bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between vitamin D receptor gene polymorphism and cardiomyopathy in response to adriamycin treatment among breast cancer patients
Authors: Mokhtar R , Al-Ansary I , Hassan S , Schaalan M , Sarhan N
Published: November 2023

Background

Chemotherapy-induced cardiomyopathy (CIC) is a common side effect affecting patients with breast cancer treated with anthracyclines chemotherapeutic agents. Vitamin D receptor gene polymorphism seemed to play a crucial role in developing CIC, as vitamin D deficiency was found to increase the risk of many diseases including colon, breast, prostate and ovarian cancer.

Purpose

The current study is primarily to investigate the effect of vitamin D receptor gene polymorphism (ApaI, TaqI, BsmI and FokI) on the incidence of CIC in adult patients with local/advanced or metastatic breast cancer on anthracyclines. Another aim is to detect the association of the gene polymorphism with the response to treatment with chemotherapeutic agents. Moreover, the current study investigated the expression of miR-155 in patients and analyzed its relationship with CIC occurrence.

Methods

This case-control study recruited 60 breast cancer patients with CIC and 30 breast cancer patients without CIC from cardiology and oncology clinics between February 2017 and November 2021. Genomic DNA was extracted from peripheral blood samples and VDR gene polymorphisms were detected using TaqMan techniques.

Results

For the ApaI (rs7975232) and TaqI (rs731236) single-nucleotide polymorphisms (SNPs), the heterozygous (CA) and heterozygous (GA) genotypes increased the risk of CIC among breast cancer patients compared to the control group (OR = 4.31, P < 0.001; OR = 3.2, P = 0.015, respectively). In contrast, homozygous (CC) carriers of the BsmI SNP (rs1544410) had a significantly lower risk for CIC among breast cancer patients (P < 0.001). Finally, for the FokI SNP (rs2228570), there was no significant association with CIC risk. Levels of miR-155 were significantly increased in CIC group compared to the control group (P = 0.015).

Conclusion

The C allele carriers of ApaI SNP and A allele carriers of TaqI SNP are at higher risk of CIC among breast cancer patients; in contrast, the homozygous (CC) carriers of the BsmI SNP are protective against CIC among breast cancer patients. Additionally, higher levels of miR-155 are associated with CIC increased risk among breast cancer patients.
Usefulness of the baseline risk assessment guidelines to predict cancer therapy-related cardiac dysfunction in early-stage HER2 positive breast cancer
Authors: Oristrell Santamaria G , Vila-Sanjuan S , Vila R , Alvarez C , Aguilar R , Arumi M , Escriva-De-Romari S , Saura C , Miranda B , Valente F , Ferreira-Gonzalez I
Published: November 2023

Introduction

Treatment of HER 2-positive breast cancer (HER2+BC) with anthracyclines and HER2-targeted therapy is associated with a high incidence of cancer therapy-related cardiac dysfunction (CTRCD). Baseline risk assessment is crucial to determine patients at high risk of developing CTRCD. Heart Failure Association-International Cardio-Oncology (HFA-ICOS) risk stratification has recently been developed but validation with the new definition of CTRCD is needed (1).

Purpose

To investigate whether the HFA-ICOS baseline risk stratification is useful to identify patients at risk for CTRCD in patients with early-stage HER2+BC.

Methods

95 patients with early-stage HER2+BC were consecutively included in a specialized cardio-oncology unit. In this cohort, patients with previous exposure to antineoplastic treatment, patients with left ventricular ejection fraction (LVEF) < 50% and patients with moderate-severe valvular heart disease had been excluded. All patients underwent a baseline echocardiography study and every 3 months until the end of the chemotherapy. Ultrasensitive troponin I was determined before and immediately after each cycle of chemotherapy.

Results

In our cohort, 48.4% of patients received sequential treatment with anthracyclines and anti-HER2 therapy, while 51.6% received anti-HER2 therapy without anthracyclines. HFA-ICOS baseline risk assessment identified 40 (42,1%) patients with low risk, 27 (28,4%) with moderate risk and 28 (29,5%) with high risk of CTRCD. Table 1 showed the distribution of HFA-ICOS risk factors in our cohort. Only 1 patient with high risk and 3 patients with moderate risk received cardioprotective drugs. At a median follow-up of 13,6 months, 38 patients (40%) did not develop CTRCD, 53 (55,8%) mild-CTRCD, 3 (3,2%) moderate-CTRCD, 1 (1,1%) severe-CTRCD. 3 out of the 4 patients who presented with moderate or severe CTRCD were properly identified as moderate or high risk. However, 52,5% of patients with low risk of CTRCD developed some degree of CTRCD and 19 out of the 38 patients (69,4%) who did not present CTRCD were wrongly identified as moderate or high risk. Table 2 showed the relation between HFA-ICOS risk assessment and the development of CTRCD.

Conclusions

Treatment of early-stage HER2+BC was associated with a high incidence of CTRCD. In our cohort of early-stage HER2+BC, HFA-ICOS baseline risk assessment was useful in identifying patients at risk of developing moderate or severe CTRCD, but was not useful in identifying patients at low risk of CTRCD.HFA-ICOS risk factors and CTRCDHFA-ICOS risk assessment and CTRCD
CerS2 ko in vivo reduces pro-inflammatory ceramides and improves doxorubicin mediated cardiotoxicity
Authors: Kretzschmar T , Bekhite M , Gruen K , Mueller T , Graeler M , Nietzsche S , Westermann M , Schulze P C
Published: November 2023

Background

Ceramides and their role in various signaling pathways are believed to regulate distinct cellular effects. Accumulation of ceramides seems to be associated with an inflammatory phenotype negatively affecting cardiomyocyte vitality and mitochondrial homeostasis.

Aim

The purpose of our study is to identify underlying ceramide signaling pathways and characterize downstream effects on cell vitality of cardiomyocytes.

Methods

A CerS2 ko mouse model was generated and the animals were treated with 7 cumulative doses of 3 mg/kg BW Doxorubicin (Dox). Subsequently, hearts were extracted and analyzed, including mRNA (qPCR) and protein expression (WB) and ceramide level (mass spectrometry).

Results

The CerS2 ko was stable and Dox injection did not increase CerS2 protein expression. Mass spectrometry revealed an increase of long chain ceramides (C≤20) with the highest peak for C18:0 (5.08 ± 0.21, p<0.001) but a decrease of the pro- inflammatory very long chain ceramides C24:0 (0.65 ± 0.20, p = 0.02) and C24:1 (0.23 ± 0.22, p<0.001). qPCR showed a decrease of TNFα (0.18 ± 0.49, p<0.001), IL-1β (0.43 ± 0.27, p<0.001) and BNP (0.28 ± 0.53, p<0.001). Furthermore, mitochondrial homeostasis improved by a reduction of the mitochondria fission related gene Mitochondrial fission factor (Mff) (0.74 ± 0.23, p = 0.007).

Conclusion

CerS2 ko and subsequent ceramide reduction improves cardiomyocyte vitality on a cellular level by a reduction of inflammation and an improvement of mitochondrial function. Thus, regulation of ceramide levels through control of CerS2 activity might represent a novel therapeutic option for the control of cardio toxicity.
Initial phase of anthracycline cardiotoxicity involves metabolic switch and activation of cardiac fibroblasts
Authors: Urbanek K , Donniacuo M , Cappetta D , Telesca M , Riemma M , Bellocchio G , Berrino L , Rossi F , Castaldo G , De Angelis A
Published: November 2023

Background

Doxorubicin (DOX) is an effective anticancer drug, but its application is hampered by cardiotoxicity with asymptomatic diastolic dysfunction as the earliest manifestation. Interstitial fibrosis leads to impaired relaxation, but the timing of fibrotic process and the mechanisms that operate shortly after DOX exposure are not clear. While changes in energy metabolism by DOX is recognized in cardiomyocytes, the effects of DOX on cardiac fibroblasts (CFs) metabolism are unknown.Thus, in a model of anthracycline cardiomyopathy, we asked whether the activation of CFs anticipates the onset of DOX-induced early diastolic dysfunction and evaluated the effects of DOX on the activation and metabolism of CFs.

Methods

Fischer 344 rats were exposed to 6 injections of 2.5 mg/kg of DOX over 2 weeks. Heart function was assessed by echocardiography and left ventricular catheterization. To test the very early in vivo effects of DOX on CFs, primary CFs were isolated from hearts of DOX-treated rats after the first injection of DOX. In another set of experiments, CFs were exposed to DOX in vitro. Cell metabolism was measured by a Seahorse-XF Real-Time ATP assay and cell phenotype was determined by immunocytochemistry and molecular biology.

Results

Early effects of DOX consisted of unchanged ejection fraction and the evidence of diastolic dysfunction. Markers of pro-fibrotic remodeling and histological evidence of CFs transformation were present in the heart immediately after treatment completion. Importantly, at the very beginning of the DOXO exposure, when cardiac function was normal and there was no histological evidence of increased fibrosis, the conversion of CFs to myofibroblasts, evidenced by SMA, was detected. Oxygen consumption rate and extracellular acidification, revealed the increased metabolic activity of CFs after DOX exposure and the switch to the glycolytic energy production. These effects were consistent in CFs isolated from the hearts of DOX-treated animals and in naive CFs exposed to DOX in vitro. The metabolic switch was paralleled with the phenotype change of CFs towards extracellular matrix-producing cells. Upon DOX, CFs upregulated markers of myofibroblast differentiation and the activation of pro-fibrotic signaling (aSMA, TGFb and phospho-SMAD). CFs maintained their functional properties in scratch assay. CFs upregulated also NOX2, indicating these cells as an intramyocardial source of reactive oxygen in the initial phase of the disease.

Conclusion

The metabolic switch and activation of CFs anticipate the onset of DOX-induced early diastolic dysfunction. The effect of DOX on the metabolic profile in CFs represents a novel and potentially targetable component of the very early phase of the pathogenesis of anthracycline cardiomyopathy.
Right ventricular dysfunction in the absence of pulmonary hypertension in HFpEF
Authors: Popovic D , Alogna A , Omar M , Sorimachi H , Kazunori O , Reddy Y N V , Borlaug B A
Published: November 2023

Background

Right ventricular (RV) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), portends worse prognosis, and is believed to be caused by contractile impairment and remodeling due to afterload mismatch from pulmonary hypertension (PH). The goal of this study was to examine the right heart in patients with HFpEF and resting mean pulmonary arterial (PA) pressure (MPAP)≤20 mmHg.

Methods and results

Among 621 patients with HFpEF undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing, 159 (26%) had resting MPAP≤20 mmHg (HFpEFMPAP≤20mmHg). In comparison to 73 controls, they were more obese, had more coronary disease and atrial fibrillation. After adjusting for BMI, there were no differences in plasma volume but NTproBNP was higher and peak oxygen consumption lower in HFpEFMPAP≤20mmHg than in controls (p = 0.002, <0.001, respectively). While RV dimension was similar, tricuspid annular plane systolic excursion and RVs’ were lower in HFpEFMPAP≤20mmHg (18±5 vs. 22±4 mm, p = 0.005; 10±2 vs. 12±2 cm/s, p = 0.047, respectively). HFpEFMPAP≤20mmHg and controls displayed similar pulmonary vascular resistance, MPAP and right atrial pressure at rest, but during exercise, MPAP and right atrial pressure were higher in patients with HFpEFMPAP≤20mmHg (41±10 vs. 33±10 mmHg; 18±7 vs. 12±4 mmHg, p<0.001, respectively). PA compliance was lower at both rest and exercise (rest 4.1±2.1 vs. 5.0±1.8; exercise 2.9±1.4 vs. 3.2±1.4 ml/mmHg, p<0.001, for both).

Conclusion

Right heart dysfunction is present in patients with HFpEF even in the absence of frank PH. These patients display greater pulsatile RV loading by PA compliance even as resistance is not markedly elevated. These data support further study into novel therapies targeting pulsatile RV afterload in HFpEF.
Left bundle branch area pacing improves right ventricular function in heart failure with preserved ejection fraction: evidence from PROPHET trial
Authors: Su Y
Published: November 2023

Background

Left bundle branch area pacing (LBBAP) has emerged as a promising pacing strategy, especially for patients with heart failure. However, the impact of LBBAP on hemodynamics and cardiac function in heart failure with preserved ejection fraction (HFpEF) has not been investigated yet.

Aim

To investigate the hemodynamic response and change of cardiac function of LBBAP in patients with HFpEF.

Methods

This prospective cohort study enrolled patients with preserved left ventricular ejection fraction who were receiving LBBAP, and two cohorts (non-HFpEF cohort and HFpEF cohort) were built based on diagnosis of HFpEF. Hemodynamics before and after LBBAP were measured using right heart catheterization (RHC). And the changes of cardiac function were evaluated by transthoracic speckle tracking echocardiography (STE).

Results

30 consecutive patients were included in the study, with 17 patients in the non-HFpEF group and 13 patients in the HFpEF group. Preprocedural STE showed worsened right ventricular function in the HFpEF group indicated by global longitudinal strain rate, free-wall strain rate, fractional area change, Tricuspid annular pulmonary systolic excursion and Tei index. And RHC showed elevated right ventricular stroke work index (RVSWI, 8.6±4.1 non-HFpEF vs 15.0±5.6 HFpEF, P = 0.170). While post-LBBAP evaluation showed a more significant reduction in RVSWI in the HFpEF group (6.7±2.5 (reduction 22.1%) non-HFpEF vs 8.0±1.0 (reduction 46.7%) HFpEF, P = 0.043). Besides, post-LBBAP STE showed improvement of right ventricular function, despite no significant difference in the extent of improvement was found between groups.

Conclusion

LBBAP might be more beneficial to patients with HFpEF as it could improve right ventricular function by alleviating the workload of right ventricle. Long-term benefit of LBBAP in HFpEF requires further investigation.
Functional mitral regurgitation and ventricular arrhythmias in patients with cardiac resynchronization therapy
Authors: Yoshimura A , Suzuki A , Yoshida A , Kanai M , Hasegawa S , Kataoka S , Yazaki K , Saito C , Yagishita D , Domoto S , Shiga T , Ashihara K , Shoda M , Niinami H , Yamaguchi J
Published: November 2023

Introduction

In patients with heart failure (HF), the occurrence of ventricular arrhythmias (VAs) is associated with prognosis, and advanced HF can cause VAs. In HF patients developed moderate to severe functional mitral regurgitation (FMR), a transcatheter mitral valve repair therapy has significantly reduced the hospitalization and mortality rates compared to guideline-directed medical therapy. Although the mechanisms of arrhythmias are multiple, it is unclear whether FMR is involved in the development of VAs advanced HF patients.

Methods and results

We retrospectively examined 176 cardiac resynchronization therapy (CRT) patients (78% men, median age 67 years) without FMR before CRT implanted between 2010 and 2018. Worsening FMR was defined as developing moderate to severe FMR after CRT. During median follow-up of 40 (quartile range, 23-60) months, worsening FMR was detected in 26 (15%) patients at a median of 30 (quartile range, 12–75) months after CRT implantation. There was no difference in age, New York Heart Association functional class, QRS width before CRT and the rate of responders between patients with and without worsening FMR. Patients with worsening FMR had a tendency of larger left ventricular end-systolic dimension (58 [53-68] vs. 53 [47-60] mm, p<0.10), a significantly higher rate of female (38% vs. 19%, p<0.05) and a significantly larger left atrial volume index (LAVI) (63 [43-81] vs. 48 [35-62] ml/m2, p<0.05). By multivariate logistic regression analysis, female gender (odds ratio 4.3) and baseline LAVI (odds ratio 1.04 per a ml/m2 increase) were independent factors associated with worsening FMR. There was a significantly higher incidence of HF hospitalization (50% vs 15%, log-rank P<0.05) (Figure 1) and a higher incidence of VAs, defined as sustained ventricular tachyarrhythmias requiring implantable-cardioverter defibrillator therapy or external defibrillation, in patients with worsening FMR than patients without worsening FMR (65% vs 38%, log-rank P<0.05) (Figure 2). Multivariate analysis showed that worsening FMR was independently associated with the development of VAs (hazard ratio 2.77, 95% confidence interval 1.13-6.83).

Conclusions

In patients with HF and CRT, female gender and baseline LAVI were associated with worsening FMR after CRT. We need to pay attention to changes in the FMR that can be associated with developing VAs after CRT implantation.
Characterization and prognostic impact of ischemic etiology in heart failure with reduced left ventricular ejection fraction
Authors: Perea Armijo J , Heredia Campos G , Lopez Aguilera J , Castillo Dominguez J C , Anguita Sanchez M
Published: November 2023

Introduction and objectives

Ischemic heart disease is the cause of 50-60% of cases of heart failure with reduced left ventricular ejection fraction (HF-rEF). The impact of ischemic etiology on left ventricular ejection fraction (LVEF) improvement and prognosis remains unclear. Our main objective was to analyze the differential clinical profile between ischemic and non-ischemic etiology, as well as its medium-to-long term prognosis.

Methods

Prospective study of a cohort of patients with HF-rEF in real clinical practice. A comparative analysis was performed between patients with HF-rEF of non-ischemic etiology (Group 1) and ischemic etiology (Group 2). Clinical, analytical, echocardiographic and therapeutic variables were analyzed, and the medium-to-long term impact in terms of mortality and hospital readmissions for HF was evaluated.

Results

409 patients were analyzed. 276 patients (67.5%) had non-ischemic etiology and 133 patients (32.5%) had ischemic etiology. Group 2 was older (65.8±13.3vs70.8±10.3;p<0.001), more men (68.1%vs86.5%;p<0.001), higher prevalence of arterial hypertension (62.3%vs76.7%;p = 0.004), diabetes mellitus (38.8%vs67.7%; p<0.001), dyslipemia (52.4%vs82.7%;p<0.001), chronic kidney disease (34.4%vs56.4%;p<0.001), anemia (24.3%vs47.4%;p<0.001) and vascular comorbidity (25.7%vs54.9%;p<0.001) and lower prevalence of atrial fibrillation (56.2%vs44.4%;p = 0.025). In Group 2 there was a lower proportion of de novo HF (60.1%vs45.1%;p = 0.004) with longer HF evolution time (24.4±48.8vs61.5±89.3; p<0.001), a lower proportion of patients improving LVEF at follow-up (51.6%vs21.1%;p<0.001) and a higher baseline NTproBNP concentration [4463(IQR 1976-10431)vs5746(IQR 2336.5-13789);p = 0.039]. Regarding baseline treatment, in Group 1 there was a higher prescription of mineralocorticoid receptor antagonists (78.3%vs63.9%;p = 0.002) and less ICD implantation (6.5vs14.3%;p = 0.01), with no differences in the rest of the treatment. With a mean follow-up of 60 months, Group 2 had a higher readmission rate (39%vs50.3%;p<0.01) and higher HF mortality (26.8%vs41%;p<0.01), with differences from early stages.

Conclusions

Patients with HF-rEF of ischemic etiology associate a greater number of comorbidities, a lower percentage of de novo HF, longer time of HF evolution, lower percentage of LVEF improvement and higher baseline NTproBNP.
Effect of vericiguat on cardiovascular outcomes in patients with heart failure with and without diabetes: Insights from the VICTORIA trial
Authors: Khan S , Butler J , Young R , Lewis B S , Escobedo J , Refsgaard J , Reyes E , Roessig L , Blaustein R O , Lam C S P , Voors A A , Ponikowski P , Anstrom K J , Armstrong P
Published: November 2023

Objective

To investigate the impact of type 2 diabetes mellitus (T2D) on outcomes in patients with worsening heart failure with reduced ejection fraction (HFrEF) and to assess the efficacy of vericiguat in these patients.

Methods

Patients with HF and a left ventricular ejection fraction ≤45% were randomized to receive vericiguat or placebo in addition to standard therapy. The primary outcome was a composite of cardiovascular death or first hospitalization for HF (HHF). A Cox proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to assess if the effect of vericiguat differed by history of T2D.

Results

Of the 5048 patients, 2369 (46.9%) had T2D. The risks of the primary outcome, HHF, and all-cause and cardiovascular death were already very high in those without T2D and even higher in patients with T2D. The beneficial effect of vericiguat on the primary outcome did not differ in patients with (HR, 0.91 [95% CI, 0.80–1.03]) or without (HR, 0.87 [95% CI, 0.76–0.99] (P-interaction = 0.64) T2D (Figure). No significant differences were noted among patients with and without T2D with respect to the effect of vericiguat on HHF and all-cause or cardiovascular death.

Conclusion

Notwithstanding the increased incidence of cardiovascular death and HHF conferred by T2D, in this post-hoc analysis of VICTORIA, vericiguat compared with placebo significantly reduced the risk of cardiovascular death or HHF in patients with worsening HFrEF regardless of T2D status.
Increased clonal hematopoiesis mutational burden and accelerated dynamic evolution of circulating clones in patients with ischemic heart failure
Authors: Kirschbaum K , Rieger M , Leistner D , Dimmeler S , Zeiher A , Cremer S
Published: November 2023

Background

Clonal hematopoiesis (CH) - defined as the age-related acquisition of mutations in hematopoietic stem cells giving rise to mutated circulating leukocytes - is associated with increased risk of death in patients with heart failure with reduced ejection fraction (HFrEF). While the mutational landscape of CH in peripheral blood (PB) of patients with HFrEF is well characterized, the mutational burden in bone marrow (BM) samples of patients with HFrEF as well as its dynamics over time have not been investigated.

Methods/Results

We analyzed matched BM and PB cells from 68 patients with ischemic HFrEF by deep error-corrected targeted sequencing of 56 CH-driver genes with a detection threshold of VAF ≥0.5%. In PB, 56/68 patients carried at least one CH mutation, whereas 63/68 patients had mutations in BM. The absolute numbers of detectable mutations were significantly higher in BM compared to PB (215 mutations vs 120 mutations; p<0.0001) (Fig. 1A). Likewise, the cumulative VAF was significantly higher in BM compared to PB (3.83 +/- 0.5% vs 3.0% +/-0.7%; mean +/- SEM, p = 0.0025) (Fig. 1B). However, there was a strong correlation between mutation load in PB and BM (r = 0.54, p<0.0001). Among the two most common mutations, DNMT3A mutations were either present in BM only or both compartments (PB only/BM only/ both compartments 2/12/10), whereas TET2 mutations were strikingly enriched in BM cells (PB only/BM only/both compartments 0/16/2).

To study the dynamic evolution of CH clones in patients with HFrEF, we serially analyzed PB samples from 19 patients. At baseline, 16/19 patients carried at least one mutation in a CH driver gene and a total of 31 mutations. After a median follow-up of 12 months, 19/19 patients had at least one detectable mutation and a total of 43 mutations were identified (mean number of mutations per patient 1.63 +/- 0.033 vs 2,26 +/- 0.27; mean +/- SEM, p = 0,0410), indicating an increased mutation load over time (Fig. 2A). Moreover, cumulative VAF increased from 1.59 +/-0.36 % to 2.01 +/- 0.38 %).

Conclusion

Patients with ischemic HFrEF display a high burden of CH mutations compared to values reported for healthy individuals, which is further amplified in the bone marrow compartment. Clones with new mutations arise rapidly in longitudinal samples of patients with HFrEF and clonal expansion occurs with high momentum. The overrepresentation of mutations in the BM is indicative for augmented DNA damage in the hematopoietic stem cells of patients with HFrEF, while the rapid expansion of mutated circulating clones over time suggests that heart failure itself may expedite the expansion of hematopoietic cells harboring CH-driver mutations.
Left ventricular thrombus in patients with heart failure with improved ejection fraction
Authors: Puwanant S , Peerawat Puwatnuttasit P P , Suksiriworaboot T S , Sinphurmsuksakul S S , Ariyachaipanich A A , Siwamoksatham S S , Boonyaratavej S B
Published: November 2023

Background

This study sought to: (1) determine the prevalence of LV thrombus at baseline and at the time of recovered ejection fraction (EF) in patients with heart failure with improved ejection fraction (HF-imp EF), (2) examine clinical and echocardiographic factors associated with the presence of LV thrombus, and (3) determine the prevalence of thromboembolic events when LVEF was improved and oral anticoagulant (OAC) was discontinued.

Methods and results

Patients with nonischemic HF-imp EF defined as a baseline LVEF of ≤ 40%, a ≥ 10% increase from baseline LVEF, and a second measurement (6 months apart) of LVEF of > 40% were consecutively enrolled in advanced HF clinic in a tertiary center. Patients with recent myocarditis, recent coronary revascularization, active chemotherapy, hypertrophic cardiomyopathy, cardiac amyloidosis, and tachycardia induced cardiomyopathy were excluded. A total of 104 consecutive patients (age 51 ± 15 years; 66% were male) with HF-imp EF were included. Of these, 14 patients (14%) had LV thrombus at baseline. Baseline LVEDD, LVEF, and LV global longitudinal strain (GLS) were 61 ± 10 mm, 23 ± 15%, and -5.9 ± 3.3%, respectively. Younger age, absence of atrial fibrillation, receiving oral diuretics, lower LVEF, reduced LV GLS, and reduced RV free wall (FW) GLS were significantly associated with LV thrombus at baseline (p < 0.05 for all) (Table 1). All patients (100%) with LV thrombus at baseline received oral anticoagulants (OAC). At the median follow-up of 27 months, 14 (100%) had complete resolution of LV thrombus when LVEF > 40%. Of 14 patients, 11 (79%) who were in sinus rhythm discontinued OAC. After a median further follow-up of 27.4 months following OAC discontinuation, there was no thromboembolic event or all-cause mortality in these patients. One of 11 patients developed worsening LVEF and recurrent LV thrombus at 25 months after LVEF improvement (> 40%).

Conclusions

Approximately 1 in 6 patients with HF-imp EF had LV thrombus at baseline. LV thrombus formation was associated with more impaired LV and RV systolic function and myocardial deformation implicating more thromboembolic milieu. Complete resolution of LV thrombus occurred in all patients who were on OAC therapy at the time of imp-EF. Discontinuation of OAC when LVEF > 40% was safe. However, recurrent thrombus formation can occur when LV systolic function was deteriorated. Annual or bi-annual echocardiographic follow-up may be essential in these patients.
Prognostic value of left atrial strain in heart failure with reduced ejection fraction
Authors: Tas Ozbek B , Modin D , Sengloev M , Joergensen P G , Bruun N E , Fritz-Hansen T , Biering-Soerensen T
Published: November 2023

Background

The prognostic value of left atrial (LA) strain in patients with heart failure with reduced ejection fraction (HFrEF) has not been fully elucidated. Therefore, this study investigated the prognostic value of left atrial strain in HFrEF patients in relation to allcause mortality.

Methods

A total of 822 echocardiograms from HFrEF patients admitted to a heart failure clinic were analyzed offline. To calculate left atrial resevoir strain (LA RS) and left atrial contractile strain (LA CS), left atrial two-dimensional speckle tracking was performed in the 4-chamber, 2-chamber and 3-chamber view. The end-point was all-cause mortality. The association between left atrial strain parameters and outcome was examined using Cox regression.

Results

The median follow-up time was 40 months and follow-up was 100% complete. During follow-up, a total of 137 patients (16.7%) died of all causes. In a final multivariable model adjusted for clinical and echocardiographic parameters including global longitudinal strain, LA RS and LA CS were significantly associated with all-cause death during follow-up (LA RS, HR 0.96, 95% CI 0.92-0.99 p = 0.014, pr. 1% increase) (LACS, HR 0.95, 95% CI 0.92-0.98 p = 0.002, pr. 1% increase) (Table 1). When added to the final multivariable model, both LA RS and LA CS contributed with incremental prognostic value as determined by C-statistic (LA RS: C-stat difference 0.007, 95% CI 0.000-0.020, p = 0.050) (LA CS: C-stat difference 0.009, 95% CI 0.000-0.023, p = 0.030).

Conclusion

In HFrEF patients, LA RS and LA CS were associated with all-cause mortality and contributed with incremental prognostic value in addition to established prognostic measures.Table 1
The effect of iron deficiency treatment with intravenous ferric carboxymaltose on the arrhythmic burden of patients with HFrEF and cardiac implantable electronic devices
Authors: Tsarouchas A , Mouselimis D , Bakogiannis C , Papadopoulos C , Antoniadis A , Tsavousoglou C , Kelemanis I , Triantafyllou K , Strati E , Giannopoulos G , Fragakis N , Efthimiadis G , Vassilikos V
Published: November 2023

Background

The deleterious effect of iron deficiency (ID) on cardiomyocyte electrochemical stability is well-documented. In patients with heart failure and reduced ejection fraction (HFrEF), ID represents a key comorbidity associated with increased morbidity and mortality. Thus, it has been hypothesized that treating ID may lead to reduced incidence of arrhythmias in HFrEF patients.

Purpose

To study the effect of intravenous ferric carboxymaltose (IV FCM) treatment on the iron stores, arrhythmic burden, functional capacity and quality of life in HFrEF patients with ID and cardiac implantable electronic devices (CIEDs).

Methods

Patients with HFrEF, ID and CIEDs scheduled to receive IV FCM as per ESC guidelines were invited to participate. Follow-up lasted 12 months. The primary outcome was related to the amelioration of patients’ iron status. Secondary outcomes relative to arrhythmic burden included (i) the incidence of device-detected ventricular tachycardias (VTs) between the year before recruitment to the study and the follow-up period, (ii) patients’ Lown and Wolf classification as derived from 24hour Holter monitoring. Data related to non-invasive arrhythmic markers such as late potential, microvolt T-wave alternans and deceleration capacity were also available.

Results

This real-life cohort included 79 patients (84% male). Patients’ median age was 70.8 [IRQ:11.7] years. Median ferritin increased to 150 [125] ng/mL at 12 months (baseline 55 [68] ng/mL, P<0.001). At their final visit, 45 (57%) patients no longer met the ESC criteria for iron deficiency (P<0.001). The CIED-derived incidence of VT episodes decreased significantly after 12 months of IV FCM treatment (0.26±0.83 episodes per patient per year compared to 0.8±2.36, P = 0.048). Patients were also significantly likely to shift to a more favorable Lown and Wolf arrhythmic burden classification (P = 0.01). Patients’ late potential results and microvolt T-wave alternans also improved significantly (P = 0.01 for both tests).

Conclusion

The results of this real-life cohort analysis suggest significant reduction of the arrhythmic burden in HFrEF and ID after restitution of iron stores. Further studies are needed to further evaluate the impact of these results.
Heterogeneity of patients phenotyped as heart failure with mildly reduced ejection fraction
Authors: Kerkhof P L , Heyndrickx G R , Diaz-Navarro R A , Handly N
Published: November 2023

Background

Current phenotyping of heart failure (HF) is based on the ejection fraction (EF) criterion, resulting into three types including the mildly reduced (mr) category. Little is known about the heterogeneity of the volumetric (ie left ventricular [LV] size) and clinical characteristics (including myocardial oxygen consumption, MVO2) of patients who are assigned to the HFmrEF class.

Method

The metric EF combines details on end-systolic volume index (ESVi) and end-diastolic volume index (EDVi). Both volumetric measures can be presented in the volume regulation graph (VRG), allowing the graphical inspection of the behavior of EF under a variety of conditions, with stratification options based on age, sex or other clinically relevant determinants. To overcome the limitations intrinsic to ratio-based metrics such as EF, we introduced a logical EF-companion (EFCi), defined as the square root of (ESVi² + EDVi²). In other studies the EFCi has been shown to offer incremental value beyond the single use of EF.

Patients

LV volumes were determined by biplane angiocardiography in 190 HF patients (69 women), and retrospectively analyzed.

Results

Average ESVi values for mrEF are 57.9 and 60.2 mL/m² for men (n = 22) and women (n = 10), respectively. The distribution of {EDVi, ESVi} data pairs in the VRG is shown in Figure 1, stratified for women and men. Patients categorized as HFmrEF are indicated by separate markers, and located in the region between the lines that indicate the 40 and 50% limits for EF. The double arrowed yellow bar refers to the wide ESVi range (27 to 118 mL/m²) for the patients within this narrow EF bandwidth. As ESVi refers to the extent of (reverse) remodeling and is associated with MVO2, there is a clear need the consider ESVi or EFCi for patients, in addition to their nearly similar EF values. Figure 2 shows the distribution of EFCi (range 59.5 to 231.8 mL/m2) for all HFmrEF patients, and clearly illustrates the supplementary value of the companion to the ratio-based metric EF.

Conclusions

As the bandwidth for EF narrows, the specificity of EF decreases and the higher the need to rely on EFCi. Thus, in contrast to the current view indicating that HFmrEF patients form a well-defined rather homogeneous phenotype exhibiting comparable clinically relevant characteristics, we found a relatively pronounced heterogeneity within the HFmrEF phenotype group. Distinguishing individual patients within the HFmrEF phenotype can be realized by considering the newly introduced parameter EFCi. This approach resolves most of the criticism thus far expressed regarding limitations of EF. The proposed additional dimension beyond EF offers a more comprehensive description of these patients, and will allow a personalized analysis based on a more careful characterization. Further investigations are warranted to explore implications for patient management.Figure 1.VRG for HF patients (n = 190)Figure 2.HFmrEF vs EFCi (n = 32)
Cause-specific death in heart failure across the ejection fraction spectrum
Authors: Settergren C , Benson L , Dahlstrom U , Savarese G , Thorvaldsen T , Shahim B , Lund L H
Published: November 2023

Background

Heart failure (HF) is associated with increased cardiovascular (CV) and non-CV mortality, but little data is available on underlying causes of death in HF phenotypes based on ejection fraction (EF). Knowledge about causes of mortality may have implications for healthcare decisions, treatment priorities and clinical trial design.

Purpose

To examine cause-specific mortality in patients with HF with reduced EF (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF).

Methods

Patients enrolled in the Swedish Heart Failure Registry between 2000-2021 were included. The causes and incidence rates of death across the EF categories were studied. In addition, to examine the association between EF categories and cardiovascular (CV) and non-CV mortality, sub-distributional hazards models were performed accounting for competing risk of death from other causes and adjusted for age and sex.

Results

Among 100,584 patients (23% HFpEF, 23% HFmrEF, 53% HFrEF), median age (IQR) was 75.0 (66.0-82.0) and 36.5% were females. Of those who died within 5 years, most deaths were ascribed to CV deaths across all EF categories (65% in HFrEF, 59% in HFmrEF and 58% in HFpEF, respectively). Within 5 years, patients with HFpEF had higher risk of non-CV mortality (adjusted HR 1.38, 95% CI 1.33-1.43, p< 0.001) and lower risk of CV mortality (adjusted HR 0.80, 95% CI, 0.78-0.83, p< 0.001) compared to patients with HFrEF. Ischemic heart disease (IHD) was the most common cause of CV-death while cancer was the most common cause of non-CV death across all EF categories. The incidence rate of CV death due to IHD was higher in HFrEF while the incidence rates of CV death due to pulmonary vascular disease, stroke, valvular heart disease and atrial fibrillation were higher in HFpEF compared to HFrEF and HFmrEF (Figure 1). Patients with HFpEF had higher incidence rate of non-CV deaths due to cancer, respiratory disease, accidents and infections including covid -19 compared with HFrEF and HFmrEF patients (figure 2).

Conclusion

In this large and contemporary cohort of patients with HF, CV death was more common than non-CV death across all EF categories although the risk of non-CV mortality within 5-years was higher with increasing EF. IHD and cancer were the most common causes of CV and non-CV deaths, respectively, regardless of EF category. Patients with HFpEF had a higher burden of non-CV causes of death than patients with HFrEF and HFmrEF.Incidence rate CV deathIncidence rate non-CV death
Usefulness of a scoring evaluation for practical introduction of the guideline-directed medical therapy (GDMT) in heart failure patients
Authors: Matsukawa R , Itonaga J , Kisanuki H , Hara A , Sada M , Okabe K , Okahara A , Tokutome M , Kawai S , Matsuura H , Mukai Y
Published: November 2023

Backgrounds

Guideline-directed medical therapy (GDMT) has been recommended for heart failure (HF) with reduced EF (HFrEF) based on the accumulating clinical evidence. However, it is difficult to introduce all the trial-proven drugs to every patient in a real-world setting.

Purpose

We developed a simple GDMT score consisting of RAS (renin-angiotensin system) inhibitor, beta-blocker, MRA (mineralocorticoid receptor antagonist), and SGLT2 (sodium-glucose cotransporter 2) inhibitor, which is a modification of the previously proposed GDMT score, and investigated whether this score is related to the prognosis of HF patients and how this score can be used in daily clinical practice.

Methods

We retrospectively analyzed 1782 consecutive patients with ADHF at our hospital from April 2015 to March 2022. One thousand fifty-four patients with HFrEF and HFmrEF (HF with mildly reduced EF) were extracted, excluding 61 patients who died in hospital, 53 patients with dialysis, and 614 patients with HFpEF. First, we calculated the simple GDMT score in these patients. Then, the association with clinical outcomes (composite outcome: HF readmission or all-cause death, HF readmission, all-cause death) was examined.

Results

The cut-off value for the association between the composite outcome and the simple GDMT score was 4 points (AUC = 0.607, 95%CI = 0.57-0.64) using the receiver operating characteristic (ROC) curve. Multivariate analysis showed that high simple GDMT score (more than 5 points) was strongly associated with the composite outcome (HR = 0.606, 95%CI = 0.403-0.912, p = 0.016), HF readmission (HR = 0.207, 95%CI = 0.077-0.558, p = 0.001) and all-cause death (HR = 0.250, 95%CI = 0.093-0.669, p = 0.005). The Kaplan-Meier curve showed that events were less frequent in the group with a high simple GDMT score group. Furthermore, a simple GDMT score of 5 or higher was associated with a good prognosis in both subgroups.

Conclusions

The designed GDMT score was associated with prognosis in HFrEF and HFmrEF patients. Even if for some reason all four drugs cannot be introduced, a regimen with the simple GDMT score ≧ 5 may improve the prognosis in HF patients.
Comparison of long-term prognostic impact of sarcoidosis as etiology with dilated cardiomyopathy in patients with heart failure in a nationwide heart failure registry
Authors: Bollano E , Bobbio E , Pivodic A , Bjorkestam M , Dahlstrom U , Fu M
Published: November 2023

Background

It remain largely unknown whether the prognostic impact of sarcoidosis (SC) prior to heart failure (HF) differs from dilated cardiomyopathy in patients with HF over time.

Aim

To investigate the prognostic impact of prior sarcoidosis in HF patients and compare to those with HF due to dilated cardiomyopathy (DCM) by access to Swedish Heart Failure Registry which is further validated by cross linkage with Swedish National Patient Register and supplemented by Swedish National Cause of Death Register.

Methods

Patients with sarcoidosis before HF diagnosis (SC-HF group) versus patients with HF due to DCM (DCM-HF group) were identified from the Swedish Heart failure Registry between 2003-2020. The primary outcome is all-cause mortality and secondary outcome is composite CV death or hospitalization due to worsening HF in both overall cohort and propensity score-matched cohort.

Results

A total of 422 patients (69.6±13.5, male 60,7%) in SC-HF group and 6913 patients (61.7±13.5, male 72.5%) in DCM-HF group were identified. Patients with DCM were younger, had less comorbidities (renal failure, hypertension, atrial fibrillation, valvular heart disease, chronic obstructive pulmonary disease, diabetes, stroke, cancer, musculoskeletal disease) and more prescriptions of ACEI/ARB/ARNI, beta blockers and MRA) and less treatment with corticosteroids (10.6% vs 44.1%) but similar in diuretics and device therapy (ICD, CRT). In overall cohort, after adjustment for age, sex, HF duration, NYHA, LVEF, NT-proBNP cat., eGFR, the risk for all-cause mortality in SC-HF was significantly higher in SC-HF than DCM-HF [the hazard ratio (95% CI): 1.54 (1.32 - 1.81) p = <.0001]. Likewise, the risk for composite CV death or HF hospitalization in SC-HF was significantly higher in SC-HF than DCM-HF (the hazard ratio (95% CI): 1.21 (0.95 - 1.54), p = 0.131.40 (1.24 - 1.59), p = <.0001. Furthermore, in a propensity score-matched cohort in which 365 from SC-HF group were compared with 736 patients in DCM-HF group. Over a median follow -up of 3,1 years (1.4-5.79), SC-HF group has a higher risk of all-cause mortality [ HR: 1.35 (1.11 - 1.65), p = 0.0033], and of CV death or HF Hospitalization [1.28 (1.09 - 1.50), p = 0.0021] than DCM-HF group.

Conclusion

Sarcoidosis has greater negative impact on prognosis for heart failure than dilated cardiomyopathy with increased risk for both mortality and morbidity.
Elevated plasma adiponectin in risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction: observational and mendelian randomization studies
Authors: Nielsen M B , Colak Y , Benn M , Mason A , Burgess S , Nordestgaard B
Published: November 2023

Background and purpose

Adiponectin, an adipocyte-secreted protein-hormone, may play an important protective role in heart failure and associated cardiovascular diseases through insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. We hypothesized that plasma adiponectin is associated observationally and causal, genetically with risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction.

Methods

In the Copenhagen General Population Study (CGPS), we examined 30,045 individuals with plasma adiponectin measurements observationally and 96,903 individuals genetically in one-sample Mendelian randomization analyses using five genetic variants. In the HERMES, UK Biobank, The Nord-Trøndelag Health Study (HUNT), deCODE, the Michigan Genomics Initiative (MGI), DiscovEHR, and the AFGen consortia, we performed two-sample Mendelian randomization analyses in up to 1,030,836 individuals using 12 genetic variants.

Results

In observational analyses, a 1 unit log-transformed higher plasma adiponectin was associated with a hazard ratio of 1.51 (95% confidence interval: 1.37–1.66) for heart failure, 1.63 (1.50–1.78) for atrial fibrillation, 1.21 (1.03–1.41) for aortic valve stenosis, and 1.03 (0.93–1.14) for myocardial infarction; levels above the median was also associated with increased risk of myocardial infarction. Corresponding genetic, causal risk ratios were 0.92 (0.65–1.29), 0.87 (0.68–1.12), 1.55 (0.87–2.76), and 0.93 (0.67–1.30) in one-sample Mendelian randomization analyses, while corresponding causal risk ratios were 0.99 (0.89–1.09), 1.00 (0.92–1.08), 1.01 (0.79–1.28), and 0.99 (0.86–1.13) in two-sample Mendelian randomization analyses, respectively.

Conclusion

Elevated plasma adiponectin was associated with increased risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. However, genetic evidence did not support causality for those associations.Observational associationObservational and genetic association
Prevalence of pulmonary hypertension in reduced left ventricular systolic function and its influence on outcomes
Authors: Ratwatte S , Stewart S , Playford D , Strange G , Celermajer D
Published: November 2023

Background/Introduction

Reduced left ventricular (LV) systolic function can lead to pulmonary hypertension (PHT). However, the significance of PHT complicating reduced LV systolic function remains poorly characterised.

Purpose

We aimed to describe the prevalence and prognostic importance of PHT in a large cohort of adults with at reduced left ventricular ejection fraction (LVEF).

Methods

We analysed the National Echocardiography Database of Australia (data from 2000-2019). Adults with a recorded tricuspid regurgitation (TR) peak velocity and LVEF <50% were included. Patients with moderate or greater left sided valvular pathology were excluded, as were patients with prior aortic or mitral valve replacements. These subjects (n= 23675) were then categorised according to their TR peak velocity. The relationship between PHT severity and mortality outcomes were evaluated (median follow-up of 2.9 years, interquartile range 1.0-5.4years).

Results

Subjects were aged 70±15years and 31.7% were female. Overall, 8801 (37.2%), 7061 (29.8%), 5676 (24.0%), and 2137 (9.0%) patients had normal (TR peak velocity <2.5m/sec), borderline (2.5-2.8m/sec), intermediate (2.9-3.4m/sec), or high risk PHT (>3.4m/sec), respectively. An echocardiographic phenotype for ‘left heart disease’ was evident with worsening PHT, showing rising E:e’ ratio and a greater proportion of right ventricular (RV) dilation and dysfunction (p<0.0001 for all). Left and right atrial sizes increased from low-intermediate risk, before plateauing at high risk PHT (p<0.0001). With increasing risk of PHT, 1- and 5-year actuarial mortality increased from 13.3% and 43.8%, to 41.5% and 81.4% respectively (p<0.0001). After adjustment for age, sex, LVEF, LV end diastolic diameter and LA volume index, the risk of mortality increased as TR peak velocity increased (adjusted hazard ratio (aHR) 1.31, 95% confidence interval 1.23-1.38 in borderline risk, to aHR2.38, 95%CI 2.21-2.56 in high risk PHT) (Figure 1). The cohort was also assessed in two groups based on LVEF severity according to guidelines. The sub-group of patients with mildly reduced LVEF (40-49%, n = 12495) showed that mortality risk increased as risk of PHT increased; (aHR 1.38, 95%CI 1.27-1.50 in borderline risk, to aHR2.82, 95%CI 2.52-3.15 in high risk PHT). Similarly, those with reduced LVEF (<40%, n = 11180) mirrored these trends (aHR 1.23, 95%CI 1.14-1.33 in borderline risk, to aHR2.07, 95%CI 1.88-2.28 in high risk PHT). There was a mortality threshold seen from TR peak velocity 2.41m/sec onwards (aHR1.18, 95%CI 1.04-1.33) (Figure 2).

Conclusion(s)

In this large cohort study, we demonstrate that PHT risk is common in patients with reduced LV systolic function and mortality increases as PHT becomes more severe. A threshold for higher mortality lies within the range of "borderline-intermediate" risk PHT.Adjusted Risk for All-Cause MortalityThreshold for Mortality