bluuebunny/crossref_metadata_2025 huggingface dataset:
Synchrotron-based X-ray phase contrast imaging of transmural cardiac tissue in patients treated for advanced heart failure
Authors: Li K Y C , Loncaric F , Skreb N , Bonnin A , Dejea H , Garcia-Canadilla P , Ilic I , Gasparovic H , Milicic D , Bijnens B , Cook A C , Planinc I , Cikes M
Published: November 2023

Background

Cardiac imaging is essential for identifying structural changes in advanced heart failure (HF) and understanding underlying pathophysiology. Synchrotron radiation-based X-ray phase contrast imaging (X-PCI) is a non-destructive imaging modality that can provide high resolution three-dimensional (3D) visualisation of cardiac tissue on the microstructural level. Thus far, such analyses including the quantification of myocyte aggregates ranging from the epicardium to the endocardium, have been confined to animal models and human fetal tissue. We aimed to explore the feasibility of using X-PCI to quantify and compare structural organisation and orientation of myocyte aggregates in the myocardium across different advanced HF aetiologies.

Methods and design

Four adult patients were included - two receiving a left ventricular assist device (LVAD), and two undergoing heart transplantation (HTx). Aetiology of advanced HF in both the LVAD and HTx group was ischaemic heart disease and dilated cardiomyopathy (DCM), respectively. Transmural tissue samples were obtained by left ventricular apical coring (LVAD) and from the explanted hearts (HTx). The tissue specimens were imaged by X-PCI at the TOMCAT beamline using an effective pixel size of 5.8 µm. Orientation of aggregates of cardiomyocytes was assessed using a structure tensor-based method and morphological parameters were derived - the helical angle (HA), or the angle between the circumferential left ventricular plane and myocyte aggregates, and fractional anisotropy (FA), the degree of anisotropy or disorganisation of the local myocardium.

Results

The general patient characteristics are shown in Table 1. X-PCI enabled 3D visualisation of transmural myocardial tissue samples showing differences in organisation of myocardial structure in different HF aetiologies (Figure 1). The epicardial adipose layer was thicker in DCM, paired with a thinner epicardial myocyte layer (yellow arrows). Furthermore, the epi-to-endocardial HA transition was clearly visualized in ICM (double arrows), whereas there was clear disruption of the HA gradient in DCM samples – a finding further quantified via FA (green arrows).

Conclusion

X-PCI allows non-destructive advanced imaging of ex-vivo tissue. By harnessing the power of digital 3D imaging on a cellular level, it provides a novel insight to differential information on tissue organisation in different aetiologies of advanced heart failure.Table 1Figure 1
Myocardial structural and functional changes in cardiac amyloidosis - insights from a prospective observational patient registry
Authors: Duca F , Rettl R , Binder C , Dachs T M , Camuz Ligios L , Agis H , Kain R , Koschutnik M , Dona C , Badr Eslam R , Nitsche C , Loewe C , Hengstenberg C , Kammerlander A A , Bonderman D
Published: November 2023

Background

Within the last decade, cardiac amyloidosis (CA) has been acknowledged as a significant cause of heart failure and patients who are affected face a dismal prognosis, especially in later stages of the disease. The pathophysiological hallmark of cardiac amyloidosis (CA) is the deposition of amyloid within the myocardium. Consequently, extracellular volume (ECV) of affected patients increases. However, studies on ECV progression over time and its' impact on prognosis are lacking.

Objectives

We aimed to investigate the progression of ECV and its prognostic impact in CA patients.

Methods

Serial cardiac magnetic resonance (CMR) examinations, including ECV quantification were performed in consecutive CA patients.

Results

Between 2012 and 2021, 103 CA patients underwent baseline and follow-up CMR, including ECV quantification.

Median ECVs at baseline of the total (n = 103), transthyretin [(ATTR) n = 80], and [light chain (AL) n = 23] CA cohorts were 48.0%, 49.0%, and 42.6%. During a median follow-up period of 12 months, ECV increased significantly in all cohorts (48.0% to 50.5%, p<0.001; 49.0% to 50.5%, p<0.001; 42.6% to 50.6%, p = 0.026). Separate analyses for treatment-naïve (n = 14) and treated (n = 66) ATTR patients revealed that the median change of ECV from baseline to follow-up was significantly higher among untreated patients (5.5% versus 2.7%, p = 0.035).

Survival analyses demonstrated that median change of ECV was an independent (adjusted for troponin t and NT-proBNP) predictor of outcome in all CA cohorts [total: hazard ratio (HR): 1.114, 95% confidence-interval (CI): 1.045 – 1.189, p<0.001; ATTR: HR: 1.099, 95% CI: 1.014 – 1.192, p = 0.022; AL: HR: 1.142, 95% CI: 1.006 – 1.297, p = 0.040].

Conclusions

The present study demonstrates that ECV, quantified by CMR T1 mapping, increases significantly in CA patients over the course of 12 months. While ECV increased, irrespective of amyloid type our analyses showed the highest increase among untreated ATTR patients. Moreover, the change of ECV was an independent predictor of adverse outcomes in AL, as well as ATTR patients emphasizing the usefulness of CMR T1 mapping in the management of CA patients.Figure 1.Dot PlotsFigure 2.Kaplan Meier Curves
Dietary sodium intake and outcomes: a secondary analysis from SODIUM - HF
Authors: Colin-Ramirez E , Saldarriaga C I , Alemayehu W , Ezekowitz J
Published: November 2023

Background

Sodium restriction is common advice provided to patients with heart failure, however, evidence from the SODIUM-HF trial and a subsequent meta-analysis failed to show a beneficial effect of dietary sodium restriction on outcomes.

Purpose

This secondary analysis of SODIUM HF is aimed to assess association between baseline dietary sodium intake, the change in dietary sodium at 6 months and a composite of cardiovascular hospitalization, emergency department visit, and all-cause death at 12 and 24 months.

Methods

Multivariable Cox proportional hazard regression model was used to assess association of dietary sodium level measured at randomization with primary and secondary endpoints. Adjusted Hazard ratios and 95% confidence intervals were presented. A responder analysis also explored the achieved dietary sodium at 6 months with subsequent risk for clinical outcomes.

Results

792 participants were included. At baseline, sodium intake was ≤ 1500 mg/day in 19.9% (n = 158), >1500-3000 mg/day in 56.5% (n = 448) and >3000 mg/day in 23.4% (n= 186) of the participants. Women, older patients, and those with lower glomerular filtration rate and higher ejection fraction were more often represented in the group with sodium intake ≤1500 mg/day; conversely, diabetes, prior smoking, use of mineralocorticoid receptor antagonists, and ICD were observed in the groups of higher sodium intake levels (>3000 mg/day)(Table 1). Cox proportional hazard regression analysis showed no association between sodium level (per doubling) at baseline with clinical outcomes (all associations p=ns), however, adjusted models exhibited a trend towards a decreased risk of CV hospitalizations at 2 years. In the responder analysis, a trend towards a decreased adjusted risk for composite outcome and CV hospitalizations at 1 year in those achieving a sodium level <1500 mg at 6 months was observed (Table 2). Adjusted Cox proportional hazard regression analysis showed no association for 1- and 2-year outcomes per 500 mg increase in absolute difference in sodium level between baseline and 6 months.

Conclusion

In SODIUM HF, there was no association between sodium level at baseline with clinical outcomes at any time point but there is a trend towards a decreased risk of CV hospitalizations at 2 years and in patients achieving <1500 mg / day by 6 months, a trend towards fewer subsequent clinical events was present. This finding should be explored via a prospective clinical trial.Baseline characteristics of populationOutcomes
Trends of phosphorus levels after intravenous administration of ferric carboxymaltose
Authors: Borrellas A , Domingo M , Lupon J , Pulido A , Gonzalez B , Rivas C , Velayos P , Bares D , Diaz V , Crespo E , Martinez S , Codina P , Santiago-Vacas E , Cediel G , Bayes-Genis A
Published: November 2023

Background

Iron deficiency and anaemia are present in a large number of patients with heart failure. Intravenously ferric carboxymaltose (FCM) is the recommended treatment, but it may be associated with hypersensitivity reaction and hypophosphatemia, the later mainly in subjects with normal renal function. The prevalence of hypophosphatemia driven by FCM in patients with heart failure (HF) is not well established.

Purpose

To assess the prevalence and trends of serum phosphorus levels after FCM administration in outpatients with HF.

Methods

Prospective, observational, consecutive, and descriptive study of patients admitted in a HF clinic eligible to receive FCM between January 2022 and June 2022. Phosphorus and calcium homeostasis regulators (magnesium, vitamin D, parathyroid hormone, alkaline phosphatase) were drawn at baseline and after 3 weeks of the infusion. In those patients with documented hypophosphatemia after iron administration, a third measurement was performed at three months from baseline. Paired T-test was used to compare mean values and logistic regression to predict relationship of changes in serum phosphorus with other factors.

Results

101 patients were included (71.5 ± 10.6 years, 31.7% women, LVEF 43.9 ±11.9%, 49.5% of ischaemic aetiology, glomerular filtration rate 39.44 ±10 mL/min/m2). Mean baseline phosphorous was 3.64 ± 0.66 mg/dL, declining to 2.74 ±0.88 mg/dL (p for trend = 0.001). Calcium, magnesium, and vitamin D also showed a post-infusion declining tendency (p = 0.001, p = 0.05 and p= 0.002, respectively), whereas PTH significantly increased (p = 0.015). At three weeks, 38 (37.6%) patients had phosphorous levels below the normal threshold (mean 2.15 ± 0.76 mg/dl), which normalized at three months from baseline (mean 3.12 ±0.77 mg/dl; p = 0.71) without specific treatment. Figure 1 shows phosphorus dynamics of the 38 patients with infusion hypophosphatemia. There was no predicted correlation between FCM dose, glomerular filtration rate and phosphorous trends (p = 0.627, P = 0.234 respectively). No clinical adverse event was reported.

Conclusion

Ferric carboxymaltose infusion in patients with HF is associated with a decline in circulating phosphorous, with 1 in 3 patients showing frank hypophosphatemia. This effect is transient and does not require treatment nor active phosphorus monitoring.Trends of hypophosphatemia
Similar heart failure hospitalization and survival benefits are associated with Sacubitril/Valsartan therapy in CRT non responders and in HFrEF patients with no CRT indication
Authors: Szabo K , Toth A , Racz V , Szuromi L , Nagy L , Barta J , Borbely A , Csanadi Z
Published: November 2023

Background

Sacubitril/Valsartan (S/V) induced reverse remodelling and improved heart failure (HF) hospitalisation and survival in HF with reduced ejection fraction (HFrEF) in recent trials. Data on the clinical effectiveness of S/V in the specific HF patient cohort of CRT non-responders (CRT-NRs) are limited.

Aim of the study: Herein, we compared the impact of S/V on hospitalisation and mortality in CRT-NRs and in HFrEF patients with no CRT indication. In addition, we evaluated the outcome in patients with versus without a more marked response to S/V therapy.

Methods

Database search was performed to identify patients based on the following criteria. Group I: Patients implanted with a CRT pacemaker or ICD who demonstrated a less than 10% increase in left ventricular ejection fraction (LV EF) 6 months after device implantation on optimal medical therapy (CRT-NRs). In addition, these CRT-NRs were initiated on S/V as a replacement of ACEi/ARB therapy at least 6 months after device implantation. Group II: HFrEF patients with no CRT indication initiated on S/V. Patents were on S/V treatment at least for 6 months in both groups. Hospitalization and mortality rates were compared in both groups during follow-up. A subgroup analysis was also performed based on the improvement in LV EF on S/V. Patients with a more than 10% improvement were defined as S/V Super-responders, while those with a less than 10% increase as S/V Moderate responders.

Results

70 patients were enrolled in Group I, and 135 in Group II. During a follow-up of 21.9±1.6 no significant differences were detected in the rates of hospitalization (31% vs 28%; p:0.742) and mortality (18.5% vs 17.2%; p = 0.456) in Group I and II, respectively. In group I, 13 (18.5%), and in Group II, 24 (17.7%) patients were identified as SV Super-responders. Rates of hospitalization were similar in S/V Super-responders and in SV Moderate responders in Group I (23.1% vs 31,6%, p = 0.464) as well as in Group II (25% vs 30.7%, p = 0.602). Mortality rates were similar, alike in in S/V Super-responders and in SV Moderate responders in both groups (Group I:15.4% vs 24.6%, p = 0.320, Group II: 20.8% vs 25.3%, p = 0.789).

Conclusion

Similar hospitalization and mortality rates were demonstrated on S/V in CRT-NR and in HFrEF patients with no CRT indication during a 21-month follow-up. A more than 10% increase of LV EF on S/V treatment did not predict improved hospitalization and survival as compared to a more moderate response in either group.
Statin and risk of dementia in patients with heart failure
Authors: Ren Q W , Chan H C , Tse Y K , Wu M Z , Xu X , Yiu K H
Published: November 2023

Background

Non-cardiovascular morbidity and mortality of heart failure (HF) patients rose immensely in recent years, with dementia emerging as one of the key comorbidities. Our study aims to investigate the association between statin use and the risks of dementia and its subtypes in HF patients.

Methods

104 295 patients with incident HF diagnosis from 2004 to 2018 were identified and followed up until December 2020. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates between statin users (N = 54004) and non-users (N = 50291). The primary outcomes were incident all-cause dementia, including subtypes of Alzheimer’s disease, vascular dementia, and unspecified dementia. Cox proportional-hazard model with competing risk regression was performed to estimate the sub-distribution hazards ratio (SHR) with corresponding 95% confidence intervals (CI) of the risks of all-cause dementia and its subtypes that are associated with statin use.

Results

Of all eligible HF patients, the mean age was 74.2 ±13.6 years old and 52,511 (50.3%) were male. Over a median follow-up of 9.9 years (interquartile range [IQR]: 6.4 to 13.0), 10,031 (9.6%) patients were diagnosed with dementia, among which Alzheimer's disease (N = 2,250), vascular dementia (N = 1,831), and unspecified dementia (N = 5,950) were quantified separately. After IPTW, statin use was associated with a 20% lower risk of incident dementia compared with non-use (multivariable-adjusted SHR 0.80, 95% CI 0.76 to 0.84). Stratified by subtypes of dementia, statin use was associated with a 27% lower risk of Alzheimer’s disease (SHR 0.72, 95%CI 0.63 to 0.82), 18% lower risk of vascular dementia (SHR 0.82, 95%CI 0.70 to 0.95), and a 20% lower risk of unspecified dementia (SHR 0.80, 95%CI 0.75 to 0.85).

Discussion

In patients with HF, statin use was associated with a significantly lower risk of all-cause dementia and its subtypes, including Alzheimer’s disease, vascular dementia, and unspecified dementia.
Mediators of the benefit of sotagliflozin in patients with worsening heart failure in SOLOIST-WHF
Authors: Szarek M , Bhatt D , Steg P G , Davies M J , Pitt B
Published: November 2023

Background

In SOLOIST-WHF, the dual SGLT1 and SGLT2 inhibitor sotagliflozin (SOTA) reduced primary endpoint events – total occurrences of cardiovascular (CV) death and hospitalizations and urgent visits for heart failure (HF) – by 33% relative to placebo (PBO) among 1222 patients hospitalized for worsening HF. The extent to which treatment group differences in biomarkers assessed during study follow-up contributed to this benefit of SOTA is unknown.

Purpose

The contributions of 20 biomarkers (identified in published mediation analyses of SGLT2 inhibitors: HbA1c; weight; BMI; systolic and diastolic BP; heart rate; serum creatinine, urate, albumin, sodium, and magnesium; eGFR; hematocrit; hemoglobin; erythrocytes; total cholesterol; LDL-C; HDL-C; non-HDL-C; triglycerides) to the reduction of primary endpoint events by SOTA relative to PBO were quantified via mediation analyses to describe the mechanisms of SOTA.

Methods

Patients were randomized 1:1 to SOTA 200 mg/day (with possible increase to 400 mg/day) or PBO and followed for a median 9 months. Two conditions must be met for a biomarker to be a mediator: there had to be a treatment group difference on the biomarker and an association between the biomarker and risk of primary endpoint events. For the first condition, treatment group differences in change from baseline in each biomarker were analyzed by mixed effects repeated measures models. For the second condition, time-varying values of each biomarker were related to the risk of primary endpoint events by calculating the time-weighted moving average (TWMA) for each variable, using all values for a given patient. Each was analyzed in a competing risks marginal model for total events (stratified according to left ventricular ejection fraction at baseline and geographic region of enrollment), in which non-CV deaths were treated as competing terminal events and TWMA values were included as a time-varying covariate. The individual and joint mediation of those biomarkers determined to be mediators were assessed in competing risks marginal models that included treatment assignment. If biomarkers that would otherwise be included in multivariable models were strongly correlated (baseline values R2>0.5), the marker with the greatest univariate mediation was included. All analyses were intention-to-treat.

Results

Among the biomarkers considered, serum urate, hemoglobin, and total cholesterol met the criteria for being mediators. Serum urate was the strongest single mediator, while the joint mediation for these three biomarkers was 22.3% (Figure 1).

Conclusion

In SOLOIST-WHF, a fraction of the benefit of SOTA was attributable to effects on biomarkers accounting for most of the treatment benefits of other SGLT2 inhibitors on CV death and HF events. Further investigation is therefore needed to identify what unique biomarker treatment effects might account for the majority of SOTA benefit.Figure 1
Safety, tolerability, and pharmacokinetics of AZD5462, a small molecule agonist of the RXFP1 relaxin receptor
Authors: Rosenmeier J , Connolly K , Matsson E , Astrand M , Althage M , Pettersen D , Whittaker A , Turton M , Kujacic M , Gabrielsen A
Published: November 2023

Introduction

Despite multiple new drug advancements for patients with heart failure in recent years (specifically, sodium-glucose co-transporter-2 and sacubitril/valsartan), morbidity and mortality remain high. AZD5462 is a selective RXFP1 agonist which mimics the pregnancy hormone relaxin and its actions on systemic hemodynamics and kidney function.

Purpose

To assess the safety, tolerability, and pharmacokinetics (PK) of AZD5462 in a first-in-human study following single ascending dose (SAD) and multiple ascending dose (MAD) administration in healthy participants.

Methods

This was a phase 1 randomized, double-blind, placebo-controlled study. The SAD evaluated doses of 20, 80, 400, 750, and 1000 mg across 7 cohorts, with 2 cohorts comprising solely participants of Japanese descent. The MAD evaluated doses of 40, 120, 250, and 500 mg BID for 10 days across 5 cohorts, with 1 cohort of Japanese descent. There were approximately 8 participants in each cohort, randomized 6:2 to AZD5462 or placebo. AZD5462 was administered as an oral liquid solution.

Results

Overall, 98 participants were randomized and 92 completed the study (56 of 56 in SAD; 36 of 42 in MAD). The majority of participants randomized were male, and the median age was 39 years in the SAD and 36 years in the MAD. There were no major safety and tolerability concerns up to the highest dose administered (1000 mg SAD; 500 mg BID MAD). Pre-specified study stopping criteria were not met. There were no deaths or other serious adverse events. AEs were more common in the pooled AZD5462 group than placebo (approximately 40% for AZD5462 and 20% for placebo). The most common AEs were GI disorders (nausea, abdominal pain, vomiting), headache, medical device site dermatitis, and orthostatic heart rate response increase, but without clear relationship to dose. Three participants discontinued the MAD due to dizziness, supraventricular tachycardia, and positive COVID-19 test. There was no clear pattern in the effect on SBP with 120 mg and higher doses in the MAD. There was a trend for DBP decrease but no signs of hypotension. HR increased in all cohorts, which was dose-dependent in SAD but without clear relationship to dose in MAD. Treatment with AZD5462 led to a dose-dependent increase in plasma renin in all but the lowest SAD dose. AZD5462 was rapidly absorbed with a median Tmax between 0.53 hr and 1.75 hr. Plasma concentrations declined in a biphasic manner, with a geometric mean terminal half-life after a single dose between 3 h and 6 h. The exposure to AZD5462 increased more than proportionately with dose.

Conclusions

AZD5462 was generally well tolerated at all dose levels in this phase 1 study. These data pave the way for development of a chronic oral relaxin therapy for patients with heart failure.
Heart rate reduction and outcomes in heart failure outpatients
Authors: Memenga F , Rybczynski M , Gossling A , Kirchhof P , Kondziella C , Fluschnik N , Blankenberg S , Berisha F , Bernadyn J , Bremer W , Becher M , Magnussen C , Knappe D
Published: November 2023

Aim

Pharmacologic reduction of heart rate (HR) with beta blockers (BB) and/or ivabradine has been associated with improved survival in patients with heart failure (HF) in sinus rhythm. We analyzed the impact of different HR-reducing drug treatments on outcomes in a cohort of outpatients with heart failure (HF).

Methods

Consecutive patients with HF and sinus rhythm (SR) referred to a specialized tertiary HF service offering advanced therapy options including assist device and heart transplantation were prospectively enrolled from August 2015 until March 2018. Clinical characteristics were assessed at baseline. We performed Cox regression analyses to examine the effect of the resting HR and the drug regimen (BB in submaximal dose [group 1], BB in maximum tolerated dose [group 2], or BB in maximum tolerated dose plus ivabradine [group 3]) on all-cause mortality and a combined, disease-related endpoint of "death from any cause or heart transplantation".

Results

Of 278 patients included, 213 (76.6%) were male. Median age was 57.0 years (interquartile range 49.0-66.1). HF was due to non-ischemic origin in 167 patients (60.1%). HFrEF was present in 185 patients (73.7%). There was a decent use of guideline-recommended HF medication (MRA in 82%, RAS blocker [ARNI/ACEI/ARB] in 97%). Most patients received treatment with a BB in submaximal [n = 118, group 1], or maximum tolerated dose [n = 136, group 2]. Patients treated with BB in maximum tolerated dose plus ivabradine [n = 24, group 3] were younger (53.0 vs. 58.0 years) and had a lower left-ventricular ejection fraction on echocardiography (EF, 25 vs. 31%) than those without ivabradine.

Over a mean follow-up period of 3.1 years, 30 patients died, and 11 underwent heart transplantation. Upon regression analyses, higher resting HR was associated with an increased risk of death or heart transplantation (hazard ratio HR 1.03 [1.01, 1.06], p = 0.0072, even after adjusting for age and sex. Neither the type of heart rate-reducing therapy (BB with or without ivabradine), nor the dose of BB or ivabradine affected outcome.

Conclusion

Our prospective study underlines the importance of heart rate reduction in HF with SR but failed to demonstrate a better risk reduction in patients with up-titrated BB doses or on a combination of BB plus ivabradine.Study profileKM-curves for the composite endpoint
Effect of sodium-related glucose transporter 2 -Inhibitors on exercise capacity in heart failure patients with reduced ejection fraction, does etiology matter?
Authors: Coppo E , Giraldez Valpuesta A , Gamaza Chulian S
Published: November 2023

Introduction

Recently sodium-related glucose transporter 2 (SGLT2) inhibitors were found to improve cardiovascular outcomes significantly, however their effects on exercise capacity are yet unclear.

Aim

To assess in patients with heart failure with reduced ejection fraction (HFrEF), if etiology may have a role in treatment response to SGLT2-I and exercise improvement.

Methods

We included patients with a recent diagnosis of HF with ejection fraction ≤ 40%, between June 2014 and September 2022. An exhaustive initial evaluation was performed with laboratory tests, echocardiography, and exercise tolerance test, performing a 6-minute-walking test (6MWT). Patients were reassessed after 6 months, prior treatment optimization. Finally, patients were divided according to the HF etiology into ischemic and non-ischemic, comparing the results between the patients who received SGLT2-i and those who did not.

Results

Among the 462 patients included (275 non-ischemic and 187 ischemic; mean age 64.1 ±14.0 vs 61.9 ± 19.8 years, women 27.5% vs 15.8%), 45 and 41 patients respectively, received treatment with SGLT2-i. In both groups, patients who received SGLT2-i, had a significant higher prevalence of hypertension, dyslipidemia, and diabetes mellitus (Non-ischemic: hypertension 68.9 % vs 50.9%, p = 0.02; dyslipidemia 42.2% vs 25.8%, p= 0.02; diabetes mellitus 55.6% vs 28.3 %, p <0.001; Ischemic: hypertension 68.3% vs 50.3%, p = 0.04, dyslipidemia 75.6% vs 47.9, p< 0.02, diabetes mellitus 78% vs 38.4% p<0.001) and were as well treated with ARNI on a higher percentage (Non-ischemic 35.6% vs 13.9% p< 0.001, Ischemic: 39% vs 17.8%, p = 0.004). In the non-ischemic group, patients treated with SGLT2-i had a higher mean age (68.2±12.2 vs 63.3±14.3; p = 0.03). No other differences were observed between the baseline characteristics and the treatment. Treatment with SGLT2-i improved performance in 6MWT (+32.5 m [95% CI 10.7-54.4]) only in non-ischemic group while no differences have been found in ischemic patients.

Conclusions

Treatment with SGLT2-inhibitors has been associated with an improvement in exercise ability at six months only in patients with HFrEF of non-ischemic etiology whereas in patients with ischemic etiology it has not shown improvement in functional capacity. Our study suggests that, in clinical setting, non-ischemic patients may have a greater benefit with SGLT2-inhibitors treatment in term of exercise capacity.
Acoramidis produces near-complete TTR stabilization in blood samples from patients with variant transthyretin amyloidosis that is greater than that achieved with tafamidis
Authors: Ji A , Wong P , Judge D P , Graef I A , Fox J , Sinha U
Published: November 2023

Introduction

Transthyretin (TTR) amyloidosis (ATTR) is a progressive, fatal disease caused by destabilizing TTR variants (TTRv) and age-related factors. Dissociation of tetrameric TTR initiates protein misfolding, aggregation, and tissue deposition which constitutes the mechanism of disease. More destabilizing variants drive more severe clinical phenotypes. TTR stabilizers have demonstrated clinical benefits for neuropathic and cardiovascular outcomes correlated with the extent of TTR stabilization. Acoramidis (AG10) is a novel TTR stabilizer in development for the treatment of TTR amyloid cardiomyopathy.

Hypothesis: Acoramidis achieves near-complete in vitro TTR stabilization, exceeding levels achieved with clinically relevant concentrations of tafamidis (a TTR stabilizer in clinical use), when added to blood samples from ATTRv patients across a spectrum of destabilizing TTR variants.

Methods

Two established assays assessed TTR stabilization: fluorescent probe exclusion (FPE; measures binding site occupancy), and Western blot (WB; quantifies tetrameric TTR persistence under conditions of accelerated dissociation). Over 60 individual patient samples representing 18 unique TTRv across a spectrum of intrinsic instability and clinical phenotypes were assayed. Acoramidis was added at its target clinical trough concentration (10 µM) and compared to tafamidis added at its clinical peak (26 µM) and trough (16 µM) concentrations reported for its maximal approved dose.

Results

Acoramidis bound serum TTR to a greater extent (103 ± 13%) than either peak (87 ± 14%) or trough (71 ± 14%) concentrations of tafamidis. WB assays showed that addition of acoramidis resulted in significantly greater and more durable TTR stabilization (93 ± 14%) than adding tafamidis (peak: 49 ± 14%, trough: 36 ± 13%) in all paired individual patient plasma samples tested (Figure 1, p < 0.0001). Rare variants (A97S, D38A, F64L, L58H, P24S, Y114C) also demonstrated near complete stabilization upon in vitro addition of acoramidis.

Conclusions

At its target therapeutic trough concentration, acoramidis achieved near-complete TTR stabilization across 18 unique genotypes; in the subset of paired samples, the stabilization was significantly greater for acoramidis than for tafamidis even at its peak clinical concentration. This observation held across a range of destabilizing mutations, including a∼2-fold greater stabilization than tafamidis for the prevalent cardiomyopathic V122I variant. Based on the mechanism of disease and the association between TTR destabilization and severity of clinical outcomes, these data suggest that acoramidis has the potential to be a clinically differentiated and efficacious treatment option for patients with ATTRv, independent of variant genotype.
Beta-blockers effects according to sex: does selectivity and dose equally matter?
Authors: Salvioni E , Paolillo S , Galotta A , Mapelli M , Mattavelli I , Basile C , Vignati C , Moscucci F , Piepoli M , Agostoni P
Published: November 2023

Background

β-blockers are one of the four recommended disease-modifying classes of drugs for the treatment of heart failure with reduced ejection fraction (HFrEF). Although their efficacy and prognostic role is unquestionable in the general population of HFrEF patients, the differences in their effect in relation to sex have not been yet investigated in detail. The present study analyzed a large, real-world, Italian population of HFrEF patients aiming to highlight any prognostic difference between males and females in relation to dose and β-selectivity of the ongoing β-blocker treatment.

Methods

Out of the 7900 HFrEF patients included in the MECKI score registry, we retrospectively analyzed those treated with β-blockers. We investigated the prognostic role of β-selectivity, dividing the population in assuming β1/β2-receptor blockers (carvedilol) vs. β1-selective blockers (bisoprolol, nebivolol or metoprolol), according to sex, and the prognostic role of daily carvedilol-equivalent β-blocker dose in relation to sex. The primary outcome of the study was the composite of all cause mortality, urgent heart transplant and LVAD implant analyzed at 5 years, both as raw data and after correction of potential confounders.

Results

6784 HFrEF patients treated with β-blockers were analyzed (1215 females, 5569 males). Patients median follow-up was 4.05 years [1.72-7.47]: 4.37 [1.6-8.13] for females and 3.99 [1.75-7.3] for males (p=ns). According to β-selectivity no prognostic differences were found in the general population, as in female or males (Fig. 1 right panel). Stratification of patients according to β-blockers equivalent dose showed significant difference among groups: mortality decreases with increasing β-blockers dose in both males and females (Fig. 1, left panel), both at baseline and after adjustment for the main confounders (LVEF, age, peakVO2, systolic pressure, hemoglobin, rest heart rate; VE/VCO2 slope, etiology. ICD, MDRD).

Conclusions

In a large, real-life population of chronic HFrEF patients analyzed according to sex, no prognostic differences were found between stratifying for β-selectivity. A better outcome was observed in subjects receiving a high daily dose, independently from sex.Fig 1Table 1
Evaluation of disease progression in patients with ATTR amyloidosis with cardiomyopathy following treatment with patisiran: post-hoc analysis of the APOLLO-B study
Authors: Damy T , Shah Z , Drachman B , Schwartzmann P , Tinoco Mesquita C , Polydefkis M , Obici L , Jay P , Bender S , Capocelli K , Hanna M
Published: November 2023

Introduction

Transthyretin-mediated (ATTR) amyloidosis is a progressive, fatal disease in which cardiac deposition of transthyretin (TTR) amyloid commonly manifests as cardiomyopathy. Patisiran, an RNA interference therapeutic that reduces TTR synthesis, is approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. The Phase 3 APOLLO-B study (NCT03997383) evaluated the clinical efficacy and safety of patisiran in patients with ATTR amyloidosis with cardiomyopathy (CM).

Purpose

This post-hoc analysis evaluated disease progression in APOLLO-B patients following treatment with patisiran vs placebo, based on the European Society of Cardiology (ESC) expert consensus on monitoring patients with ATTR amyloidosis with CM every 6–12 months using three domains: Clinical/Functional, Laboratory Biomarker, and Imaging/Electrocardiography (ECG).

Methods

Patients with ATTR amyloidosis with CM were randomised (1:1) to intravenous patisiran 0.3 mg/kg or placebo every 3 weeks for 12 months. Disease progression was defined at Month 12 (M12) relative to baseline using Clinical/Functional criteria (≥1 heart failure-related hospitalisation, increased New York Heart Association class ≥1, decline in Kansas City Cardiomyopathy Questionnaire ≥5, or decline in 6-minute walk test ≥30 metres), Laboratory Biomarker criteria (increased N-terminal prohormone B-type natriuretic peptide ≥30% and absolute change ≥300 ng/L, troponin I ≥30%, or ATTR disease stage ≥1), and Imaging/ECG criteria (conduction disturbances or change in left ventricular wall thickness ≥2 mm, change in diastolic dysfunction grade ≥1, or change in systolic function measurements). One marker from each domain provides the minimum criteria for disease progression.

Results

At M12, the patisiran group (N = 180) had improved odds of no disease progression compared with the placebo group (N = 178; odds ratio [OR] 1.4; 95% confidence interval [CI] 0.77, 2.55) (Figure). The patisiran group had benefits in Clinical and Functional markers vs placebo at M12 (OR 1.58; 95% CI 1.03, 2.42). Patisiran also showed favourable changes in Laboratory Biomarkers vs placebo at M12 (OR 2.14; 95% CI 1.33, 3.43) and a favourable trend in Imaging assessments/ECG vs placebo at M12 (OR 1.31; 95% CI 0.80, 2.15).

Conclusion

In this post-hoc analysis of APOLLO-B, fewer patisiran-treated patients had disease progression with respect to clinical, functional, and biomarker parameters vs placebo. The risk of disease progression was lower by Clinical/Functional and Laboratory Biomarker composite criteria, and trended lower by individual criterion from the ESC consensus statement among patisiran-treated patients at 12 months vs placebo patients. Long-term follow-up will further assess the impact of patisiran in patients with ATTR amyloidosis with CM.Figure 1
Survival analysis of tafamidis use in patients with ATTR cardiac amyloidosis
Authors: Starr N , Razvi Y , Bolhuis R E , Hague O , Petrie A , Fontana M , Gillmore J
Published: November 2023

Introduction

Transthyretin cardiac amyloidosis (ATTR-CM) is a condition in which amyloid fibrils are deposited within the myocardium causing a restrictive cardiomyopathy & resulting heart failure condition. With increasing recognition, a challenge posed, surrounds decisions on optimal treatment strategies. For patients with predominant cardiac amyloidosis, without peripheral/autonomic nervous system involvement, targeted treatments are limited, although the medication tafamidis – a TTR stabiliser, is available since approval by the FDA in 2019 & the European commission in 2020.

Aim

This study aims to analyse the real-world benefit of tafamidis use in patients with ATTR-CM attending the National Amyloidosis Centre (NAC), UK with regards overall survival from diagnosis when compared to those not on targeted treatment.

Methods

This was a retrospective study using data taken from a database at the NAC, as all patients included attend the NAC, UK. Patients on tafamidis were matched to control patients (not on targeted treatment) for age, ATTR NAC stage at diagnosis and type of ATTR (i.e. variant or wild-type). Outcome and survival analysis were determined using cox regression analysis and Kaplan-Meier curve using SPSS (V9.0).

Results

The demographics of patients in both groups are detailed in figure 1. There were 75 patients in both the treatment & control groups. The median follow-up time from diagnosis to data acquisition in the control group was 3.7 years [IQR1.8-5.8] compared to 4.3 years [IQR 3.6-5.4] in the treatment group (p = 0.03). Of note the median duration from diagnosis to starting tafamidis was 2.1 years [1.2-3.2]. Using cox regression analysis, tafamidis use was predictive of a reduced likelihood of death (R = -1.4, p<0.001) [OR 0.24 95%CI 0.12-0.47]. Increasing NAC stage at diagnosis (R = 0.42, P = 0.03), [OR1.5, 95%CI 1.04-2.22] was predictive of increased likelihood of death. Increasing age (R = 0.03, p = 0.07) [OR 1.03, 95%CI 0.98-1.07] was non-significantly associated with increased likelihood of death. There was similarly a significant increase in mortality within the control/non-treatment group of patients (P<0.001) which was reflected in the Kaplan-Meier survival curve (p<0.001).

Conclusions

In this retrospective analysis, tafamidis use in 75 patients with ATTR-CM, initiated after a median of 2.2 year [IQR1.2-3.2] following diagnosis, was associated with significantly reduced mortality when compared to an untreated matched control group. Survival from diagnosis was similarly improved in the tafamidis group as depicted by the Kaplan-Meier curve. This real-world data suggests support for the use of tafamidis in treating those with ATTR-CM.
Non-adherence to prescribed medications in ambulatory patients with heart failure assessed using liquid chromatography tandem mass spectrometry
Authors: Sze S , Lane D , Krishnan S , Clark A L , Gupta P , Squire I B
Published: November 2023

Background

Reported rates of medication non-adherence in patients with heart failure (HF) vary widely, ranging between 5-60%, depending on the method of assessment. Very few studies have assessed non-adherence objectively by measuring the plasma level of medications or metabolites; the true prevalence of medication non-adherence in HF patients is unknown.

Objectives

To report prevalence and clinical associates of medication non-adherence in a cohort of ambulatory HF patients assessed using liquid chromatography–tandem mass spectrometry analysis of plasma levels of prescribed, evidence-based treatments.

Methods

We assessed adherence in 172 consecutive patients with HF attending a routine clinic follow-up visit. We used liquid chromatography-tandem mass spectrometry to measure the presence of prescribed medications (angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blocker (ARB), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), diuretics and digoxin) in plasma samples collected during the visit. No patient knew in advance that the blood test would be used to assess adherence.

Results

69% were male; median (IQR) age 76 (67-82) years; median NTproBNP 1036 (433-2340) ng/L; 62% HF with reduced ejection fraction (HFrEF, LVEF <40%). 1 in 5 patients had severe symptoms (NYHA III/IV) and 38% patients had Clinical Frailty Scale ≥ 5.

120 (70%) had all prescribed medications of interest detectable in plasma; in 52 (30%) patients, at least one prescribed medication was not detected. In none of the patients were no prescribed medications detected (Figure 1).

Among the 125 patients prescribed diuretics, 18 (14%) were non-adherent. Among the 106 patients with HFrEF, 25 (24%) were at least partially non-adherent to a disease modifying medication (ACEi/ ARB/BB/MRA). Amongst medication groups studied, the highest non-adherence rate was with ACEi/ARB and diuretics (14% for each) (Figure 2).

Comparing non-adherent patients to those who were adherent, there was no significant difference in age, sex or number of medications prescribed. Frailty was more common in the non-adherent compared to adherent group (46% vs 34%). Systolic/ diastolic blood pressure and heart rate were higher in non-adherent patients [median (IQR) SBP: 150 (137-174) vs 140 (125-164) mmHg; median (IQR) DBP 80 (69-89) vs 75 (64-83) mmHg; median (IQR) HR 76 (67-85) vs 69 (60-77) mmHg, each p<0.05]. NTproBNP tended to be higher in those who were non-adherent [median (IQR): 1309 (673-2302) vs 891 (353-2391) ng/L].

Conclusion

Medication non-adherence, assessed using a single spot plasma measurement of medication levels, appears to be common in ambulatory patients with HF. 1 in 3 patients were at least partially non adherent to prescribed medications. Our observations have implications for the assessment and management of patients with HF.
Balloon surface temperature–controlled ablation using a second-generation radiofrequency HotBalloon: an in vivo feasibility study
Authors: Shinoda Yasutoshi , Yamasaki Hiro , Murakoshi Nobuyuki , Kohno Tsunesuke , Yamane Teiichi , Aonuma Kazutaka , Ishizu Tomoko
Published: November 2023

Aims

The first-generation radiofrequency HotBalloon (RHB) is a size-adjustable single-shot device used in atrial fibrillation. The energy output is determined by its central temperature and not by its balloon surface temperature (BST), thus limiting its efficacy and safety. Therefore, a second-generation RHB was developed to monitor BST and enable BST-controlled ablation. This animal study aims to evaluate the accuracy of a newly developed BST-monitoring system and validate the optimal BST for ablation.

Methods and results

In Protocol 1, thermocapsules were attached to the superior vena cava (SVC) epicardium. The accuracy of BST monitoring was examined during SVC isolation. In Protocol 2, the efficacy and safety of different BST-controlled ablations were examined. In the acute model, electrophysiological and pathological findings were assessed after energy applications with BST at 51, 54, 57, and 60°C. In the chronic model, the lesion durability and pathological findings were assessed 8 weeks after BST-controlled ablation (57 and 60°C). A significant positive correlation was found between the epicardial temperature and the BST-monitoring value (r = 0.98). In the acute model, all target veins were electrically isolated with BST-controlled ablation at ≥57°C (18/18, 100%). In the chronic model, durable lesions were observed in all veins at 60°C, while 44% of the veins showed reconnection at 57°C. In both pathological analyses, significantly greater lesions were observed at 60°C than at 57°C. There were no significant differences in adverse events between the two groups.

Conclusion

Balloon surface temperature–controlled ablation at 60°C using the second-generation RHB may be optimal for creating durable lesions without compromising safety.
Massive contractions of myotonic dystrophy type 2-associated CCTG tetranucleotide repeats occur via double-strand break repair with distinct requirements for DNA helicases
Authors: Papp David , Hernandez Luis A , Mai Theresa A , Haanen Terrance J , O’Donnell Meghan A , Duran Ariel T , Hernandez Sophia M , Narvanto Jenni E , Arguello Berenice , Onwukwe Marvin O , Mirkin Sergei M , Kim Jane C
Published: November 2023

Myotonic dystrophy type 2 (DM2) is a genetic disease caused by expanded CCTG DNA repeats in the first intron of CNBP. The number of CCTG repeats in DM2 patients ranges from 75 to 11,000, yet little is known about the molecular mechanisms responsible for repeat expansions or contractions. We developed an experimental system in Saccharomyces cerevisiae that enables the selection of large-scale contractions of (CCTG)100 within the intron of a reporter gene and subsequent genetic analysis. Contractions exceeded 80 repeat units, causing the final repetitive tract to be well below the threshold for disease. We found that Rad51 and Rad52 are involved in these massive contractions, indicating a mechanism that uses homologous recombination. Srs2 helicase was shown previously to stabilize CTG, CAG, and CGG repeats. Loss of Srs2 did not significantly affect CCTG contraction rates in unperturbed conditions. In contrast, loss of the RecQ helicase Sgs1 resulted in a 6-fold decrease in contraction rate with specific evidence that helicase activity is required for large-scale contractions. Using a genetic assay to evaluate chromosome arm loss, we determined that CCTG and reverse complementary CAGG repeats elevate the rate of chromosomal fragility compared to a short-track control. Overall, our results demonstrate that the genetic control of CCTG repeat contractions is notably distinct among disease-causing microsatellite repeat sequences.
Whole Genome Assembly and Annotation of Blackstripe Livebearer Poeciliopsis prolifica
Authors: Zhang Ying , Reynoso Yuridia , Reznick David , Wang Xu
Published: November 2023

The blackstripe livebearer Poeciliopsis prolifica is a live-bearing fish belonging to the family Poeciliidae with high level of postfertilization maternal investment (matrotrophy). This viviparous matrotrophic species has evolved a structure similarly to the mammalian placenta. Placentas have independently evolved multiple times in Poeciliidae from nonplacental ancestors, which provide an opportunity to study the placental evolution. However, there is a lack of high-quality reference genomes for the placental species in Poeciliidae. In this study, we present a 674 Mb assembly of P. prolifica in 504 contigs with excellent continuity (contig N50 7.7 Mb) and completeness (97.2% Benchmarking Universal Single-Copy Orthologs [BUSCO] completeness score, including 92.6% single-copy and 4.6% duplicated BUSCO score). A total of 27,227 protein-coding genes were annotated from the merged datasets based on bioinformatic prediction, RNA sequencing and homology evidence. Phylogenomic analyses revealed that P. prolifica diverged from the guppy (Poecilia reticulata) ∼19 Ma. Our research provides the necessary resources and the genomic toolkit for investigating the genetic underpinning of placentation.