bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of VEGF-B alters cardiac lipid metabolism and predisposes to heart failure
Authors: Tirronen A , Huusko J , Lehtonen M , Hamalainen W , Hokkanen K , Auriola S , Yla-Herttuala S
Published: October 2022

Background

The compensatory phase of left ventricular hypertrophy (LVH) is characterised by sufficient mitochondrial density and energy production, but prolonged stress leads to cardiac decompensation and decreased mitochondrial biogenesis. This results in energy deficiency and compromised contractile ability, eventually leading to heart failure (HF). Vascular endothelial growth factor B (VEGF-B) is a potent inducer of cardiac angiogenesis and LVH, and more recently it has been associated with lipid metabolism and cardiac function. However, its exact role in these processes has remained unresolved.

Purpose

We wanted to elucidate the effects of VEGF-B overexpression on cardiac metabolism and the development of LVH and HF.

Methods

We used mice expressing VEGF-B transgene under cardiac-specific MHCα promoter and induced pressure overload with angiotensin II infusion. We monitored the cardiac function with high-resolution transthoracic echocardiography and performed immunohistochemical analyses to assess the level of cardiac fibrosis. Furthermore, we analyzed cardiac lipid metabolism with non-targeted LC-MS metabolite profiling and performed functional 3H -labelled triolein uptake studies combined with quantitative RT-PCR.

Results

In this study, we show that the cardiac-specific overexpression of VEGF-B leads to increased plasma triglyceride and free fatty acid levels but reduced cardiac lipid accumulation. Non-targeted LC-MS profiling analysis revealed that the level of cardiac glycerolipids and glycerophospholipids were significantly downregulated although changes in cardiac lipid uptake on functional or gene expression level were not detected. To assess how these metabolic changes affect the development of LVH and HF, we subjected MHCα-VEGF-B mice to angiotensin II infusion. Surprisingly, the survival of MHCα-VEGF-B mice dramatically started to decline after four days of angiotensin II infusion and was only 30% at the 14-day time point. Echocardiographic measurements revealed that the MHCα-VEGF-B mice developed severe HF seen as reduced ejection fraction when compared to control mice (32.2% vs. 64.2% respectively), significantly increased LV end-diastolic diameter and LV volume when compared to the controls. VEGF-B overexpression during pressure overload resulted in severe cardiac fibrosis and downregulation of genes responsible for lipid and glucose uptake, metabolic regulation and mitochondrial function indicating severe cardiac energy deficit. Interestingly, a high fat diet feeding prevented the development of HFrEF by 100% and the suppression of all metabolic pathways.

Conclusion

VEGF-B regulates cardiac energy production and the overexpression of VEGF-B results in cardiac energy deficit that during pressure overload leads to HFrEF and severe mortality.

Funding Acknowledgement

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERC and H2020
Role of impaired iron transport on exercise performance in heart failure patients
Authors: Lo Russo G , Agostoni P G , Campodonico J , Junod D , Carulli E , Gaudenzi Asinelli M , Doni F , Bonomi A
Published: October 2022

Aims

Impaired iron transport (IIT) occurs frequently in heart failure (HF) patients, even in the absence of anaemia and it is associated with a poor quality of life and prognosis. The impact of IIT on exercise capacity, as assessed by the cardiopulmonary exercise test (CPET), in HF is at present unknown. The aim of this article is to evaluate in HF patients the impact on exercise performance of IIT, defined as transferrin saturation (TSAT) <20%.

Methods and results

We collected data of 676 patients hospitalised for HF. All underwent laboratory analysis, cardiac ultrasound, and CPET. Patients were grouped by the presence/absence of IIT and anaemia (haemoglobin <13 and <12 g/dL in male and female, respectively): Group 1 (G1) no anaemia, no IIT; Group 2 (G2) anaemia, no IIT; Group 3 (G3) no anaemia, IIT; Group 4 (G4) anaemia and IIT. Peak oxygen uptake (peakVO2) reduced from G1 to G3 and from G2 to G4 (G1: 1266±497 mL/min, G2: 1011±385 mL/min, G3: 1041±395 mL/min, G4: 833±241 mL/min), whereas the ventilation to carbon dioxide relationship slope (VE/VCO2 slope) increased (G1: 31.8±7.5, G2: 34.5±7.4, G3: 36.1±10.2, G4: 37.5±8.4). At multivariate regression analysis, peakVO2 independent predictors were anaemia, brain natriuretic peptide (BNP), and left ventricular ejection fraction, whereas VE/VCO2 slope independent predictors were IIT and BNP.

Conclusions

In HF IIT is associated with exercise performance impairment independently from anaemia, and it is a predictor of elevated VE/VCO2 slope, a pivotal index of HF prognosis.

Funding Acknowledgement

Type of funding sources: Private hospital(s). Main funding source(s): Centro cardiologico Monzino, Italy
Low-dose dopamine improves ventilatory efficiency during exercise in heart failure with preserved ejection fraction through inhibition of tonic activity of peripheral chemoreceptors
Authors: Kulej-Lyko K , Niewinski P , Tubek S , Ponikowski P
Published: October 2022

Introduction

Peripheral chemoreceptors (PChRs) play an important role in adequate oxygenation by 1) maintaining baseline ventilation (tonic activity) and 2) providing hyperventilation in response to acute hypoxia (reflexia). It has been previously shown that in patients with heart failure with reduced ejection fraction hypertonicity and/or hyperreflexia of PChRs contribute to exercise intolerance (ExIn). It is unknown whether similar mechanisms are present in heart failure with preserved ejection fraction (HFpEF) and which component of PChR functionality has a decisive role in this matter.

Purpose

The aim of this study was to evaluate the role of PChRs in ExIn in patients with HFpEF.

Methods

All patients underwent assessment of PChRs which included measurements of: 1) tonic activity (TA, decrease in ventilation following pharmacological inhibition of PChRs), 2) reflex response (RR; an increase in ventilation in the response to acute hypoxia). The inhibition of PChRs was achieved with low-dose dopamine infusion (3 μg kg–1 min–1) and the acute hypoxia was produced with brief nitrogen gas administrations. Enrolled patients underwent symptom-limited cardiopulmonary exercise test using cycle ergometer from which peak oxygen consumption (peakVO2) and the slope relating ventilation to carbon dioxide (VE/VCO2 slope) were derived. All measurements (including PChRs' function tests and cardiopulmonary exercise test) were performed twice in a randomized, double-blinded and placebo-controlled manner (dopamine vs normal saline).

Results

We included 12 stable patients with HFpEF (age: 73±7 years, LVEF: 58±3%). During exercise the inhibition of PChRs with dopamine resulted in the improvement (decrease) in VE/VCO2 slope comparing to placebo (36±3.6 vs 34.3±3.7, p=0.04) but no change regarding peakVO2. There was a correlation between TA and relative magnitude of improvement in VE/VCO2 following PChRs inhibition (R=0.76, p=0.005). We also found a trend for correlation between RR and VE/VCO2 measured during placebo (R=0.56, p=0.059). There was no correlation between TA and RR (p=0.24).

Conclusion

Both TA and RR of PChRs are involved in ventilatory inefficacy during exercise in HFpEF – but in different ways. While augmented RR is likely an indicator of high VE/VCO2, the elevated TA indicates the magnitude of the improvement in exercise tolerance following PChRs deactivation. Thus, further interventions aimed at the modulation of PChRs should enroll patients based on TA rather than RR.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre, PRELUDIUM grant
Myeloperoxidase as therapeutic target in HFpEF
Authors: Lejeune S , Ginion A , Menghoum N , Horman S , Beauloye C , Pouleur A C
Published: October 2022

Background

Inflammation and oxidative stress are thought to play an important role in the pathophysiology of HFpEF through the development of endothelial dysfunction. Myeloperoxidase (MPO), a leukocyte-derived enzyme, functions as a link between oxidative stress and inflammation and is an interesting therapeutic target.

Purpose

To compare MPO levels between HFpEF and old controls and to define clinical characteristics associated with high levels of MPO.

Methods

Patients with HFpEF (N=55) and controls >60 years (N=18) were prospectively included. All subjects underwent complete echocardiography and standard biology. MPO levels were dosed by ELISA assay. Endothelial function was assessed by peripheral arterial tonometry through the reactive hyperemia index (RHI). Characteristics were compared using independent samples t-test or chi square test.

Results

Patients with HFpEF (80±8.5 years, 65% female) had higher levels of myeloperoxidase compared to controls (74±6.2 years, 72% female) (34.7 ng/mL [22.7; 43.9] versus 22.5 [18.1; 31.9], p=0.026) (Figure 1). HFpEF patients with levels of MPO above the median were more often men and diabetic and had higher levels of NTproBNP and CRP. However, MPO levels were not associated with endothelial function measured by RHI (Table 1).

Conclusion(s)

HFpEF patients have higher levels of myeloperoxidase than control subjects, reflecting leukocyte activation and oxidative stress. Myeloperoxidase levels are associated with inflammation and disease severity. Myeloperoxidase inhibitors could be useful for the treatment of HFpEF patients, especially in the subgroup of patients with diabetes.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Fondation Damman
The adverse effects of the respiratory effort on the pulmonary circulation are independent of the ejection fraction and heart failure etiology
Authors: Markovitch N , Rispler S , Feld Y , Solomonica A , Yalonetsky S , Musallamis A , Kerner A , Roguin A , Landesberg A
Published: October 2022

Introduction

Heart failure (HF) is associated with hemodynamic lung congestion that leads to dyspnea and excessive respiratory effort.

Purpose

We hypothesized that this HF induced excessive respiratory effort adversely affects both ventricles loading conditions, leading to a vicious cardiopulmonary cycle and progressive cardiac deterioration, and that this vicious cardiopulmonary cycle is independent of HF etiology.

Methods

The hemodynamic and respiratory indices were simultaneously measured in patients undergoing right heart catheterization for the diagnosis of dyspnea. The pulmonary wedge pressure (PCWP) is modulated by the changes in the intrathoracic pressure. The latter is determined by the respiratory effort. To quantify the respiratory effort, the PCWP was decomposed into cardiac and respiratory waves. The respiratory effort (Presp) was defined as the peak to peak amplitude of the respiratory wave that modulated the PCWP. The immediate effects of the respiratory effort on the pulmonary capillary wedge pressures (PCWP) were scrutinized by asking the patients to perform intentional vigorous breathing and short apneic events.

Results

The HF patients (N=50) exhibited a high Presp of 9.3±5.0 mmHg, ∼3.5-fold higher than the normal respiratory effort. The baseline end-expiratory PCWP (PCWPee) and end-expiratory pulmonary artery pressure of the HF patients have linear relationship with the baseline Presp with slops of 0.78±0.05 and 1.42±0.09 respectively. The changes in PCWPee appeared immediately, within a single breathing-cycle (t =1.65±0.39 sec) in all patients, when each patient intentionally changed the respiratory effort from apnea to his maximum Presp of 19.8±8.6 mmHg. The PCWP during apnea underestimated the HF severity and yielded lower PCWPee while severe respiratory effort markedly increased the PCWPee. Interestingly, similar slope of the instantaneous relationship between the varying Presp and observed PCWPee was obtained for all the patients, independently of the baseline PCWPee-. The PCWPee rose immediately by 0.43±0.15 for every 1 mmHg of Presp. Similar slope was observed in HF patients with ischemic (N=24) and non-ischemic (N=26, p=0.36) HF diseases (p=0.26), and in those with preserved (N=35) or reduced (N=15) ejection fractions (p=0.91).

Conclusions

The respiratory effort has immediate effects on the hemodynamic congestion and the workloads of the heart, and this adverse effects are independent of HF etiology. The observations support the existence of a vicious cardiopulmonary cycle that can lead to decompensation, where the respiratory effort plays a pivotal role. It may explain the similar prognosis of patients with various ejection fractions and etiologies, but with similar dyspnea severity and clinical symptoms.

Funding Acknowledgement

Type of funding sources: None.
Association between prognosis and the use of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blocker in frail patients with heart failure with preserved ejection fraction
Authors: Sunaga A , Hikoso S , Tamaki S , Yano M , Hayashi T , Oeun B , Kida H , Sotomi Y , Dohi T , Okada K , Mizuno H , Nakatani D , Yamada T , Yasumura Y , Sakata Y
Published: October 2022

Background

The effectiveness of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) has not been demonstrated in patients with heart failure with preserved ejection fraction (HFpEF). We recently reported significant interaction between the use of ACE-I and/or ARB (ACE-I/ARB) and frailty on prognosis in patients with HFpEF.

Purpose

In the present study, we examined the association between ACE-I/ARB and prognosis in patients with HFpEF stratified by the presence or absence of frailty.

Methods

We examined the association between the use of ACE-I/ARB and prognosis according to the presence (Clinical Frailty Scale (CFS) ≥5) or absence (CFS ≤4) of frailty in patients with HFpEF in a post-hoc analysis of registry data. Primary endpoint was the composite of all-cause mortality and heart failure admission. Secondary endpoints were all-cause mortality and heart failure admission.

Results

Of 1059 patients, median age was 83 years and 45% were male. Kaplan-Meier analysis showed that the risk of composite endpoint (log-rank P=0.001) and all-cause death (log-rank P=0.005) in patients with ACE-I/ARB was lower in those with CFS ≥5, but similar between patients with and without ACE-I/ARB in patients with CFS ≤4 (composite endpoint: log-rank P=0.830; all-cause death: log-rank P=0.192). In a multivariable Cox proportional hazards model, use of ACE-I/ARB was significantly associated with lower risk of the composite endpoint (hazard ratio = 0.52, 95% CI: 0.33–0.83, P=0.005) and heart failure admission (hazard ratio = 0.45, 95% CI: 0.25–0.83, P=0.010) in patients with CFS ≥5, but not in patients with CFS ≤4 (composite endpoint: hazard ratio = 1.41, 95% CI: 0.99–2.02, P=0.059; heart failure admission: hazard ratio = 1.43, 95% CI: 0.94–2.18, P=0.091). The association between ACE-I or ARB and prognosis did not significantly differ by CFS (CFS ≤4: log-rank P=0.562; CFS ≥5: log-rank P=0.100, for with ACE-I vs. ARB, respectively). Adjusted HRs for CFS 1–4 were higher than 1.0, but were less than 1.0 at CFS 5.

Conclusions

In patients with HFpEF, use of ACE-I/ARB was associated with better prognosis in patients with frailty as assessed with the CFS, but not in those without frailty.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Roche
Sex-based differences in treatment outcomes in HFpEF: a systematic review
Authors: Moore C , Mordi I , Lang C C
Published: October 2022

Background

Heart failure with preserved ejection fraction (HFpEF) is the prevailing heart failure phenotype among women. Disease-modifying treatment in HFpEF has proved a challenge and little is known on sex-based differences in treatment outcomes in HFpEF.

Purpose

This systematic review aimed to identify drug and non-drug exercise randomized controlled trials that stratified treatment outcome by sex.

Methods

A systematic literature search of PubMed for randomised controlled trials that assessed treatment outcomes by sex (pre-specified, secondary, post-hoc analysis) for HFpEF was performed until January 2021.

Results

This systematic review included 36 drug and 2 exercise RCTs. There was an increased benefit in reducing the composite outcome of first and recurrent HF hospitalisation and cardiovascular death among women (HR 0.73, 95% CI 0.59–0.90) compared to men (HR 1.03, 95% CI, 0.84–1.25, p-interaction = 0.017) treated with sacubitril-valsartan. However, women (HR 1.41, 95% CI 1.02–1.97) had higher risk of new-onset AF compared to men (HR 0.79, 95% CI 0.55,1.14, p-interaction 0.019) taking sacubitril-valsartan, and men (Δ2.8, 95% CI 1.3–4.3) were more likely to show improvements in the KCCQ-CSS compared to women (Δ-0.6, 95% CI −2.1,0.8, p-interaction=0.003). There may be benefit among women treated with sacubitril-valsartan in lowering blood pressure and characteristic impedance. A superior risk reduction in all-cause mortality was reported in women treated with spironolactone (HR 0.66, 95% CI 0.48–0.90) when compared with men (HR 1.06, 95% CI 0.81–1.39, p-interaction=0.024). No differences in treatment outcomes by sex were reported with SGLT2 inhibitors or with exercise interventions in HFpEF.

Conclusions

Women may respond to HFpEF treatment differently than men. Identifying sex-based differences in treatment outcomes should be prioritised in future research and taken into consideration in the development of guidelines for the management of HFpEF.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): British Heart Foundation
Trimetazidine in heart failure with preserved ejection fracton: a randomized, double-blind cross-over trial
Authors: Van De Bovenkamp A A , Bakermans A J , Geurkink K J T , Oosterveer F T P , De Man F S , De Kok W E M , Nederveen A J , Van Rossum A C , Handoko M L
Published: October 2022

Introduction

Impaired myocardial mitochondrial function plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and there is evidence indicative of a causal relationship between observed impaired energy homeostasis and diastolic dysfunction. Improvement of mitochondrial function with metabolism-modulating drugs may be a promising novel therapeutic approach in HFpEF. Trimetazidine – a fatty acid oxidation inhibitor – shifts mitochondrial metabolism towards glucose oxidation, which results in higher mitochondrial oxygen efficiency. In this study we investigated whether trimetazidine improves diastolic function during exercise in HFpEF by improving the myocardial energy homeostasis.

Methods

The DoPING-HFpEF trial was a phase II single-center, double-blind, placebo-controlled, randomized cross-over trial. The study consisted of two treatment periods of three months separated by a 2-week wash-out period (Figure 1). Patients were treated with placebo or trimetazidine three times a day (or twice daily in case of an impaired kidney function). The primary endpoint was change in pulmonary capillary wedge pressure (PCWP) measured with right heart catheterization at multiple stages of exercise. Secondary endpoint was change in phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance (MR) spectroscopy. Additional exploratory endpoints were 6-minute-walking-distance, diastolic and systolic parameters measured with echocardiography or cardiac MR, NT-proBNP levels, and quality of life.

Results

Twenty-five HFpEF patients were included and completed the trial, 80% of which were included based on previously established elevated (exercise) PCWP, and 20% were included based on diastolic dysfunction grade ≥II on echocardiography and elevated NT-proBNP levels. There was no effect on the primary outcome PCWP at multiple levels of exercise, with an average change in PCWP of 0±4 (SD) mmHg (Figure 2A, P=0.97). Myocardial PCr/ATP in the trimetazidine arm was similar to placebo (Figure 2B, P=0.08). There was no change by trimetazidine in the exploratory parameters 6-minute walking distance, NT-proBNP, overall quality of life, or other parameters for diastolic function measured with echocardiography and cardiac MR. There was no indication of period or cross over effect.

Conclusion

Trimetazidine did not improve diastolic function or myocardial energy homeostasis in patients with HFpEF.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation (DHF) and “Out-of-the-Box” grant from the Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam, The Netherlands.
Clinical trajectory and outcomes of patients with heart failure with preserved ejection fraction with normal or indeterminate diastolic function
Authors: Oeun B , Hikoso S , Nakatani D , Okada K , Dohi T , Sotomi Y , Kida H , Sunaga A , Sato T , Seo M , Yano M , Hayashi T , Yamada T , Yasumura Y , Sakata Y
Published: October 2022

Background

Heart failure (HF) with preserved ejection fraction (HFpEF) is a chronic and progressive disease, but limited therapeutic strategies are currently available. Although left ventricular diastolic dysfunction (DD) is a prominent mechanism of HFpEF, a certain number of patients with HFpEF have a normal diastolic function (ND) or indeterminate diastolic function (ID). With the progressive nature of HFpEF, diastolic function may change over time. However, the change of diastolic function, its predictor and prognosis in patients with clinically established HFpEF remains unknown.

Purpose

To investigate the clinical trajectory and outcomes of patients with HFpEF with ND or ID and to identify factors associated with progression from ND or ID at discharge to DD at 1-year follow-up.

Methods

Using data from a prospective multicenter observational study of patients with HFpEF, we extracted 289 patients with HFpEF with ND or ID at discharge who had echocardiographic data at 1-year follow-up for the re-evaluation of diastolic function. Diastolic function was assessed according to the 2016 American Society of Echocardiography recommendations. Patients were classified according to the absence or presence of progression from ND or ID to DD at 1 year. The primary endpoint was a composite of all-cause death and HF rehospitalization.

Results

Median age was 81 years, and 138 (47.8%) patients were female. At 1 year, 107 (37%) patients progressed to DD. During a median follow-up of 709 days, the composite endpoint occurred in 90 (31.1%) patients. Compared to patients without progression to DD, those with progression to DD had a significantly higher cumulative incidence rate of the composite endpoint (incidence rate: 11.7/100 person-year versus 23.3/100 person-year, P<0.001). Progression to DD (adjusted HR: 2.014, 95% CI: 1.239–3.273, P=0.005) was independently associated with the composite endpoint. Age (adjusted OR: 1.046, 95% CI: 1.008–1.087, P=0.018), body mass index (BMI) (adjusted OR: 1.107, 95% CI: 1.029–1.192, P=0.006), and serum albumin (adjusted OR: 0.459, 95% CI: 0.216–0.974, P=0.042) were independently associated with progression from ND or ID to DD at 1 year.

Conclusion

More than one-third of patients with HFpEF with ND or ID progressed to DD at 1 year and had poor clinical outcomes. Age, BMI, and serum albumin were independently associated with this progression.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by grants from Japan Society for the Promotion of Science KAKENHI (No. JP 17K09496) and Japan Agency for Medical Research and Development (No. JP16lk1010013).
Reduction in heart failure hospitalizations by sacubitril/valsartan; a post-hoc analysis of the PARALLAX trial
Authors: Wachter R , Pieske B , Baldridge A , Ibram G , Zhao Z , Shah S J
Published: October 2022

Background

The PARALLAX trial recently showed a significant reduction in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations by angiotensin receptor neprilysin inhibition with sacubitril/valsartan (S/V) compared to standard medical therapy (SMT) in patients with heart failure and ejection fraction ≥40%. As NT-proBNP reductions have been associated with a reduction in future heart failure hospitalizations (HHF), we aimed to investigate the impact of S/V on this endpoint in comparison to standard medical therapy.

Methods

The PARALLAX study was a 24-week, randomized, active-controlled, parallel group study to evaluate S/V compared to SMT for comorbidities. Eligible patients were stratified into three strata according to their individual RASi treatment (ACEi, ARB, ACEi/ARB-naïve) and randomized within each stratum 1:1 to S/V (N=1281; target dose (td), 97/103 mg b.i.d.) or individual comparator (N=1285; enalapril (td 10 mg b.i.d), valsartan (160 mg b.i.d.), or placebo). Hospitalizations for cardiac failure reported as serious adverse events by investigators were analysed in this post-oc secondary analysis.

Results

2566 patients with heart failure and LVEF ≥40%, were randomized to receive either S/V or SMT according to RASi stratum (n=1,016 ACE inhibitor stratum, n=1,174 ARB stratum, n=326 no RAS stratum). After 12 weeks, adjusted geometric mean ratio of NT-proBNP showed a 16.4% greater reduction sith S/V vs. SMT (p<0.0001). S/V reduced the risk for cardiac failure events leading to hospitalization by 51% (hazard ratio (HR) 0.49; 95% CI 0.30, 0.81; p=0.005). Similar results were obtained in all three strata: HR 0.55 (0.25–1.19) in ACE inhibitor stratum, HR 0.50 (024–1.02) in ARB stratum and HR 0.37 (0.10–1.38) in no RAS stratum.

Conclusion

The significant reduction of NT-proBNP plasma levels by S/V in comparison to SMT in PARALLAX was associated with a significant reduction in heart failure hospitalisations. These results, together with evidence from the PARAGON trial, support the use of S/V in HFpEF for avoiding heart failure hospitalizations.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Novartis
Digoxin improves systolic cardiac function in patients with AF and HFpEF: the RATE-AF randomised trial
Authors: Bunting K V , Mehta S , Gill S K , Steeds R P , Kotecha D
Published: October 2022

Background

The RAte control Therapy Evaluation in permanent AF trial (RATE-AF; NCT02391337) was the first head-to-head controlled trial of beta-blockers versus digoxin in patients with permanent atrial fibrillation (AF) and symptoms of heart failure. Patients randomised to digoxin had similar physical-related quality of life and heart rate, with significantly improved functional class, reduced N-terminal pro-brain natriuretic peptide (NT-proBNP) and substantially less adverse events. The impact of rate control therapy on measures of cardiac function is not currently understood.

Purpose

To compare the effect of digoxin versus beta-blockers on systolic and diastolic cardiac function according to heart failure sub-type.

Methods

Blinded echocardiograms assessing systolic and diastolic function were performed at baseline and 12 month follow-up, using a robust method to account for rhythm irregularity (average of three index-beats acquired in appropriate cardiac cycles). Outcomes were the change in left-ventricular ejection fraction (LVEF), systolic tissue Doppler velocity (s'), stroke volume, global longitudinal strain (GLS), diastolic tissue Doppler (e'), mitral E wave deceleration time, E/e', pulmonary vein diastolic deceleration time, isovolumic relaxation time and left atrial ejection fraction. Analyses were stratified by baseline LVEF (≥50%, 40–50% and <40%).

Results

160 patients were randomised, of which 145 patients survived to 12-month follow-up with median age 75 years (IQR 69–82) and 44% women. Median baseline heart rate was 96 beats/min (IQR 86–112), blood pressure 135/85 mmHg (IQR 124/77–146/91), NTproBNP 1049 pg/mL (744–1463) and mean NYHA class 2.4 (SD 0.6). In 119 patients with LVEF ≥50% at baseline, diastolic and systolic parameters improved over time with digoxin therapy. There was a significantly greater improvement in systolic function in 63 patients on digoxin compared to 67 with beta-blockers; Figure 1. Patients randomised to digoxin had a higher LVEF at follow-up (adjusted mean difference [AMD] 2.3%, 95% CI 0.3–4.2; p=0.021), higher s' (1.1cm/s, 1.0–1.2; p=0.003) and higher stroke volume (6.5mL, 0.4–12.6; p=0.037) compared to beta-blockers, without any difference in diastolic parameters (Figure 2). In 16 patients with LVEF 40–50% at baseline, s' significantly increased with digoxin compared to beta-blockers (AMD 1.5 cm/s, 1.2–1.7; p=0.001), with no difference for other systolic or diastolic parameters. 10 patients with LVEF <40% at baseline showed no difference between digoxin and beta-blockers for any echocardiographic measures.

Conclusion

Patients randomised to digoxin with permanent AF, heart failure symptoms and preserved LVEF have significantly greater improvement in multiple parameters of systolic function compared to conventional treatment with beta-blockers.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): National Institute of Health Research
Role of left atrial strain response to exercise in the transition from the preclinical to overt heart failure
Authors: Jasic-Szpak E , Woznicka A K , Serafin A , Kotwica T , Ponikowski P , Przewlocka-Kosmala M , Kosmala W
Published: October 2022

Impaired left ventricular (LV) functional reserve has been shown to contribute to exercise intolerance in heart failure. Little is known about the role of left atrial (LA) functional response to exertion in this context. LA strain has recently emerged as a valuable diagnostic marker reflecting both LA and LV performance.

Aim

To investigate the association between LA strain response to exercise and exercise capacity across different stages of heart failure with preserved ejection fraction (HFpEF).

Methods

Transthoracic echocardiography (including peak atrial longitudinal strain (PALS) and LV global longitudinal strain (GLS) assessment) was performed at rest and immediately post exercise test in 55 patients with stage A, 62 patients with stage B and 54 patients with stage C HFpEF.

Results

There was a progressive worsening of peak oxygen uptake from stage A through stage B to stage C, which was accompanied by a gradual impairment of changes from rest to exercise in PALS, GLS, tissue early diastolic velocity e', LA ejection fraction and E/e' ratio (Table 1). In multivariable analysis including LV and LA components of cardiac functional reserve, changes from rest to exercise in PALS (beta 0.34, SE 0.07, p<0.001), e' (beta 0.29, SE 0.07, p<0.001) and GLS (beta 0.17, SE 0.07, p=0.014) were among the independent correlates of exercise capacity. However, after adjustment for age, sex and beta-blocker treatment, only the former two remained statistically significant.

Conclusions

LA strain response to exercise progressively deteriorates from stage A through stage B to stage C HFpEF, and is independently associated with exercise capacity. Accordingly, it might be considered in the risk stratification of the transition from the asymptomatic phase to overt HFpEF.

Funding Acknowledgement

Type of funding sources: None.
Response to heart failure treatment in patients with anthracyclines and trastuzumab induced left ventricular dysfunction
Authors: Del Castillo S , Fileni L , Llamedo C , Capdeville S , Scarponi C , Belziti C , Falconi M , Perez De Arenaza D , Rossi E , Pizarro R
Published: October 2022

Background

Chemotherapy treatments with anthracyclines and Trastuzumab are widely used in different hematologic or solid malignancies but myocardial injury and left ventricular dysfunction, usually called cardiotoxicity (CTX), is a frequent adverse effect. Some studies have demonstrated that early detection and treatment of CTX is essential for the recovery of left ventricular ejection fraction (LVEF), however its behavior after starting treatment is not well established.

Purpose

Evaluate the behavior of LVEF after starting treatment for heart failure in patients with diagnosis of CTX.

Methods

Patients with diagnosis of solid or hematologic malignancies scheduled to receive therapy including anthracyclines and/or trastuzumab were prospectively included. Echocardiogram was performed before starting treatment, and then 3 and 6 months after. CTX was defined, according to guidelines, as a drop of LVEF ≥10% to a value <53% and in these patients treatment of left ventricular dysfunction with B blockers and Enalapril/Losartan was promptly initiated and up-titrated to the maximal tolerated dose. Myocardial injury was defined as a drop of LVEF ≥10% and a value ≥53%, with a watchful waiting strategie, considering these patients as a control group. LVEF was re-evaluated 6 months after starting treatment or after diagnosis of myocardial injury. Primary endpoint was defined as a recovery of LVEF ≥10%.

Results

Of a total of 141 patients of the entire cohort (mean age 56±15 years, 85,8% women and 61,7% with diagnosis of breast cancer),17 patients (12%) met criteria of CTX and 21 (14,9%) of myocardial injury. There were no differences in relation to clinical characteristics or chemotherapy schemes between groups. In patients with CTX (intervention group), 88,2% reached the primary endpoint of recovery of LVEF ≥10% while only 23,8% did it in the control group (p<0,001). Patients with CTX had lowest LVEF at baseline, however no significant differences were observed at 12 months of follow up. Figure 1 represents the behavior of LVEF at baseline, 3, 6 and 12 months. A paired before-after analysis was performed between LVEF at baseline and at 12 months. Patients who received treatment showed no differences in LVEF (63,3±7,2% vs 61,5±9,6%, p=0,5). In contrast, patients who did not receive treatment showed a significant drop in LVEF (72,7±4,4% vs 66,2±5,4%; p<0,001) (figure 2).

Conclusion

Treatment of left ventricular dysfunction in patients with CTX is associated with a greater recovery of LVEF.

Funding Acknowledgement

Type of funding sources: None.
Usefulness of ultra-sensitive troponin to predict anthracyclines and trastuzumab related cardiac dysfunction
Authors: Del Castillo S , Llamedo C , Capdeville S , Fileni L , Scarponi C , Belziti C , Rossi E , Falconi M , Perez De Arenaza D , Pizarro R
Published: October 2022

Background

Cancer therapeutics–related cardiac dysfunction usually known as cardiotoxicity (CTX) is a common adverse effect of anthracyclines and anti-Her2 agents. In recent years, evidence of usefulness of ultrasensitive troponin for early diagnosis of CTX has increased, however the cut-off values of this biomarker remain uncertain.

Purpose

To assess the usefulness of ultrasensitive troponin T (UsTnT) to identify patients at risk of developing CTX and determine cut-off values for this biomarker.

Methods

Patients with diagnosis of solid or hematologic malignancies scheduled to receive therapy including anthracyclines and/or trastuzumab were prospectively included. Echocardiogram was performed prior to chemotherapy, and repeated 3 and 6 months later. UsTnT was measured at baseline and 3 months after starting chemotherapy and the increase of this biomarker from baseline was calculated. This UsTnT has a range of 3–10,000 pg/mL with a 99th percentile <15 pg/mL. Receiver operating characteristic curve was used to find out the best cut-off values followed by a multivariate analysis. The primary endpoint was the presence of CTX defined as a decline of left ventricular ejection fraction (LVEF) ≥10% at 6 months from baseline.

Results

A total of 141 patients were included (mean age 56±15 years, 85,8% were women, the most frequent diagnosis being breast cancer: 61.7%). Thirty-three patients (23.4%) met criteria of the primary endpoint of CTX. Patients with CTX showed significantly higher values of UsTnT at 3 months (18.2±14,9 vs 11.8±10,7 pg/mL, p=0.008) and also showed a higher increase of UsTnT from baseline (11.8±12.8 vs 5±8.2 pg/ml, p<0.001) (figure 1).

The value of UsTnT at 3 months ≥13 pg/mL and an increase of UsTnT from baseline ≥14 pg/mL were selected as the best cut-off values. Figure 2 resumes sensitivity, specificity and predictive values. Those patients who had UsTnT at 3 months ≥13 pg/mL had a 3.8 fold increased risk of developing CTX in a multivariate analysis adjusted by age and left ventricular hypertrophy (OR: 3.8 [95% CI: 1.6–9.3], p=0.003) while an increase of UsTnT from baseline ≥14 pg/mL showed almost 12 fold increased risk for the primary endpoint in the same model (OR: 11.95 [95% CI: 3.9–36.6], p<0.001).

Conclusions

UsTnT is a good biomarker for detecting early myocardial injury which allows the identification of patients at risk for developing CTX with only two measurements during cancer treatment.

Funding Acknowledgement

Type of funding sources: None.
Risk of heart failure following short-term non-steroidal anti-inflammatory drug use in patients with type 2 diabetes mellitus
Authors: Holt A , Strange J E , Rasmussen P V , Blanche P , Nouhravesh N , Jensen M H , Schjerning A M , Schou M , Torp-Pedersen C , Gislason G H , Hansen M L , McGettigan P , Lamberts M K
Published: October 2022

Background

Fluid retention is a known but underappreciated side-effect of non-steroidal anti-inflammatory drug (NSAID) use. As type 2 diabetes mellitus (T2DM) has been linked to both subclinical cardiomyopathy and a decline in kidney function, short-term NSAID use could lead to subsequently development of heart failure (HF) due to aberrations in fluid balances.

Purpose

We investigated associations between short-term NSAID use and the risk of HF in a nationwide cohort of patients with T2DM.

Methods

Using nationwide Danish registers, we identified patients diagnosed with T2DM during 1998–2018. Follow-up began 120 days after first-time T2DM diagnosis among patients without prior heart failure or a rheumatological diagnosis indicating long-term NSAID use.

To describe use of NSAID among patients with T2DM, we reported proportions of patients claiming at least 1, 2, 3 or 4 prescriptions of NSAID within one year of start of follow-up. We investigated associations between use of NSAIDs (celecoxib, diclofenac, ibuprofen and naproxen) and new-onset HF hospitalizations using a case-crossover design with 28-day exposure windows and reported odds ratios (OR) with 95% confidence intervals (CI). The case-crossover design uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding. Sensitivity analyses using exposure windows of 14 and 42 days were performed as well.

Results

A total of 334,950 patients with T2DM was included (47.7% female, median age of 61 [interquartile range 50–70]). Celecoxib and naproxen were rarely used; on the contrary, prescriptions of diclofenac and ibuprofen were claimed at least once within one year from the beginning of follow-up by 4.9% and 15.5% of patients, respectively–0.9% and 2.7% claimed at least four prescriptions (Figure 1).

The risk of new-onset HF hospitalization was increased following use of diclofenac or ibuprofen with corresponding ORs of 1.3 (95% CI 1.0 to 1.7) and 1.3 (95% CI 1.1 to 1.5) using 28-day exposure windows. An increased risk following use of celecoxib or naproxen was not found (Figure 2).

Conclusion

NSAIDs diclofenac and ibuprofen were both widely used and associated with an increased risk of new-onset HF hospitalization in patients with T2DM. This suggests a previously unknown and serious, clinically relevant concern of NSAID use in patients with T2DM.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Ib Mogens Kristiansens Almene FondHelsefonden
Myocardial work analysis for early detection of type 1 CTRCD and patient risk stratification
Authors: Moya A , Buytaert D , Paolisso P , Verstreken S , Goethals M , Dierckx R , Beles M , Penicka M , Vanderheyden M , Heggermont W
Published: October 2022

Aim

This prospective longitudinal study analyses the potential role of Myocardial Work in early detection of cardiotoxicity during chemotherapy and its added value for prognosis and patients' risk stratification.

Methods

We enrolled 47 consecutive female patients with HER2-positive breast cancer referred for anti-cancer therapy based on anthracycline and taxane. Patients with depressed LV function at baseline were excluded. Medical therapy, clinical parameters and echocardiographic data were recorded at baseline and at 3, 6, 12 months follow-up. Additionally, cuff blood pressure was measured at the time of 2D-TTE examination and adequate echocardiographic images were stored for off-line analysis.

Results

CTRCD was detected in 17 patients (36%) while 30 patients remained free of CTRCD (64%). There were no intergroup differences for age, body mass index, resting heart rate and brachial arterial pressure. Both groups presented unaltered LV systolic function after 3 months follow-up yet overt cardiac dysfunction showed up in the CTRCD group at 6 months with significant decline in LVEF, GLS, MWI, MWE and CW from baseline values (LVEF, %: 56.0±4.1 vs 52.2±6.5; GLS, %: −20.9±1.9 vs −17.6±3.2; MWI, mmHg%: 2125±348 vs 1704±620; MWE, %: 95±2.6 vs 93±3.9 and CW, mmHg%: 2562±3567 vs 2212±455, p<0.05). Additionally, GLS, MWI and MWE at 6 months were significantly worse in the CTRCD group vs non-CTRCD group (GLS, %: −17.6±3.2 vs −20.6±1.8; MWI, mmHg%: 1704±620 vs 2087±347; MWE, %: 93±3.9 vs 96±1.5, p<0.05). Depressed LV systolic function persisted after 1 year follow-up (Figure 1). After 3 months, only de relative change in GLS and WW from baseline were significantly worse in CTRCD vs non-CTRCD (ΔGLS: +3.7±11 vs −3.9±10, ΔWW: +46.1±83 vs +2.2±45). Whereas no correlation was found, the combination of both ΔGLS and ΔWW at 3 months showed stronger prognostic value for CTRCD than each parameter alone, AUC of 0.72 (Figure 2).

Conclusion

These findings point the superiority of Myocardial Work for early type 1 CTRCD detection in comparison to the current diagnostic tools. Additionally, we suggest the add-on value of ΔWW on top of ΔGLS quantification for better patient risk stratification. These are promising results for better clinical surveillance of cardiac function during cancer treatment.

Funding Acknowledgement

Type of funding sources: None.
The hemodynamic and prognostic impact of systolic pressure change during right ventricular ejection in patients with HFREF
Authors: Schmeisser A , Rauwolf T , Tanev I , Meissler S , Hansen M , Groscheck T , Luani B , Steendijk P , Braun-Dullaeus R
Published: October 2022

Background and purpose

The gold-standard method to evaluate right ventricular (RV) function in pulmonary hypertension (PH) relies on invasive pressure-volume loop (PV-loop) measurement of RV-pulmonary artery (PA) coupling defined as the ratio of end-systolic RV elastance to pulmonary arterial elastance (Ees/Ea). The normal RV PV-loop has a triangular shape with a peaking early systolic pressure (early-SP). With progression of PH the PV-loop changes from trapezoid to a rectangular and ultimately to a trapezoid shape. Along with these geometric changes, the ratio between early-SP and end-systolic pressure (ESP) decreases from >1 to <1 with a late systolic peaking of RV pressure. How all these changes relate to RV afterload, RV-PA coupling, non-invasive RV function, and prognosis in PH due to left heart disease is incomplete understood.

Methods

We analyzed and categorized the conductance catheter-derived single-beat RV PV-loops in 133 patients with HFREF (110 patients: a post-hoc analysis of the Magdeburg CRT Responder Trial, 23 from a local PV-L-derived CRT-optimization trial) according their shape (triangular, rectangular, trapezoid), and determined the early-SP/ESP ratio.

Results

Using multivariate linear regression analysis (adjusted for afterload parameter PVR, PA-compliance, PCWP, PAmean), only PCWP (beta=−0.17) and PA-compliance (beta=0.61) remained significant determinants of the early-SP/ESP ratio and PV-loop shape. In turn, early-SP/ESP ratio seems to be an important determinant of RV-PA coupling efficiency (Ees/Ea) of the RV to afterload (r=0.8, p<0.001). The association between early-SP/ESP ratio and Ees/Ea ratio was closer than Ees/Ea ratio to the other afterload parameters Ea (r=−0.7), PVR (r=−0.41), and PA-compliance (r=0.62). Furthermore, the early-SP/ESP ratio was significantly associated with parameters of non-invasive RV function such as TAPSE (r=0.67), FAC (r=0.76), RVEF (r=0.7), and the non-invasive RV-PA coupling parameter TAPSE/PASP (r=0.8) (all p<0.001). In cox regression analysis, the early-SP/ESP ratio was a strong indicator for long-term survival (median FU 4.2 years) (OR 0.025, CI 95% 0.007–0.09). Simple categorization of the RV PV-loop shapes into “triangular” (early-SP/ESP ratio >1.1, mean survival 7.7 years), “rectangular” (0.9–1.1, 6.4 years) and “trapezoid” (<0.9, 3.2 years) clearly differentiated long-term survival of HFREF patients (log rank, Chi square 50.1, p<0.001).

Conclusion

The early-SP/ESP ratio determines the shape of RV-PV-loops and is closely associated with predominately pulsatile PA load, RV-PA coupling capacity, RV function, and long-term prognosis of patients with HFREF.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Boston Scientific