bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of nutritional status in patients with heart failure with preserved ejection fraction, with and without atrial fibrillation: insights From PURSUIT-HFpEF Registry
Authors: Kawasaki M , Yamada T , Watanabe T , Morita T , Furukawa Y , Tamaki S , Kikuchi A , Kawai T , Seo M , Fukunami M , Yasumura Y , Hayashi T , Yano M , Hikoso S , Sakata Y
Published: November 2020

Background

Malnutrition is one of the most important comorbidities among heart failure (HF) patients, and serum cholinesterase (CHE) has been reported to be a prognostic factor in HF patients. On the other hand, atrial fibrillation (AF) is frequently observed in patients with HF with preserved ejection fraction (HFpEF). However, there is little information available on the prognostic value of nutritional status in HFpEF patients, with and without AF. We sought to clarify the prognostic value of CHE in HFpEF with and without AF and compare it with that of other nutrition indices such as gastric nutritional risk index (GNRI), controlling nutritional status (CONUT), and the prognostic nutritional index (PNI).

Methods and results

Patients data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study, which is a prospective multicenter observational registry for acute decompensated heart failure patients with left ventricular ejection fraction ≥50% in Osaka. We analyzed 380 patients (median age: 80 [75–87] years, male: 46%) after exclusion of patients with in-hospital death, missing follow-up data, or missing data to calculate nutritional indices. On admission, 155 patients had AF. Laboratory data were obtained at discharge. During a mean follow up period of 1.1±0.6 years, 131 patients had a composite endpoint (CE) of all-cause death and hospitalization for worsening heart failure or cerebrovascular disorder. In multivariate Cox analysis, in patients with AF, CHE was significantly associated with CE independently of age, gender and body mass index after the adjustment with serum albumin, total cholesterol levels and total lymphocyte count, while it was not significantly associated with CE in patients without AF. C-index of CHE (0.708) was higher than that of GNRI (0.555, p=0.0028), CONUT (0.651, p=0.208) and PNI (0.635, p=0.208) in AF patients, while there were no significant differences in those nutritional indices in patients without AF. Kaplan-Meier curve analysis revealed that AF patients with lower CHE (<208 U/L = median value) had higher risk of CE than those with higher CHE (44% vs 18%, adjusted HR 3.26 95% CI [1.66–6.67], p=0.0005), while there was no significant difference in the occurrence rate of CE between patients with and without higher CHE in non-AF group (42% vs 31%, adjusted HR 1.28 95% CI [0.78–2.13], p=0.33).

Conclusions

Prognostic value of CHE would be stronger than other nutritional indices in HFpEF patients with AF, while it would be weak in HFpEF patients without AF.

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): Roche Diagnostics K.K.; Fuji Film Toyama Chemical Co. Ltd.
Left ventricular noncompaction in patients with heart failure with preserved ejection fraction characterized by multimodality imaging
Authors: Visoiu I.S , Mihalcea D , Rimbas R.C , Nicula A , Magda L.S , Mihaila-Baldea S , Luchian M.L , Chitroceanu A , Marinescu A.V , Velcea A , Vinereanu D
Published: November 2020

Background

Left ventricular non-compaction (LVNC) is associated with increased risk of heart failure (HF). If LVNC or hyper-trabeculation in HF with preserved ejection fraction (HFpEF) is an adaptive or stand-alone condition that contribute to generation of HF is not clearly understood yet.

Aim

To describe LV functional and structural parameters in HFpEF with LVNC by comparison with HFpEF without LVNC.

Methods

We assessed 42 patients with HFpEF, 21 with LVNC (61±9 yrs) and 21 without LVNC, age and risk factors matched (LVC), by NTproBNP, 2D echocardiography (2DE), speckle-tracking (STE), and cardiac magnetic resonance (CMR) (Figure 1). LVNC diagnosis was based on Petersen and Jacquier criteria, by the NC/C ratio and the percentage of NC myocardium. Two gradients were calculated: a base to apex gradient (LVbase-apex) and an endo-epicardial gradient (LVendo-epi). LV mass, LV end-diastolic volume (LVEDV), and T1 mapping with extracellular volume (ECV) were measured, while mean value of native T1 for apical segments (apicalT1), mean value of ECV for apical (apical ECV), and basal segments (basal ECV), and gradient between them (ECV base-apex) were calculated.

Results

In the LVNC, mean NC/C ratio was 2.9±0.5mm and the percentage of NC myocardium 24.4±8.8%. NTproBNP was higher in LVNC group (294±282 vs. 163±71 pg/ml, p=0.047). Functional findings were consistent with the structural changes from CMR. LVNC patients have higher native T1 in the apical segments (Table). ECV was globally expanded in LVNC compared to LVC (p=0.002) suggesting diffuse fibrosis, but the difference between groups was more relevant for apical ECV (29.6±3.9% vs 25.1±2.8%, p<0.001), with a higher ECV base-apex gradient in LVNC group. ECV base-apex gradient was negatively correlated with the percentage of NC myocardium (p=0.003, R=0.64).

Conclusion

Patients with HFpEF with LVNC have more fibrosis, with more severe changes in the apical segments on CMR than HFpEF without NC. They have also significantly decreased apical deformation, lower base to apex deformation gradient and lower transmural deformation gradient, due to non-compaction itself, which involves the endocardial layer. These findings suggests that NC in HFpEF is an independent condition rather than an adaptive one.

Figure 1

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): Ministry of Research and Innovation, CNCS-UEFISCDI.
Diagnostic usefulness of passive leg raising test for detection of heart failure with preserved ejection fraction compared to cycle ergometer exercise (invasive hemodynamic study)
Authors: Hwang S.J , Kang M.G , Kim K.H , Park H.W , Koh J.S , Park J.R , Hwang J.Y
Published: November 2020

Background

Invasive diastolic stress test using cycle ergometer is gold standard for diagnosis of heart failure with preserved ejection fraction (HFpEF) by demonstrating elevation of left ventricular end diastolic pressure (LVEDP) during exercise. It is well known that passive leg raising increases preload and augments LVEDP in HFpEF patients. However correlation between passive leg raising induced increase of LVEDP and cycle ergometer exercise induced increase of LVEDP is not well established. Therefore we investigated whether passive leg raising test could substitute cycle exercise test for diagnosis of HFpEF.

Method

Forty-five patients with unexplained dyspnea and ejection fraction >50% underwent invasive exercise test. After measuring baseline LVEDP in supine position using pigtail catheter through radial artery approach, LVEDP during passive leg raising was evaluated. Then exercise LVEDP was measured after 3 minutes of 20 watt supine cycle ergometer exercise. Patients with normal resting LVEDP <16mmHg were enrolled. Patients with cycle ergometer exercise LVEDP >26mmHg were classified as HFpEF and exercise LVEDP <26mmHg were defined as noncardiac dyspnea.

Results

Among 45 patients with unexplained dyspnea with preserved EF, 30 patients with ergometer exercise LVEDP >26mmHg were grouped as HFpEF and 15 patients with exercise LVEDP <26mmHg grouped as noncardiac dyspnea (NCD). Resting LVEDP was higher in HFpEF than NCD (14±2mmHg vs 11±3mmHg, P=0.01) but there was substantial overlap (figure 1) showing poor differentiation power of resting LVEDP. Passive leg raising increased LVEDP in both HFpEF and NCD but this was more marked in HFpEF group than in NCD group with minimal overlap (24±4mmHg vs 17±2mmHg, P<0.001) (figure 2). Passive leg raising LVEDP was well correlated with cycle ergometer exercise LVEDP (R2=0.60, P<0.01). The best cutoff value for passive leg raising LVEDP to detect HFpEF was 20mmHg (sensitivity, 0.87; specificity, 1.00), giving an area under the curve of 0.93 (95% confidence interval, 0.80 to 0.99). Positive predictive value of passive leg raising LVEDP >20mmHg for diagnosis of HFpEF was 96% and negative predictive value was 77%.

Conclusion

Passive leg raising induced augmentation of left ventricular end diastolic pressure (LVEDP) was well correlated with cycle exercise induced elevation of LVEDP in HFpEF patients. Passive leg raising test may be used for detecting HFpEF with good accuracy in substitution for cycle ergometer exercise test.

Funding Acknowledgement

Type of funding source: None
Cardioprotective Effects of Kv4.3 on Oxidative Stress in Heart Failure
Authors: Wang Y , Cheng J
Published: November 2020

Background

Oxidative stress is a pathogenic mediator in heart failure (HF) development, causing excessive Ca2+/calmodulin-dependent kinase II (CaMKII) activation and consequent cardiac dysfunction. We previously reported that Ito channel subunit Kv4.3 couples to CaMKII and inhibits Ca2+-induced CaMKII activation. However, whether Kv4.3 also blocks the oxidation-induced CaMKII activation and the impact on cardiac function in failing heart remain undetermined.

Methods and results

Dissociation of Kv4.3 from Kv4.3-CaMKII units by 4-AP incubation or down-regulation of Kv4.3 by transfection with Kv4.3 antisense adenovirus in adult mouse ventricular myocytes enhanced H2O2-induced increase in CaMKII oxidation and autophosphorylation. Co-immunoprecipitation of Kv4.3 with CaMKII, rather than its oxidative or phosphorylated forms, was detected with H2O2 Incubation. Fluorescence spectra assay showed that Kv4.3 binding prevented the transformation of inactive CaMKII to its active conformation in the presence of Ca2+/CaM and H2O2. In pressure-overload HF mice, transfection with Kv4.3 adeno-associated virus (AAV9) had no impact on the content of reactive oxygen species but effectively suppressed CaMKII oxidation and the oxidative CaMKII activation. Importantly, AAV-Kv4.3 transfection led to remarkable improvement in both systolic and diastolic function in failing heart, which is associated with the reduction in ventricular fibrosis, increase in Ca2+ transient and sarcomere shortening in ventricular myocytes with unchanged Ca2+ decline and sarcomere relaxation and preserved myofilament sensitivity to Ca2+.

Conclusion

Our results demonstrated that Kv4.3 is an important endogenous regulator that blocks CaMKII oxidation and oxidation-induced CaMKII activation by binding to CaMKII and preventing Ca2+/CaM-induced conformational change. Restoration of Kv4.3 expression improves both systolic and diastolic function, manifesting a promising strategy for HF therapy.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China (NSFC) and National Institutes of Health (NIH) of America
Importance of familial predisposition to heart failure to the risk of anthracycline related cardiotoxicity: a nationwide study
Authors: Banke A , D'Souza M , Andersson C , Nielsen D , Torp-Pedersen C , Gislason G.H , Moller J.E , Kober L , Madelaire C , Schou M
Published: November 2020

Background/Introduction

Anthracycline-based chemotherapy has improved the prognosis in cancer and hematological malignancies but is associated with the development of heart failure (HF). Besides well-known cardiac risk factors and cumulative dose of anthracycline, recent research has suggested that genetic variations associated with cardiomyopathies may increase the risk of HF associated with anthracycline. However, the importance of familial predisposition for the risk of developing anthracycline associated cardiotoxicity is unknown.

Purpose

To evaluate the risk of anthracycline related HF in patients with vs. without a first-degree relative with HF.

Methods

In the nationwide Danish registries, patients treated with anthracycline from 2004–2016 were identified. Primary outcome was a subsequent diagnosis of HF. Follow-up was 10 years or December 31, 2017. Familial relations were identified in the Danish Family Registry, which hold all persons born since 1942. Exposure was a first-degree biological relative (parent or sibling) with a diagnosis of HF. Risk of HF was evaluated in a cumulative incidence function with death as competing event and in a Fine and Grey model adjusted for age, sex, prevalent ischemic heart disease, atrial fibrillation, hypertension and chronic obstructive pulmonary disease.

Results

A total of 11.651 patients (mean age 48.0 (SD±8.6), 12.2% male gender) were evaluated after exclusion of 46 with pre-anthracycline HF. Mean follow-up was 4.4 years (SD±2.9). In the group with a first-degree relative with HF (n=1.608) 35 patients (2.2%) was diagnosed with HF vs. 133 (1.3%) in the group without a first-degree relative with HF (n=10.043) corresponding to incidence rates per 1000 patient years of 5.2 (95% CI: 3.8–7.3) vs. 3.0 (95% CI: 2.5–3.5). The cumulative incidence of HF was higher in the first-degree relative HF group (Figure 1a), yielding an adjusted hazard ratio of 1.53 (95% CI: 1.05–2.24, p=0.03) for HF associated with anthracycline. All-cause mortality showed a trend towards higher risk in the later 5 years of follow-up in the first-degree relative HF group with a 10-year risk of 32.4% (95% CI: 28.4–36.5) vs. 26.1% (95% CI: 24.9–27.4) but no significant difference in the Kaplan-Meier estimate (p=0.08) (Figure 1b).

Conclusion

In this nationwide register-based study having a first-degree relative with HF was associated with a small but increased risk of anthracycline related HF, yielding attention towards the family predisposition, when estimating the risk of cancer therapy related cardiotoxicity.

Figure 1

Funding Acknowledgement

Type of funding source: Public hospital(s). Main funding source(s): Odense University Hospital
Cardioprotective effect of Trimetazidine in patients with early breast cancer receiving anthracycline-based chemotherapy
Authors: Delle Donne M.G , Iannielli A , Capozza P , De Caterina R , Marzilli M
Published: November 2020

Background

Anthracyclines, alone or in combination with other drugs, are among the most effective chemotherapeutic agents to treat breast cancer both in the adjuvant and neoadjuvant settings. Unfortunately, anthracycline-associated dose-dependent cardiotoxicity is a limiting factor in clinical use. Extensive efforts have been devoted to identifying strategies to prevent anthracycline-induced cardiotoxicity. However, most cardioprotective agents have shown little efficacy in clinical trials. We hypothesized that myocardial damage by anthracyclines could be rationally prevented by using trimetazidine (TMZ), previously reported to interfere with anthracycline- and trastuzumab-induced cardiotoxicity. Therefore, we planned a randomized, controlled, open trial to determine whether TMZ may prevent the development of left ventricular (LV) dysfunction in patients receiving standard treatment for breast cancer.

Methods

The trial included 73 patients (41.2±8.1 years) undergoing surgery for breast cancer, who were scheduled for adjuvant epirubicin-containing chemotherapy and, if indicated, trastuzumab. Patients were randomly allocated in a 1:1 ratio to receive TMZ or baseline therapy only (control group). The main study endpoint was a reduction in the deterioration of left ventricular ejection fraction (LVEF), as evaluated by serial echocardiography performed at randomization and then every 3 months after the start of chemotherapy and for 1 year after its completion. Secondary outcome measures included echocardiographic indices of LV diastolic dysfunction, structural myocardial alterations, as assessed by speckle tracking echocardiography, and changes in cardiac biomarkers (troponin and brain natriuretic peptide).

Results

We found no significant differences between the two groups regarding baseline clinical and echocardiographic parameters. The two groups reached a similar cumulative dose of doxorubicin. No patient died during the study and no patients withdrew from chemotherapy. Three months after the start of chemotherapy, nonsignificant changes were observed in LVEF, shortening fraction, and LV diameters. No significant changes in cardiac biomarkers were observed in either group. Tissue Doppler imaging detected a significant decrease in myocardial velocities (P=0.001) in the control group, indicating LV diastolic dysfunction. In the same group, speckle tracking imaging revealed a statistically significant alteration in ventricular deformation (P=0.01), which means a decrease in LV systolic function. In the TMZ group, no significant alterations in LV diastolic function were observed.

Conclusions

Tissue Doppler imaging and speckle tracking imaging are more sensitive than conventional echocardiograms in the early diagnosis of cardiac dysfunction and TMZ seems to have an important role in the prevention of cardiotoxicity.

Funding Acknowledgement

Type of funding source: None
Pathological assessment of osimertinib-associated cardiotoxicity in EGFR-mutated non-small cell lung cancer patients
Authors: Oka T , Kamada R , Kunimasa K , Oboshi M , Nishikawa T , Yasui T , Shioyama W , Miyashita Y , Koyama T , Kumagai T , Fujita M
Published: November 2020

Background

Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), inhibits both EGFR-TKI sensitizing mutations and resistant T790M mutations detected in non-small cell lung cancer (NSCLC) patients. Cardiac adverse events (AEs) induced by osimertinib are infrequent; however, cases of severe associated cardiac dysfunction have been reported and remain poorly understood.

Purpose

To assess pathogenesis of osimertinib-associated cardiac AEs, we analyzed myocardial specimens of three NSCLC cases with osimertinib-associated cardiac dysfunction.

Results

Analysis of LVEF prior to and after osimertinb administration in 36 NSCLC patients showed significant decrease of LVEF from 69% to 63%. Within this cohort, right ventricular (RV) biopsy was performed in 2 cases to further understand the pathophysiology of cardiac dysfunction. Case 1 was 78-year-old female with advanced NSCLC harboring an EGFR L858R mutation was treated with osimertinib as second line therapy. After 3 moths of osimetinib treatment, she presented with dyspnea, high NT-proBNP and troponin I, and significantly decreased left ventricular ejection fraction (LVEF) at 28%. RV biopsy showed moderate cardiomyocyte hypertrophy without inflammatory cell infiltration. Case 2 was 52-year-old female with advanced NSCLC harboring L858R mutation. She was treated with osimertinib as first line therapy. After 2 weeks of osimertinib, screening echocardiography revealed a reduction of LVEF from 63% to 41% without cardiac symptom. RV biopsy showed mild cardiomyocyte hypertrophy with infiltration of a few inflammatory cells in interstinum. We further analyzed death case of NSCLC. Case 3 was 63-year-old female with advanced NSCLC harboring EGFR ex. 19 del. and T790M mutations. After 6 months of osimertinib, she suffered from severe respiratory failure and severely reduced LVEF at 27%. She died on the 44th day after admission. Pathological autopsy revealed mild to moderate cardiomyocyte hypertrophy without inflammatory cell infiltration in both ventricles. These pathological findings may indicate neither myocyte injury nor myocarditis was induced by osimertinib in myocardium.

Conclusion

Although additional data collection of advanced NSCLC patients will be important in understanding the pathophysiology of cardiac AEs with osimertinib, osimertinib-associated cardiotoxicity may result from functional inhibition of myocyte contractility by osimertinib without induction of cell death or inflammation.

Funding Acknowledgement

Type of funding source: None
Intracoronary autologous bone marrow mononuclear cells for the compassionate treatment of advanced heart failure
Authors: Jones D.A , Baca G.L , Hussain M , Jardim V , Davies L.C , Veerapen J.V , Martin J.E , Lowdell M.V , Mathur A
Published: November 2020

Background

Intracoronary delivery of autologous bone marrow-derived mononuclear cells (BMCs) has been shown to be beneficial in the treatment of patients with ischaemic (IHD) and non-ischaemic dilated cardiomyopathy (DCM). Given the results of phase II clinical trials in this population, our centre initiated the only programme to offer intracoronary BMCs to patients with advanced heart failure due to IHD or DCM in the UK. Clinical data and outcomes in these patients were maintained as part of a registry, the results of which are reported herein.

Purpose

To report outcomes of the first 20 patients with DCM treated at the compassionate stem cell unit.

Methods

A total of 45 patients with advanced heart failure (left ventricular ejection fraction (LVEF) at referral of ≤45%, New York Heart Association (NYHA) classification ≥2 and no secondary cause for the cardiomyopathy) despite optimal medical therapy (OMT) were accepted into the programme and received treatment with intracoronary BMCs, manufactured and supplied as Advanced Therapy Medicinal Products, with adjunctive granulocyte colony stimulating factor (G-CSF). All patients received 5 days of G-CSF followed by bone marrow aspiration and IC infusion of cells (∼10ml of BMCs) on Day 6. LVEF was assessed by cardiac CT.

Results

Of the 20 patients with DCM, 80% were male with a mean age of 64.6±10.6 years (range 45–81 years old). Baseline LVEF was 36.1%±10.6. Baseline NYHA class distributions were 70% NYHA class II (n=14), NYHA class III 25% (n=5), and NYHA class IV – 5% (n=1). All procedures were performed successfully with no procedural complications (100% radial). One year after treatment, 71.4% of people improved by 1 or more NYHA classes with 28.6% noting no change (1 year NYHA classes I (60%), II (27%) and III (13%)). No patients felt worse. A mean increase of 3.4% (±9.6%) was seen in LVEF at 1 year compared to baseline with a corresponding mean reduction in NT-pro-BNP of 18.9% (mean 1012pmol/l vs 1250pmol/l). In terms of clinical events, at 1 year all treated patients were alive, with no reported MACE events and no admissions for heart failure.

Conclusion

IC autologous BMC injections are a novel therapy for patients with advanced HF despite OMT. These data indicate this therapy is safe and results in significant improvement in symptoms of heart failure. An improvement in the LVEF is seen at levels which support initial findings of phase II clinical trials.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): Heart Cell Foundation; Barts Heart Centre, St Bartholomew's Hospital
Age-related differences in ventricular remodeling and long-term heart failure outcomes following acute coronary syndrome
Authors: Adamson P.D , Verryt T , Frampton C.M , Troughton R , Doughty R.N , Richards A.M
Published: November 2020

Background

Older patients are at increased risk of heart failure hospitalization following acute coronary syndrome (ACS).

Purpose

We sought to determine whether this increased hazard was related to differing patterns in left ventricular (LV) remodeling over the first 12 months after ACS.

Methods

In a prospective multi-centre observational cohort study, 2,140 patients with ACS underwent echocardiography at 1, 4, and 12 months following the index event. Long-term heart failure hospitalisation events were captured for a median 4.8 (IQR 3.4–6.5) years and the relative risk compared between individuals ≤65 years and those >65 years using a multivariable Cox model adjusted for baseline clinical (sex, blood pressure, coronary revascularisation) and echocardiographic (LV end diastolic and end systolic volumes, LV ejection fraction, interventricular septal wall thickness, and E/e') variables recorded at baseline and 12 months.

Results

The 1177 (55%) participants who were >65 years were more likely to be women (34% versus 22%), had higher blood pressure, were more likely to present with non-ST elevation ACS, demonstrated smaller increases in peak myocardial biomarkers and were less likely to undergo coronary revascularization during the index admission (43.2% versus 72.3%; p<0.001 for all comparisons). At the 1 month visit, after indexing for body surface area, older patients had similar LV end diastolic but larger end systolic volumes (p=0.029), lower LV ejection fractions, and greater left ventricular mass and diastolic filling pressure estimates (E/e' 14 versus 10; p<0.001 for all) compared with the young. Systolic volumes appeared to further diverge at 12 months (p=0.064) however LV mass did not change in either group. In unadjusted analysis older patients were at increased risk of future heart failure hospitalization (HR 4.1, 95% CI 3.2–5.3). This increased risk persisted after adjustment for differences in baseline clinical and echocardiography data, and LV remodeling (adjusted HR 2.4, 95% CI 1.5–3.9).

Conclusions

Older patients experience a more eccentric remodeling pattern over the 12 months following ACS. Older individuals remain at increased risk of long-term heart failure hospitalization after accounting for clinical and echocardiographic characteristics.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): New Zealand Heart Foundation, New Zealand Health Research Council
Association of leptin serum concentration with heart adipose tissue and parameters of systolic and diastolic function in heart failure patients
Authors: Shomanova Z , Ohnewein B , Froeb E.J , Pogoda C , Granitz C , Jirak P , Lichtenauer M , Hoppe U , Reinecke H , Motloch L.J , Pistulli R
Published: November 2020

Aims

Leptin has recently been related to myocardial remodeling in animal experimentation studies on heart failure (HF). Furthermore, leptin has been reported to be related to diastolic dysfunction, however only in healthy population. With the emergence of new medical therapies targeting cardiac remodeling, there needs to be a better understanding of the metabolic pathways involving leptin. Our study aims to investigate leptin's correlation to parameters of systolic and diastolic heart function, as well as epicardial and pericardial adipose tissue (EAT and PAT) in heart failure (HF) patients.

Methods

The study included 51 patients with chronic heart failure with reduced ejection fraction (HFrEF) of ischemic (n=22) and non-ischemic (n=29) origin (NYHA II-III, mean EF 29.56%, SD 8.1; mean BMI 28.08, SD 5.8). Serum concentrations of leptin, NT-proBNP, HbA1c, LDL, and total cholesterol were also measured. Global longitudinal strain (GLS) and other LV function parameters were assessed in transthoracic echocardiography, as well as EAT and PAT in parasternal long and short-axis views.

Results

We found a significant correlation between leptin serum concentration and epicardial, as well as pericardial adipose tissue (EAT r=0.336, p=0.030; PAT r=0.565, p<0.001). There was a significant negative correlation between leptin and GLS (r=−0.332; p=0.045), as well a positive correlation between Leptin and E/E' ration (r=0.373; p=0.039). There was no significant difference between ischemic and non-ischemic HF patients.

Conclusion

We provide evidence of serum leptin correlation to remodeling parameters, as well as epicardial and pericardial fat tissue in HF patients. Whether leptin has positive effects on reversing or preventing remodeling in heart failure, needs further investigation.

Correlation of leptin vs. GLS

Funding Acknowledgement

Type of funding source: None
An epigenetic circuit linking oxidative stress and DNA hydroxymethylation in heart failure
Authors: Elbeck Z , Hossain M.B , Franzen O , Siga H , Karlsson F , Walentinsson A , Moosmang S , Milting H , Lund L.H , Vegvari A , Knoll R
Published: November 2020

Background

Heart failure is a major cause of morbidity and mortality worldwide, but the underlying molecular mechanisms remain not well defined. Reactive oxygen species (ROS) in heart failure (HF) alter multitudes of mitochondrial enzymes and metabolites, such as α-ketoglutarate and its oxidised form L-2-hydroxyglutarate (L-2HG). These metabolites are cofactors for ten eleven translocation (TET) enzymes that convert DNA's 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).

Aim

We hypothesize that oxidative stress during heart failure alters mitochondrial function through epigenetic remodeling, and that reduction of oxidative stress will improve cardiac function.

Methods and results

Targeted LC-MS/MS analysis of dilated cardiomyopathy (DCM) hearts obtained from MLP−/− and WT littermate controls showed a significant increase in the oxidized metabolite L-2HG (∼30%, p=0.004), with significant reduction of multiple TCA cycle intermediates. RNA sequencing revealed a significant reduction in mRNA levels of IDH2 in human TTN related DCM and MLP−/− HF mice. The altered activity of IDH2 contributes to ROS production in these hearts and to the production of L-2HG. No alteration in the mitochondria structures was observed. HF biopsies show decreased TET activity most likely due to increased L-2HG levels. Whole genome single base pair 5mC and 5hmC deep sequencing of gDNA from explanted human DCM heart biopsies and MLP−/− mouse model revealed significantly altered global distribution of both 5mC and 5hmC in comparison to control samples. Genes involved in hypertrophy, such as Myh7 and Fhl2 were among the top genes with differential 5mC levels. Global loss of 5hmC level was observed, especially in the intronic regions of genes involved in redox hemostasis. Reducing oxidative stress in vivo in MLP−/− using a small molecule (AZ14117925) improves heart function (EF) by 13% [EF=(Treated:47,44%, Placebo: 34,54%), n=5 (males per group), p=0.0373, unpaired t-test]. Additional bioinformatic analysis revealed that reduction of ROS most likely leads to activation of TET and activation of pro-survival pathways, anti-oxidative stress response, and significantly less activation of apoptotic pathways.

Conclusion

Alterations in TCA cycle metabolites may underlie changes in DNA methylation and gene expression in end-stage human DCM and mouse models and indicate a role for epigenetic regulation of mitochondrial function in HF. NRF2 activation may pose a novel therapeutic approach to treat this devastating disease.

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): AstraZeneca
Metabolomics and a breath sensor identify acetone as a biomarker for heart failure
Authors: Gladding P.A , Young R , Cooper M , Holland U , Loader S , Chapman L , Chapman A , Smith K , Zarate E , Villas-Boas S , Green S , Thorstensen E , Keven C
Published: November 2020

Introduction

Metabolomics delivers more biological and clinical insight than targeted investigations. We applied metabolomics to patients with heart failure (HF) with reduced ejection fraction (HFrEF).

Methods

46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LC-MS/GC-MS), nuclear magnetic resonance (NMR) metabolomics and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudal strain (GLS) <18%, ejection fraction <50% and NTproBNP ≥35 pmol/L. A low cost consumer breath acetone (BrACE) sensor validated SPME results in 69 patients.

Results

34 metabolites were identified by GCMS, 33 by LCMS and 2 volatiles by SPME (acetone, 2-pentanone in plasma and urine). Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP (r=0.59, 95% CI 0.4 to 0.7), triacylglycerol (55:9), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE >1.5 ppm discriminated HF from other cardiac pathology (AUC 0.88, 95% CI 0.77 to 0.99, P<0.0001).

Conclusion

Breath acetone was detectable in HFrEF patients using a consumer sensor ($1/test) and although not cardiac specific, discriminated HF from other cardiac pathology.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): Health Research Council of New Zealand
Classification of HFrEF based on echocardiography using machine learning to predict future HFrecEF events
Authors: Sakamoto T , Ito S , Endo A , Yoshitomi H , Tanabe K
Published: November 2020

Background

In recent years, there have been sporadic reports of heart failure with recovered ejection fraction (HFrecEF), wherein the left ventricular EF (LVEF) has been improved by considering temporal changes in the LVEF. Although patients with HFrecEF are known to have a better prognosis than other groups, the type of heart failure associated with reduced EF (HFrEF) that subsequently transitions to HFrecEF is yet to be determined.

Purpose

In this study, we examined whether it is possible to predict future HFrecEF events by stratifying the HFrEF using machine learning based on previously recorded echocardiographic indices.

Methods

For 162 patients, with HFrEF and a history of hospitalization owing to heart failure, who underwent echocardiography in a stable hemodynamic state, stratification was performed via machine learning. Regarding temporal changes in the LVEF, 73 patients who underwent another echocardiography under stable conditions were investigated (52 with continued HFrEF and 21 with HFrecEF, with a median follow up of 397 days). HFrEF was defined as a condition for patients with an LVEF of less than 50%, and HFrecEF was defined as a condition for patients who initially had an LVEF of less than 50% but later improved. Patients with severe valvular disease, acute myocardial infarction, acute myocarditis, acute pulmonary embolism, post-cardiac surgery, and pericardial disease were excluded from this group. The random forest method was used as a classification method for machine learning.

Results

When 162 patients with HFrEF were stratified using machine learning, 63 were classified into Cluster 1 and 99 into Cluster 2. Cluster 1 patients showed a significantly higher tendency to transition to HFrecEF than Cluster 2 patients (p=0.001). The Gini coefficient was calculated to identify echocardiographic indices that are important for the purpose of stratification. As a result, LVEF, left ventricular endo-diastolic volume (LVEDV), the thickness of interventricular septum (IVSth), E/A ratio, and the maximum diameter of the inferior vena cava were found to be particularly important. Compared to Cluster 2 patients, Cluster 1 patients exhibited a significantly higher LVEF (41.5±5.9% vs 27.0±7.6%, p<0.001), lower LVEDV (93.6±36.8 mL vs 141.1±51.7 mL, p<0.001), and a higher IVSth (10.8±2.6 mm vs 9.4±2.5 mm, p<0.001).

Conclusion

Stratifying HFrEF via machine learning based on echocardiographic indices can help predict temporal changes in the LVEF and deduce the echocardiographic indices useful for improving LVEF.

Funding Acknowledgement

Type of funding source: None
The effect of dapagliflozin across the spectrum of baseline risk: a post-hoc analysis of DAPA-HF
Authors: Docherty K.F , Jhund P.S , Bengtsson O , Demets D.L , Inzucchi S.E , Kober L , Kosiborod M.N , Langkilde A.M , Lindholm D , Martinez F.A , Ponikowski P , Sabatine M.S , Sjostrand M , Solomon S.D , McMurray J.J.V
Published: November 2020

Background

In DAPA-HF, compared to placebo, the sodium-glucose cotransporter 2 (SGLT-2) inhibitor, dapagliflozin, reduced the risk of cardiovascular death or worsening heart failure in patients with heart failure with reduced ejection fraction (HFrEF). The majority of patients in DAPA-HF reported mild functional limitation, however there is significant heterogeneity in prognosis among these patients.

Purpose

To examine the effect of dapagliflozin compared with placebo across the spectrum of baseline risk in DAPA-HF.

Methods

The primary composite outcome of DAPA-HF was time-to-first cardiovascular death or worsening heart failure event (hospitalization for heart failure or outpatient visit requiring intravenous therapy). We examined whether the effect of dapagliflozin was modified by baseline risk, as determined by the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score based upon 13 predictive variables giving a potential maximum score of 57. The number needed to treat (NNT) to over a median follow-up of 18.2 months was calculated by applying the overall relative risk reduction in DAPA-HF (26%, 95% CI 15–35) to the proportion of patients with a primary outcome event in the placebo group of each MAGGIC risk score category (defined by quintiles of score).

Results

The MAGGIC risk score was calculable for 4740 of 4744 patients in DAPA-HF. The median score was 22 (range 3–43). The event rate for the primary outcome was 7.2 per 100 patient-years in the lowest risk score quintile and 25.7 in the highest. A 1-point increase in score was associated with an 8% increase in the risk of a primary outcome event (p<0.001). Dapagliflozin, compared to placebo, reduced the risk of the primary outcome across quintiles of the MAGGIC risk score (Figure - Interaction p value=0.69) and when the score was analysed as a continuous variable (Interaction p value=0.56). The NNT to prevent one primary event was 39 (95% CI 29–68) in the lowest quintile of risk scores, compared with 14 (11–25) in the highest quintile (Figure).

Similar results were found for the individual components of the primary composite outcome and for all-cause mortality.

Conclusions

DAPA-HF included patients with a wide spectrum of risk. Treatment with dapagliflozin, compared to placebo, reduced the risk of cardiovascular death or worsening heart failure, irrespective of baseline risk as measured by the MAGGIC risk score.

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): DAPA-HF was funded by AstraZeneca
The effect of dapagliflozin in patients with HFrEF and COPD: a post-hoc analysis of DAPA-HF
Authors: Dewan P , Jhund P.S , Bengtsson O , Demets D.L , Inzucchi S.E , Kober L , Kosiborod M.N , Langkilde A.M , Lindholm D , Martinez F.A , Ponikowski P , Sabatine M.S , Sjostrand M , Solomon S.D , McMurray J.J.V
Published: November 2020

Background

Chronic obstructive pulmonary disease (COPD) is an important comorbidity in HFrEF, associated with worse outcomes and suboptimal treatment due to under-prescription of beta-blockers. Consequently, additional effective therapies are especially relevant in patients with COPD. In DAPA-HF, compared to placebo, the sodium-glucose cotransporter 2 (SGLT-2) inhibitor, dapagliflozin, reduced risk of cardiovascular (CV) death or worsening heart failure (HF) in patients with HF with reduced ejection fraction (HFrEF).

Purpose

To examine effect of dapagliflozin, compared with placebo, in patients with and without COPD.

Methods

Primary composite outcome of DAPA-HF was time-to-first CV death or worsening HF event (hospitalization for HF or outpatient visit requiring intravenous therapy). We examined whether effect of dapagliflozin was modified by investigator reported COPD at baseline.

Results

Overall, 585 (12.3%) of the 4744 patients randomized had an investigator-reported history of COPD, 299 (12.6%) in dapagliflozin group and 286 (12.1%) in placebo group. Incidence of primary composite outcome, in the placebo group, was higher in patients with COPD than in those without (22.8; 95% CI 18.4–28.3 vs. 14.9; 13.5–16.4) (Table). Hazard ratio (HR) for the effect of dapagliflozin, compared with placebo, on the primary outcome, was consistent in patients with and without COPD (Table); P-value for interaction was 0.467. Findings for other outcomes were similar (Figure).

Conclusions

Patients in DAPA-HF with COPD were at substantially higher risk than those without. Treatment with dapagliflozin, compared to placebo, reduced risk of CV death and worsening HF, similarly, in patients with and without COPD.

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): DAPA-HF was funded by AstraZeneca
Coronary sinus fetuin and sodium levels are independently associated with all-cause mortality in patients awaiting heart transplantation
Authors: Szczurek W , Gasior M , Skrzypek M , Romuk E , Zembala M , Malyszek-Tumidajewicz J , Szygula Jurkiewicz B
Published: November 2020

Background

Risk stratification is a critical component of selection process of the patients with end-stage heart failure (HF) who are considered for heart transplantation (HT). Due to the constantly increasing number of the patients placed on the transplant waiting lists and a global shortage of organs available for HT, the key issue becomes an accurate risk stratification of death and proper organ allocation to these patients who will benefit the most from this form of treatment.

Purpose

The aim of this study was to identify the factors associated with mortality during a 1.5-year follow-up in patients with end-stage HF awaiting HT.

Methods

We prospectively analysed 72 patients with advanced HF awaiting HT at our institution between 2015 and 2016. At the time of inclusion in the study routine laboratory tests, cardiopulmonary exercise test, echocardiography, and right heart catheterisation were performed in all patients. During right heart catheterisation, 10 ml of coronary sinus blood was collected. Fetuin serum concentration was measured by the sandwich enzyme-linked immunosorbent assay (ELISA) with the commercially available kit.The end-point was defined as all-cause mortality during a 1.5 years follow-up. Our medical university local Institutional Review Board approved the study protocol, and all patients provided informed consent. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

Results

Patients' median age was 53.00 (46.00–58.00) years, and 91.7% were men. During the 1.5-year follow-up, 31 (43.1%) patients died. The area under the receiver operating characteristic curve indicated a good discriminatory power of fetuin (AUC: 0.917 [95% CI: 0.858–0.977]). The cut-off point for fetuin (<632.36) had a sensitivity of 87% and a specificity of 83%. Patients with a lower fetuin level had a significantly worse 1.5-year survival compared to the group with a higher fetuin level (20.6% versus 89.5%; (long rank p<0.001). Fetuin OR 0.990 (0.986–0.996); p<0.001) and plasma sodium levels (OR, 0.640 [0.464–0.882]; p<0.001) were independent predictors of death during 1.5-year follow-up period.

Conclusions

Our study demonstrated that a low coronary sinus fetuin and peripheral blood sodium levels are associated with mortality patients with advanced HF accepted for HT. In addition, fetuin level, with excellent prognostic strength, allows for the risk stratification of death in analysed group of patients.

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): Medical University of Silesia
Real world experience on angiotensin receptor and neprilysin inhibition in reduced ejection fraction heart failure patients with advanced chronic kidney disease
Authors: Hsu C.Y , Chang H.Y
Published: November 2020

Background

Angiotensin receptor and neprilysin inhibition (ARNI) reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction (HFrEF) as compared with enalapril in the PARADIGM-HF trial. However, patients with glomerular filtration rate (GFR) less than 30 ml/min/1.73 m2 or systolic blood pressure less than 100 mmHg were excluded from the PARADIGM-HF trial. We assessed the potential beneficial effects of ARNI in HFrEF patients with advanced chronic kidney disease (GFR<30 ml/min/1.73 m2) by using a multicenter real-world data in Taiwan.

Methods

The TAROT-HF (Treatment with Angiotensin Receptor neprilysin inhibitor for Taiwan Heart Failure patients) study is a multicenter study which enrolled 1,694 HFrEF patients on ARNI treatment from 9 hospitals between March 2017 and December 2018. The data was compared to the outcome from the TSOC (the Taiwan Society of Cardiology)-HFrEF registry which enrolled 1,509 HFrEF patients from 21 hospitals between 2013 and 2014 prior to era of ARNI. After 1:1 propensity score matching, a total of 1,198 patients from the TAROT-HF study and 1,198 patients from the TSOC-HFrEF registry were included for analysis.

Results

During the 1 -year follow-up, the TAROT-HF cohort showed a significant superior prognosis on cardiovascular (CV) death (6.8% vs 10.6%, p<0.001) and all-cause death (8.5% vs 16.2, p<0.001) as compared with the TSOC-HFrEF study population. The patients were classified into 4 groups according to the renal function with eGFR values of <30, 30–59, 60–89, and ≥90 ml/min/1.73m2, and there was no significant interaction between matched cohorts and renal function. The beneficial effects of ARNI on CV death and all-cause death were consistent across four eGFR groups, including 387 patients with eGFR<30 ml/min/1.73m2 (16.2%).

Conclusions

Our study demonstrated the effectiveness of ARNI on HFrEF patients in real world experience, including those with advanced chronic kidney disease with eGFR<30 ml/min/1.73m2.

Funding Acknowledgement

Type of funding source: None
Risk stratification in hf with mid-range LVEF: the role of cardiopulmonary exercise testing
Authors: Rocha B.M.L , Lopes Da Cunha G.J , Lopes P.M.D , Freitas P.N , Gama F , Brizido C , Strong C , Andrade M.J , Ventosa A , Tralhao A , Aguiar C.M.T , Durazzo A , Mendes M
Published: November 2020

Background

Cardiopulmonary exercise testing (CPET) is recommended in the evaluation of selected patients with Heart Failure (HF). Notwithstanding, its prognostic significance has mainly been ascertained in those with left ventricular ejection fraction (LVEF) <40% (i.e., HFrEF). The main goal of our study was to assess the role of CPET in risk stratification of HF with mid-range (40–49%) LVEF (i.e., HFmrEF) compared to HFrEF.

Methods

We conducted a single-center retrospective study of consecutive patients with HF and LVEF <50% who underwent CPET from 2003–2018. The primary composite endpoint of death, heart transplant or HF hospitalization was assessed.

Results

Overall, 404 HF patients (mean age 57±11 years, 78.2% male, 55.4% ischemic HF) were included, of whom 321 (79.5%) had HFrEF and 83 (20.5%) HFmrEF. Compared to the former, those with HFmrEF had a significantly higher mean peak oxygen uptake (pVO2) (20.2±6.1 vs 16.1±5.0 mL/kg/min; p<0.001), lower median minute ventilation/carbon dioxide production (VE/VCO2) [35.0 (IQR: 29.1–41.2) vs 39.0 (IQR: 32.0–47.0); p=0.002) and fewer patients with exercise oscillatory ventilation (EOV) (22.0 vs 46.3%; p<0.001). Over a median follow-up of 28.7 (IQR: 13.0–92.3) months, 117 (28.9%) patients died, 53 (13.1%) underwent heart transplantation, and 134 (33.2%) had at least one HF hospitalization. In both HFmrEF and HFrEF, pVO2 <12 mL/kg/min, VE/VCO2 >35 and EOV identified patients at higher risk for events (all p<0.05). In Cox regression multivariate analysis, pVO2 was predictive of the primary endpoint in both HFmrEF and HFrEF (HR per +1 mL/kg/min: 0.81; CI: 0.72–0.92; p=0.001; and HR per +1 mL/kg/min: 0.92; CI: 0.87–0.97; p=0.004), as was EOV (HR: 4.79; CI: 1.41–16.39; p=0.012; and HR: 2.15; CI: 1.51–3.07; p<0.001). VE/VCO2, on the other hand, was predictive of events in HFrEF but not in HFmrEF (HR per unit: 1.03; CI: 1.02–1.05; p<0.001; and HR per unit: 0.99; CI: 0.95–1.03; p=0.512, respectively). ROC curve analysis demonstrated that a pVO2 >16.7 and >15.8 mL/kg/min more accurately identified patients at lower risk for the primary endpoint (NPV: 91.2 and 60.5% for HFmrEF and HFrEF, respectively; both p<0.001).

Conclusions

CPET is a useful tool in HFmrEF. Both pVO2 and EOV independently predicted the primary endpoint in HFmrEF and HFrEF, contrasting with VE/VCO2, which remained predictive only in latter group. Our findings strengthen the prognostic role of CPET in HF with either reduced or mid-range LVEF.

Funding Acknowledgement

Type of funding source: None