bluuebunny/crossref_metadata_2025_split huggingface dataset:
The acute hemodynamic effects of sodium lactate infusion: increased cardiac output and decreased afterload in a randomized trial in pigs
Authors: Hoersdal O , Moeslund N , Berg Hansen K , Nielsen R , Moeller N , Eiskjaer H , Wiggers H , Gopalasingam N 
Published: November 2023

Abstract

Background
Lactate is traditionally acknowledged as a by-product of anaerobic glucose metabolism. Recently, however, lactate has been proven to be a preferred oxidative substrate for stressed myocardium. Studies have shown that exogenous lactate infusion provides beneficial hemodynamic effects including increased cardiac output (CO). Nevertheless, the exact mechanism of action underlying the hemodynamic effects of lactate infusion has not been fully elucidated.

Aim
To identify the cardiovascular mechanisms behind the acute hemodynamic effects of exogenous sodium lactate infusion in an experimental model of healthy human-sized pigs.

Methods
We performed a randomized, assessor-blinded crossover study in eight female 60 kg pigs. In randomized order, the pigs received an infusion with 1 M sodium lactate for two hours and a control infusion with iso-osmolar and isovolumetric sodium chloride for two hours. The two infusion periods were separated by a one-hour washout period. We measured CO and pulmonary pressures hourly with a pulmonary artery catheter. A pressure-volume admittance catheter was inserted in the left ventricle to assess measures of cardiac efficiency, contractility, afterload, and preload. Hemodynamic measures as arterial blood pressure, heart rate, and mixed venous saturation (SvO2) were measured hourly as well.
The study followed the principles of laboratory animal care (NIH Publication no. 85-23 revised 1985) and national and European legislations.

Results
Lactate levels increased by 9.9 mmol/L (95% CI 9.1 to 11.0) and CO increased by 2.0 L/min (95% CI 1.2 to 2.8) during lactate infusion as compared with the control period (figure 1). During lactate infusion, ejection fraction increased by 16.0 percentage points (95% CI 1.9 to 31.0) and heart rate by 21 bpm (95% CI 9 to 32) compared with control. Arterial elastance decreased by -1.1 mmHg/ml (95% CI -2.1 to -0.18).
Lactate infusion also increased cardiac efficiency, SvO2, arterial pH, and arterial glucose concentration significantly. The infusion of lactate led to no changes in systemic arterial pressure nor pulmonary pressures including pulmonary artery wedge pressure. Also, no changes were found in left ventricle end systolic elastance (contractility). Futhermore, no change in left ventricle end-diastolic volume or -pressure (preload) were observed during lactate infusion compared with the control (figure 2).

Conclusion
High dose lactate infusion increased cardiac output by reducing afterload. No changes in left ventricular contractility or -preload were observed.Fig 1:Lactate concentration and COFig 2:Changes of endpoint parameters
Effects of dapagliflozin in heart failure with preserved ejection fraction and chronic obstructive pulmonary disease: an analysis of the DELIVER trial
Authors: Butt J , Lu H , Kondo T , Bachus E , De Boer R A , Hernandez A , Inzucchi S , Jhund P S , Kosiborod M , Lam C , Martinez F , Shah S J , Vaduganathan M , Solomon S D , Mcmurray J J V 
Published: November 2023

Abstract

Introduction
Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure (HF) with preserved ejection fraction (HFpEF) and associated with worse outcomes.

Purpose
We investigated the relationship between COPD status and outcomes, and the efficacy of dapagliflozin, compared with placebo, according to COPD status in patients with heart failure (HF) with preserved ejection fraction (HFpEF) randomized in DELIVER.

Methods
A total of 6,263 patients with HF with New York Heart Association functional class II-IV, left ventricular ejection fraction &gt;40%, evidence of structural heart disease, and elevated N-terminal pro–B-type natriuretic peptide levels were randomized to dapagliflozin or placebo. Clinical outcomes and the effect of dapagliflozin, according to COPD status at baseline, were examined. The primary outcome was a composite of cardiovascular death or worsening HF.

Results
Of the 6,261 patients with data on baseline COPD, 692 (11.1%) had a history of COPD. Compared with patients without COPD, those with COPD were older, more often men and current smokers, and they had a higher BMI, but lower systolic blood pressure. Patients with COPD also had a longer duration of HF, a higher rate of prior HF hospitalization, higher NT-proBNP, and worse NYHA functional class and KCCQ-TSS. The risk of the primary endpoint was higher in patients with COPD compared with those without COPD (adjusted HR: 1.29 (95% CI: 1.09-1.52). The benefit of dapagliflozin on the primary outcome was consistent irrespective of COPD status: no COPD, HR: 0.82 (95% CI: 0.72-0.93); COPD, HR: 0.84 (95% CI: 0.63-1.12) (Pinteraction = 0.92). Consistent effects were observed for HF hospitalization, cardiovascular death, and all-cause mortality (Table). Dapagliflozin, as compared with placebo, increased (improved) the KCCQ-TSS from baseline to 8 months to a similar extent in patients with and without COPD (Pinteraction = 0.75) (Table). Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of COPD status.

Conclusions
COPD is common in patients with HFpEF and associated with worse outcomes. Dapagliflozin reduced the risk of worsening HF or cardiovascular death, and improved symptoms, similarly in patients with and without COPD. In addition, dapagliflozin was safe and well-tolerated, irrespective of COPD status.
Comparison study of olmesartan and valsartan on myocardial metabolism in patients with dilated cardiomyopathy trial
Authors: Park K , Jo S , Park T H 
Published: November 2023

Abstract

Background
Patients with dilated cardiomyopathy (DCMP) have overactivation of the renin-angiotensin-aldosterone systems, which can adversely affect myocardial metabolism. The impairment of myocardial metabolism can contribute to the progression of left ventricular remodeling and contractile dysfunction in heart failure. The objective of this study is to compare the effects of olmesartan and valsartan on myocardial metabolism in patients with DCMP.

Methods
The OVOID study (a comparison study of Olmesartan and Valsartan On myocardial metabolism In patients with Dilated cardiomyopathy) was a non-blinded, open-label, parallel-group, prospective, randomized, controlled, multicenter clinical trial. that 40 patients with DCMP. Patients with DCMP were randomized into the olmesartan or the valsartan group. To measure myocardial metabolism, 18F-fluoro-2-deoxyglucose (FDG) cardiac positron emission tomography (PET) was performed at baseline and six months after receiving the study agent. The primary endpoint was myocardial metabolism as measured by standardized uptake value ratio (SUVR) at 6 months after treatment.

Results
The baseline clinical characteristics and 18F-FDG PET data did not differ between the olmesartan and valsartan groups. LVEF rose significantly from baseline in both groups to a similar degree between the two groups (both P &lt; 0.01). The level of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) decreased significantly from baseline in the both high- and usual-dose groups (both P &lt; 0.01). The magnitude of NT-proBNP change was not significantly different between the two groups (P = 0.33). However, six-month follow-up 18F-FDG PET showed that SUVG value was significantly lower in the olmesartan group than the valsartan (3.76±2.12 versus 7.33±4.08, P = 0.01).

Conclusions
Compared to valsartan, six months of olmesartan therapy significantly improved myocardial metabolism in DCMP patients.
Impact of sacubitril valsartan initiation in patients with HFrEF and severe mitral regurgitation referred for percutaneous mitral repair
Authors: Arroyo Monino D F , Cortes Cortes F J , Rivadeneira Ruiz M , Alcalde Calleja A , Recio Mayoral A 
Published: November 2023

Abstract

Background
In patients with heart failure with reduced ejection fraction (HFrEF), the severity of functional mitral regurgitation (MR) is a major predictor of worsened symptoms and poor outcomes.
Percutaneous MR repair has been shown to improve outcomes in HFrEF with MR. However, because MR is related to abnormal myocardial function and adverse remodeling, the optimization of guideline-directed medical therapy (GDMT) could improve loading conditions, reversal remodelling and left ventricle function and also may reduce MR severity. We sought to evaluated whether the left ventricle reverse remodeling induced by the addition of sacubitril/valsartan may reduce MR severity sufficiently to avoid need for percutaneous MR repair approach.

Methods
We performed a single-center, prospective assessor-blinded study to determine the reverse remodeling response of sacubitril/valsartan therapy in HFrEF patients (NYHA class II-IV) with MR evaluated for percutaneous MR repair. Echocardiographic images were assessed offline by 2 investigators blinded to both the clinical data and timing of echocardiograms. Doses of sacubitril/valsartan were optimized to individual tolerance. A clinical and echocardiographic 1 year follow-up was performed.

Results
Thirty-nine HFrEF patients with MR grade 3-4 were included (mean age 63 years old, 69,2% male). Optimal dose of sacubitril/valsartan was reached in 63,2% of patients. After 1-year follow-up, only 1 patient died and, as we show in Table 1, a significant improvement on NYHA functional class and NT-ProBNP values were present. Left ventricle ejection fraction improved (29.7 ± 6.7% vs 41.3 ± 13.2%; P &lt; 0.001) and left ventricular end-diastolic and end-systolic volume indexed to body surface area decreased (123.4 ± 35.7 mL/m2 vs 98.4 ± 39.7 mL/m2; P &lt; 0.001 and 87.7 ± 30.0 mL/m2 vs 61.9 ± 35.3 mL/m2; P &lt; 0.001, respectively). Volumetric remodeling was associated with a reduction in the degree of mitral regurgitation (64.1% grade 3 and 35.9% grade 4 at the beginning to 28.9% grade 1, 36.8% grade 2, 21.5% grade 3 and 13.2% grade 4 after one year of follow-up; [scale from 0-4]).

Conclusion
The optimization of GDMT with sacubitril/valsartan induced an improvement on functional class and a beneficial reverse cardiac remodelling, with enhancement of left ventricle function and reducing MR severity, enough in 24 patients to avoid need for percutaneous MR repair.
In HFrEF patients with grade 3-4 mitral regurgitation, our results reinforce importance of ensuring optimal GDMT before a percutaneous mitral valve repair approach.Table 1.Changes during follow-up.
Left ventricular reverse remodeling following initiation of sacubitril/valsartan for heart failure with reduced ejection fraction and low blood pressure
Authors: Nishihara Y , Nishimori M , Sawa T , Yamauchi Y , Shiraki H , Yamashita K , Fukuda T , Hisamatsu E , Shimizu M , Hirata K , Tanaka H 
Published: November 2023

Abstract

Background
Sacubitril/valsartan has become an important first-line drug for symptomatic heart failure (HF) patients, especially with left ventricular (LV) ejection fraction (LVEF) &lt; 50%. Since sacubitril/valsartan was reported to be more potent than renin-angiotensin-aldosterone system inhibitors for lowering blood pressure, HF patients with low blood pressure were not included in most clinical studies as a result of sacubitril/valsartan administration, and average systolic blood pressure of most enrolled patients was around 120 mmHg. Thus, the effect of sacubitril/valsartan on cardiovascular outcomes, especially LV reverse remodeling for HF patients with LVEF &lt; 50% and low blood pressure, remains uncertain.

Purpose
The aim of this study was to examine the effect of sacubitril/valsartan on LV reverse remodeling after initiation of the maximum tolerated dose of sacubitril/valsartan for HF patients with LVEF &lt; 50% and systolic blood pressure ≤ 100 mmHg, and a comparison of its efficacy with that for patients with systolic blood pressure &gt; 100 mmHg.

Methods
We retrospectively studied 164 HF patients with LVEF &lt; 50% who were treated with sacubitril/valsartan from two institutions. Echocardiography was performed before and 9.5 ± 5.1 months after initiation of maximum tolerated dose of sacubitril/valsartan.

Results
sacubitril/valsartan was discontinued for 17 (10.4%) as decided by the attending physician mainly due to hypotension. The prevalence of discontinuation of sacubitril/valsartan for the low blood pressure group was higher than that for the non-low blood pressure group, but the difference was not statistically significant (16.0% vs. 9.4%, P = 0.32). No serious adverse events occurred during this study. The maximum tolerated dose of sacubitril/valsartan was lower for the low blood pressure group than for the non-low blood pressure group (165 ± 106 mg vs. 238 ± 124 mg, P = 0.017). As expected, significant LV reverse remodeling was observed in the non-low blood pressure group after initiation of sacubitril/valsartan. It was noteworthy that significant LV reverse remodeling was also observed in the low blood pressure group after initiation of sacubitril/valsartan (LV end-diastolic volume: 177.3 ± 66.0 mL vs. 137.7 ± 56.1 mL, P&lt;0.001, LV end-systolic volume: 131.6 ± 60.3 mL vs. 94.6 ± 55.7 mL, P&lt;0.001, LVEF: 26.8 ± 10.3% vs. 33.8 ± 13.6%, P = 0.015). Relative changes in LV volumes and LVEF after initiation of sacubitril/valsartan were similar for the two groups (Figure).

Conclusions
Significant LV reverse remodeling can occur after initiation of sacubitril/valsartan even in HF patients with LVEF &lt; 50% and systolic blood pressure ≤ 100 mmHg if tolerated. This finding is expected to offer new insights for better management of HF patients.Figure
Effects of vericiguat on redox signaling in cardiomyocyte
Authors: Harada T , Kondo H , Yamasaki H , Takahashi M , Takano M , Akioka H , Teshima Y , Yufu K , Nakagawa M , Takahashi N 
Published: November 2023

Abstract

Background
Reactive oxygen species (ROS) inhibits the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway in the patients with advanced heart failure (HF) and contributes to the prognosis of HF. Vericiguat stimulates sGC independently of NO and reduced morbidity/mortality for HF patients with reduced ejection fraction. However, the effects of vericiguat on the cardiomyocyte in terms of ROS is unclear.

Purpose
We explored the cardioprotective effects of vericiguat focusing on the oxidative stress.

Methods
Cardiomyocytes isolated from the whole heart of neonatal rats were incubated with vericiguat (0μM as control, 0.1μM, 1.0μM, 10μM) for 72 hours. Administration of angiotensin II (1.0μM) was used to induce excessive ROS. Superoxide was quantified using luminometry, and whole ROS or mitochondria-derived superoxide was evaluated by using live-cell fluorescent probes. ERK 1/2 signaling pathway activity were evaluated with western blot analysis.

Results
Nicotinamide adenine dinucleotide phosphate (NADPH)-stimulated superoxide was significantly increased by the treatment of angiotensin II (40208 ± 6107 reactive light unit (RLU) / mg, p = 0.0009) and the angiotensin II-induced superoxide was significantly attenuated by vericiguat at doses of 0.1μM (28240 ± 6507 RLU / mg, p = 0.03) , 1.0μM (25221 ± 6496 RLU / mg, p = 0.007) and 10μM (8230 ± 2568 RLU / mg, p &lt; 0.0001). Corrected total cell fluorescence value of live-cell fluorescent probes revealed that whole ROS and mitochondria-derived superoxide were significantly increased by angiotensin II treatment (525.3 ± 119.6, p = 0.004 and 945.3 ± 153.0, p &lt;0.0001), which were attenuated by vericiguat (0.1μM, 431.2 ± 45.7, p = 0.48 and 548.1 ± 103.9, p = 0.0004; 1.0μM, 336.1 ± 109.0, p = 0.04 and 421.3 ± 111.9, p &lt; 0.0001; 10μM, 270.0 ± 44.4, p = 0.005 and 157.7 ± 48.3, p &lt; 0.0005) dose-dependently. Angiotensin II-induced phosphorylation of ERK 1/2 was suppressed by vericiguat at doses of 1.0μM (fold change 0.58, p = 0.04) and 10μM (fold change 0.45, p = 0.006) treatment.

Conclusion
Our results indicated that vericiguat could suppress the oxidative stress induced by angiotensin II and following activation of ERK 1/2 signaling. Suppressing the oxidative stress could lead to further activation of NO-sGC-cGMP pathway not only the stimulation by vericiguat and favorable cardio-protective cycle is expected.Quantification of superoxideQuantification of ROS or superoxide
Long-acting CRF2 peptide agonist improves cardiac function in a rat heart failure model
Authors: Stephan Y , Ozoux M L , Janiak P , Mulder P 
Published: November 2023

Abstract

Introduction
Corticotropin-releasing factor receptor type 2 (CRF2) is a G protein-coupled receptor largely expressed in the cardiorenal system. Upon CRF2 activation, endogenous ligands such as urocortin-2 (UCN-2) or urocortin-3 (UCN-3) have been reported to increase cardiac function, decrease vascular resistance and improve natriuresis and diuresis in heart failure (HF) patients and in various experimental heart failure settings. However UCN-2 or -3 suffer from a very short half-life which markedly limit further clinical investigations in HF patients. For this purpose, a very long acting CRF2 peptide agonist has been developed.

Objectives
The aim of this study is to determine the acute effect on cardiac hemodynamic of a long acting CRF2 peptide agonist, COR-1167, in a rat model of chronic heart failure.

Methods
In 10-week-old Wistar rats, a total occlusion of the left anterior descending coronary artery was performed to induce myocardial infarction. Twelve weeks after myocardial infarction, rats had developed heart failure and received COR-1167 at the dose of 0.3 µg/kg or 1 µg/kg, or placebo, administered SC. Left ventricular dimensions and function were then assessed by echocardiography and left ventricular pressure-volume analysis.

Results
Three months after left coronary artery ligation rats displayed the classical features of heart failure as illustrated by an increase in left ventricular diastolic diameter and reduced ejection fraction, and decreases in LV end-systolic pressure, dP/dtmax and LV end-systolic pressure volume relationship. Major LV diastolic dysfunction developed, as shown by the increases in LV end-diastolic pressure, and LV end-diastolic pressure volume relationship and the decrease in dP/dtmin. Echocardiography and left ventricular pressure-volume analysis showed that COR-1167 at 0.3 and 1 µg/kg SC improved in a dose-dependent manner cardiac contractility and relaxation as assessed by LVESPVR and LVEDPVR, respectively. In addition, stroke volume and cardiac output were significantly ameliorated by COR-1167 at 1.0 µg/kg SC, with no change in heart rate.

Conclusion
Single acute administration of COR-1167 improved cardiac function in a rat model of heart failure with reduced ejection fraction. Altogether these results confirm that CRF2 agonism is an attractive therapeutic target for the treatment of heart failure.
The use of 99mTc-PYP SPECT/CT in monitoring therapeutic changes of eplontersen in patients with hereditary transthyretin cardiomyopathy
Authors: Yu A , Chen Y , Tsai C , Wu Y , Su M , Chou C , Shun C , Hsueh H , Juang J , Lee M , Tseng P , Hsieh S , Cheng M , Chao C , Lin Y 
Published: November 2023

Abstract

Objective
Hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) is a progressive and fatal disease. Emerging data suggests the potential role of technetium-99m (99mTc)-pyrophosphate (PYP) scintigraphy to monitor the efficacy of ATTR-CM treatment. We aimed to determine whether eplontersen treatment alters the quantitative uptake of 99mTc-PYP in patients with ATTR-CM.

Methods
We analyzed a prospective cohort of hATTR-CM patients receiving eplontersen (45 mg/4 weeks). Patients with hATTR-CM who had not received eplontersen, inotersen, tafamidis or patisiran were identified retrospectively as the control group. 99mTc-PYP single-photon emission computed tomography/computed tomography (SPECT/CT) was performed at baseline and at 1 to 2 years later. Volumetric heart to lung (H/L) ratio was measured.

Results
Thirteen hATTR-CM patients were enrolled, of whom six received eplontersen and the other seven patients were enrolled as the control group. The median follow-up time was 544 days. A significant decrease in volumetric H/L ratio (3.774 ± 0.474 to 2.979 ± 0.354, p = 0.028) after eplontersen treatment was noted in the eplontersen group, while there was no significant change (4.141 ± 0.557 to 3.915 ± 0.3864, p = 0.237) in the control group. Comparing the two groups, the patients who received eplontersen showed a significantly greater decrease in volumetric H/L ratio compared to the control group (-20.7% ± 7.8% vs -3.4% ± 8.1%, p = 0.007).

Conclusion
99mTc-PYP uptake measured by volumetric H/L ratio significantly decreased after eplontersen treatment in patients with hATTR-CM. Our results suggest the effectiveness of eplontersen in patients with hATTR-CM and the role of 99mTc-PYP SPECT/CT to monitor the efficacy of eplontersen treatment.Workflow of volumetric H/L ratioChanges in volumetric H/L ratio
Feasibility, efficacy and safety of early and rapid initiation of evidence-based treatment for patients with HFrEF- a real world experience of the "four drugs in four weeks" strategy
Authors: Sze S , Thaitirarot C , Chan D , Nicolson W B , Krishnan S , Squire I B , Clayton L , Loke I 
Published: November 2023

Abstract

Background
Evidence-based treatment for heart failure with reduced ejection fraction (HFrEF) is associated with improved outcomes for patients. However, there is uncertainty as to how treatment with these foundational drugs should best be implemented.

Objectives
To evaluate whether early and rapid initiation of medications for patients with HFrEF using a 4 x 4 approach (4 pillars of HFrEF therapy in 4 weeks) is feasible, safe, and effective.

Methods
We recruited consecutive patients from April to July 2021 with a new diagnosis of HFrEF who were either assessed at our urgent HF clinic or had a recent HF hospitalisation. All patients had regular reviews (every 1-2 weeks, combination of telephone and face-to-face) at our hospital-based HF clinic by a HF consultant or senior HF specialist nurse for initiation and up-titration of guideline-recommended therapy including angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor neprilysin inhibitor (ARNI), beta blockers (BB), mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter inhibitor (SGLT2i).

Results
Of 100 patients approached, 19 patients were considered unsuitable for the 4x4 pathway (79% due to severe frailty or significant comorbidities). 81 patients were enrolled (61% male, median (IQR) age: 73 (67-82) years, median (IQR) NT-proBNP: 3764 (1597-7487) ng/L); 39 (48%) patients achieved "4 drugs at 4 weeks". Of the 42 patients who did not, 33 (79%) had contraindication to one or more of the drug classes at the outset, including renal impairment (28%), bradycardia (18%) and hyperkalaemia (15%). Patients who did not achieve "4 drugs at 4 weeks" were older, more symptomatic, and had higher NTproBNP and worse renal function.
During a median follow up of 554 days, 6 (7%) patients died and 31 (38%) experienced the combined outcome of all-cause death / hospitalisation. Patients who did not achieve "4 drugs at 4 weeks", compared to those who did, had a 2.5 fold increased risk of the combined outcome (Figure 1). They were also less likely to be up-titrated to targeted doses of HF medications (Figure 2). There was noticeable improvement in NTproBNP with no significant change in renal function or systolic BP in both groups. Compared to those who did not achieve "4 drugs at 4 weeks", those who did showed larger improvement in LVEF (8% vs 2%) at 6 months. 5 patients (6%) experienced significant side effects during medication up-titration: 4 had symptomatic hypotension and 1 had hyperkalaemia.

Conclusion
The 4x4 strategy is clinically feasible and safe when implemented in selected patients with HFrEF and may be associated with improved outcomes. Our results support larger studies to further investigate the generalisability and effectiveness of the 4x4 strategy.