those who progressed to diabetes at follow-up, had an increased risk of MACE. Our findings reveal that pre-diabetes is a key predictor and potential treatment target to reduce the risk of MACE in patients prescribed ACT.
SARS-COV2 infection and heart failure an intricate link of mutual impact
Authors: Cabac-Pogorevici I , Revenco V
Published: November 2023

Introduction

COVID-19 became an unprecedented global challenge affecting all fields of medicine, though being initially considered a respiratory disease, it has rapidly become clear the multiorgan involvement of the disease. The aim of our study was to assess the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia).

Methods

The research included 178 patients COVID-19, admitted to the cardiology department 18-83 years, the mean age being of 67,23 ± 13,20 years, whereas 47% (84 pts) were men and 53% (94 pts) were women. All subjects underwent physical examination, ECG and echocardiography. The following laboratory parameters were collected: haemoglobin, leukocytes (lymphocytes and neutrophils), platelets, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T or I, C-reactive protein (CRP), procalcitonin, arterial blood gases (pCO2, lactate), aspartate aminotransferase (AST), alanineaminotransferase (ALT), albumin, creatinine for calculation of eGFR, serum sodium and potassium, D-dimers, and international normalized ratio (INR).

Results

Of all patients in the CVDRF cohort, 26 (15%) patients experienced, HF events at admission or during hospitalization, of which 80 (46%) patients in the HF subgroup and 14 (8%) in the non-HF subgroup, the latter accounting for 40% of all observed HF events. In the CVDRF cohort, patients with an HF event were at a two-fold increased risk for in-hospital mortality compared with those without HF events, P < 0.001, OR 3.10 [2.24–4.29]), even after adjustment for age, sex, risk factors, and co-morbidities. Interaction for HF events and age was significant (P = 0.023), with an OR for HF events and in-hospital death of 3.41 (95% CI [1.96–5.93], P ≤ 0.001) in the <75 years age group and 2.82 (95% CI [1.71–4.65], P < 0.001) in the ≥75 years age group. There was no significant interaction between HF events and sex (P = 0.58). Age, CV diseases, CV risk factors, history of HF, atrial fibrillation, and CKD were significantly associated with HF events.

Conclusions

Hospitalized COVID-19 patients with HF are at increased risk for in-hospital death. In-hospital worsening of HF or acute HF de novo are common and associated with a further increase in in-hospital mortality.
Impaired left atrial reservoir function associated with large v wave in patients with transthyretin amyloid cardiomyopathy
Authors: Yamamoto M , Takashio S , Morikawa K , Oike F , Usuku H , Tsujita K
Published: November 2023

Background

Impaired atrial function, in addition to ventricular diastolic dysfunction, is one of the hallmarks of cardiac amyloidosis (ATTR-CM). Two-dimensional speckle tracking echocardiography is a useful technique for quantitative assessment of LA stiffness. A large v wave on pulmonary artery wedge (PAW) pressure waveform is the findings suggesting LA overload and impaired LA reservoir function. Although large v waves on PAW pressure waveforms are sometimes observed in ATTR-CM patients, their hemodynamic background and clinical significance have not been well described.

Purpose

To investigate the clinical importance of LA function obtained by echocardiography and PAW pressure waveform and the association of enhanced large PAW v wave to clinical outcomes in ATTR-CM patients.

Methods

We retrospectively analyzed central hemodynamics in 136 ATTR-CM patients without severe mitral regurgitation. Large v wave was defined 10 mmHg above mean PAW pressure. We divided 136 ATTR-CM into large v wave group (n = 27) and non-large v wave group (n = 109), and compared the differences in baseline parameters and echocardiographic parameters.

Results

Patients in the large v wave group showed higher mean PAW pressure (24mmHg vs. 14mmHg, p<0.0001). There were no significant differences in age, prevalence of atrial fibrillation, high-sensitivity cardiac troponin T levels (0.060 ng/ml vs. 0.044 ng/mL, p = 0.341), B-type natriuretic peptide levels (188.3 pg/ml vs. 178.7 pg/mL, p = 0.386). In addition, LV ejection fraction, LA diameter, E/e` and cardiac index showed no significant differences between the two groups. However, LA peak longitudinal strain (LS) and LS rate (LSR), evaluation of LA reservoir function, expressed significant depression in large v wave group (LS: 6.24 % vs 9.21 %, p<0.0001, LSR: 0.29 1/s vs 0.38 1/s, p = 0.005).

Conclusions

In ATTR-CM patients, the impaired LA reservoir function associated with extent of large v wave on PAW pressure. This result suggested that impaired LA function may be useful for assessing the progression of ATTR-CM and the deterioration of central hemodynamics.
Ventricular dysfunction after permanent pacemaker implantation in children - what are the implications?
Authors: Bhattacharya D , Namboodiri N , Nair K K M , Dharan B S
Published: November 2023

Introduction

Children (<18 years of age) account for less than 1% of patients requiring permanent pacemaker implantation (PPI), but form a complex subset of population due to technical difficulties, higher prevalence of structural abnormalities and higher rates of reinterventions. Post-pacemaker ventricular dysfunction is seen in around 10-15% and is related to the electrical and mechanical ventricular dyssynchrony. However, similar data is lacking from patients who underwent permanent pacemaker implantation below 18 years of age.

Methods

We retrospectively analysed 235 patients who underwent PPI below 18 years of age, for development of ventricular systolic dysfunction, defined by ejection fraction below 50% of the systemic ventricle.

Results

Male: female ratio was 1.1:1, with median age of implantation being 7 years. 43.4% underwent epicardial PPI, and the commonest indication being congenital complete heart block (50.2%) followed by post-operative CHB (28.1%). 65.5% underwent VVI pacemaker implantation. 41.3% had associated congenital heart disease out of which ventricular septal defect was commonest (20.6%) followed by atrial septal defect (18.6%). Over a median follow-up of 8 years, 15 (6.38%) patients developed ventricular dysfunction, with systemic ventricle of RV morphology, younger age at implantation, maternal ANA positivity, presence of post-operative CHB, associated congenital heart disease and epicardial PPI being major predictors. Five (2.1%) patients required hospitalization for heart failure, while 2 underwent upgradation to CRT. Those with ventricular dysfunction had higher mortality than those who had normal ventricular dysfunction (40% vs 1.5%, p <0.01). There was no association of ventricular dysfunction with the duration of pacing (p = 0.25), the percentage of pacing (p = 0.25) or number of chambers paced (p = 0.38).

Conclusion

Ventricular dysfunction is seen in 6.38% of patients who underwent PPI below 18 years of age, over a median duration of 8 years. It was associated with higher mortality, while younger age at implantation, maternal ANA positivity, presence of post-operative CHB, associated congenital heart disease and epicardial PPI were major predictors for development of ventricular dysfunction.
DDX5 maintains cardiac function by regulating CamkII delta alternative splicing
Authors: Jia K , Zhuang L , Ma W , Cheng H , Li H , Li Z , Wang Z , Sun H , Cui Y , Zhang H , Xie H , Lu L , Gao L , Zhang R , Yan X
Published: November 2023

Background

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease. Dead-box protein 5 (DDX5) is a master regulator of many RNA processes, though its functions in heart physiology and disease remain unclear.

Purpose

To elucidate the function of DDX5 in HF and the mechanisms underlying its role in regulating alternative splicing.

Methods and Results

We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of Ddx5 resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. Ddx5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. By integrating alternative splicing analysis and RNA immunoprecipitation sequencing data, we identified that DDX5 regulated the aberrant splicing of CamkIIδ, thus preventing the production of CaMKIIδA and maintaining Ca2+ homeostasis. In line with this, we found an increased intracellular Ca2+ transients and increased sarcoplasmic reticulum Ca2+ content in DDX5 depleted cardiomyocytes.

Conclusions

Our findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes.
Deep learning model to identify potential occurrence of reduced LVEF in patients with implantable loop recorders
Authors: Howard J , Vasudevan N , Landman S , Sarkar S , Keene D
Published: November 2023

Background

Early detection of left ventricular systolic dysfunction (LVSD) using minimally invasive electrocardiographic assessment in an ambulatory setting may be important considering the increasing economic burden of HF. Recently artificial intelligence (AI) algorithms have been reported to classify reduced ejection fraction using snapshot 12-lead ECG measurements, however the ability of AI to identify LVSD using only a single lead ambulatory ECG is unknown.

Purpose

We aimed to develop a convolution neural network (CNN) based deep learning algorithm using single lead ECG to predict ejection fraction less than 40% in ambulatory patients implanted with implantable loop recorders (ILRs).

Methods

We linked ILR patients with LVEF measurements from a de-identified database of aggregated electronic health record (EHR) data during the period of 2007-2021 to a manufacturer’s device database with ambulatory single lead ECGS. The routine ECG transmissions from the ILR devices were paired with LVEF measured within a week. The data was pre-processed to obtain the time-frequency components of ECG using wavelet transform. The wavelet coefficients were then used as input to train and validate a 2D-CNN model. An independent test dataset consisting of data from patient not included in training/validation dataset was used to assess the performance of CNN model to classify LVEF< = 40% using the metrics area under the curve (AUC), sensitivity and specificity.

Results

A total of 35,741 unique LVEF-ECG pairs collected from 2,249 ILR patients were used to train the model; an independent validation dataset consisted of 6,721 unique LVEF ECG pairs from 750 patients and independent test dataset consisted of 6,611 unique LVEF ECG pairs from 750 patients. In our CNN model, cross entropy was used as loss function and adaptive moment estimation (ADAM) was used as the optimizer. The initial learning rate was selected as 0.0001, epochs as 20 and mini batch size as 64. The threshold to delineate reduced ejection fraction (LVEF< = 40%) was set as 0.1 (Figure 1). The model yielded accuracy, sensitivity, specificity, AUC of 75%,70%, 76% and 0.8 respectively in the independent test set (Figure 2).

Conclusion

A deep learning algorithm applied to ambulatory single lead ECGs acquired by ILR can detect LVEF< = 40%. This continuous ambulatory AI-ECG monitoring may allow to identify longitudinal changes in LVEF post ILR implant via remote monitoring.Figure 1:Model output vs Actual EF rangeFigure 2:ROC
Effects of percutaneous coronary intervention on improvement of left ventricular ejection fraction among chronic coronary syndrome patients with left ventricular systolic dysfunction
Authors: Qiao L , Yibo H E , Hongyu L U , Ziyou Z H O U , Jiulin L I U , Jin L I U , Yong L I U , Jiyan C H E N
Published: November 2023

Background

At present, the therapeutic effects in response to percutaneous coronary intervention (PCI) in chronic coronary syndrome (CCS) patients with left ventricular systolic dysfunction (LVSD) remain unclear.

Methods

Based on the Cardiorenal ImprovemeNt (CIN) cohort study (NCT04407936), we analyzed data of 468 hemodynamically-stable CCS patients with LVSD accepting guideline-directed medical therapy (GDMT) from January 2007 to December 2018. The primary outcome was the improvement of left ventricular ejection fraction (LVEF) and long-term cardiac death. The association between PCI treatment combined with GDMT (PCI-GDMT) and LVEF improvement was evaluated by using propensity score matching (PSM) and logistics regression analysis.

Results

Of the 468 patients included in the study, 135 (28.8%) with GDMT alone and 333 (71.2%) cases were treated with PCI-GDMT. Patients undergoing PCI showed remarkably more vessel lesions but have better cardiac function. After fully adjusting for confounders, the LVEF among CCS patients with LVSD accepting PCI-GDMT were less likely to improve compared with GDMT alone [after PSM: risk adjusted odds ratio (aOR) 0.48, 95% confidence interval (CI): 0.25-0.88, P = 0.02]. Also, PCI therapy may did not bring significant long-term outcome benefit [all-cause death: risk adjusted hazard ratio (aHR) 1.00, 95% CI:0.62-1.62, P = 0.99; cardiac death: aHR 0.61, 95% CI:0.31-1.24, P = 0.17].

Conclusions

Our cohort suggested that PCI treatment may not favor to the improvement of LVEF and not show significant differences in long-term outcome among hemodynamically-stable CCS patients with LVSD.Central Illustration