bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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.
Soluble guanylate cyclase in heart failure: A network meta-analysis and subgroup analyses of reduced and preserved ejection fraction
Authors: Abuelazm M , Attia A M , Albakri K , Jafar U , Almaadawy O , Elzeftawy M A , Mahmoud A , Ibrahim M , Abdelazeem B
Published: November 2023

Background

Heart failure (HF), either with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), is a significant healthcare burden, with about one million hospitalizations annually in the United States alone. Soluble guanylate cyclase (sGC) stimulators have been investigated for HF treatment in several randomized controlled trials (RCTs). However, its place in the management guidelines of either HFrEF or HfpEF is still inconclusive.

Purpose

We aim to evaluate the efficacy and safety of sGC in HF and determine the most effective agent and dosage for the management of either HFrEF or HFpEF.

Methods

We conducted a systematic review and network meta-analysis synthesizing RCTs investigating sGC, including vericiguat, riociguat, and praliciguat for HF management, which were retrieved by systematically searching five databases until January 24th, 2023. Dichotomous outcomes were pooled using risk ratio (RR) along with confidence interval (CI). Frequentist random-effects network meta-analysis was conducted via R software using meta and netmeta packages.

Results

Eight RCTs with a total of 7307 patients were included in our analysis. Four RCTs investigated vericiguat, three investigated riociguat, and another investigated praliciguat. Five RCTs investigated HFpEF patients, and three investigated HFrEF patients. Vericiguat 10 mg significantly reduced the incidence of composite cardiovascular (CVS) mortality and HF hospitalization in HF (RR: 0.88, 95% CI [0.79; 0.98], P = 0.02) and in HFrEF (RR: 0.87, 95% CI [0.78; 0.97], P = 0.02); however, it was not effective in HFpEF (RR: 0.69, 95% CI [0.15; 3.05], P = 0.62). Also, vericiguat 10 mg showed no difference compared to placebo regarding the incidence of all-cause mortality (RR: 0.96, 95% CI [0.84; 1.10], P = 0.57), any adverse events (AEs) (RR: 0.94, 95% CI [0.83; 1.07], P = 0.34), any serious AEs (RR: 0.91, 95% CI [0.81; 1.01], P = 0.08), and any AEs leading to drug discontinuation (RR: 1.14, 95% CI [0.92; 1.40], P = 0.23). However, all other comparisons of vericiguat, riociguat, and praliciguat showed no difference compared to placebo regarding the composite CVS mortality and HF hospitalization, with a similar safety profile.

Conclusion

Only vericiguat 10 mg was effective in reducing the incidence of the composite CVS mortality and HF hospitalization in patients with HFrEF, with an acceptable safety profile. However, this observation is mainly weighted by the VICTORIA trial, constituting 69.2% of our analyzed sample size, which investigated vericiguat 10 mg in patients with HFrEF. Therefore, our data regarding other agents (riociguat and praliciguat) and HFpEF can be underpowered. This warrants further RCTs to clarify vericiguat 10 mg place in HFrEF management guidelines and to investigate sGC stimulators for HFpEF in large-scale adequately designed trials.Figure 1Figure 2
Initiation, titration, and discontinuation - utilization of heart failure medicines in England (EVOLUTION HF UK)
Authors: Zhang R , Mamza J B , Baruah R , Adamsson Eryd S , Bodegard J , Cleland J G F
Published: November 2023

Background

Guidelines advise early initiation and optimisation of several guideline-recommended pharmacological therapies (GRPTs) for managing heart failure (HF) with reduced ejection fraction. Recent guidelines have expanded this list to include two new classes of agents: sodium-glucose cotransporter 2 (SGLT2) inhibitors and angiotensin receptor neprilysin inhibitor (ARNI). Auditing real-world GRPT use is critical in closing the evidence-practice gap.

Purpose

To generate insights into utilization patterns of novel and established GRPTs after a recent hospitalization for HF (hHF) in England using administrative healthcare records.

Methods

New users of GRPTs within 12 months of a hHF discharge were identified using linked national electronic health records (Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics mortality data) between January 2021 — May 2022. Time to initiation of dapagliflozin (the only SGLT2 inhibitor approved for HF in January 2021), sacubitril/valsartan, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were considered separately. Titration and discontinuation of the most frequently used drug for each pharmacological class was identified and analysed as representative of the entire class. Doses and discontinuation were assessed in the 12 months following initiation. If a new package isn't collected after the previous one ends, discontinuation is assumed until a new package is collected. Target dose was defined as ≥100% of the guideline-recommended dose.

Results

Overall, 16,090 new users of GRPTs were identified. Mean times from hHF to GRPT initiation were longer for novel agents (dapagliflozin or sacubitril/valsartan) than for established agents: 195 and 137 vs 48 to 73 days. Similarly, the cumulative percentage of patients initiating a GRPT within 100 days of hHF discharge were lower for novel agents (Figure 1). In the following 12 months, the average target dose achieved was higher for novel agents: 61.8% (dapagliflozin), 32.4% (sacubitril/valsartan), 8.5% (ACE inhibitor: ramipril), 5.9% (ARB: candesartan), 7.6% (beta-blocker: bisoprolol), and 6.6% (MRA: spironolactone). Corresponding discontinuation rates were 32.0%, 24.3%, 36.3%, 38.2%, 23.4%, and 50.1%, respectively (Figure 1 and 2).

Conclusion

In the UK, early initiation of novel GRPTs after recent hHF in routine clinical practice remains a challenge. For GRPTs requiring uptitration, few patients received the target dose in the 12 months after initiation, and many discontinued treatments. Conversely, dapagliflozin was associated with relatively higher rates of target dose achievement, perhaps because only a single fixed dose is recommended. Our data highlight the need for increased access to appropriate, timely and sustained HF therapeutic optimization.
The role of infliximab in treating refractory cardiac sarcoidosis
Authors: Ahmed R , Okafor J , Azzu A , Shi R , Wechalekar K , Baksi J , Collins P , Khattar R , Sharma R , Wells A , Kouranos V
Published: November 2023

Introduction

Cardiac sarcoidosis (CS) is associated with therapeutic challenges, and a high morbidity and mortality. Tumour necrosis factor alpha inhibitors like infliximab may be a treatment option for patients with persistent myocardial inflammatory activity despite conventional immunosuppressive treatment with steroids and steroid-sparing agents.

Purpose

To identify the safety and efficacy of infliximab in the treatment of refractory cardiac sarcoidosis.

Methods

We conducted a review of refractory CS patients who had been or were actively on treatment with Infliximab at our specialist tertiary care hospital from January 2017 to January 2023. Serial echocardiographic and FDG-PET scan changes as well as long term clinical data on morbidity and mortality was recorded.

Results

Six CS patients on infliximab were retrospectively identified. The mean age at CS diagnosis was 47.0±5.9 years and mean duration between CS diagnosis and starting infliximab was 21.4±14.2 months (Table 1). Infliximab was commenced due to persistent inflammation on FDG-PET scan and/or CMR despite being on at least two agents (prednisolone and methotrexate ± hydroxychloroquine) in 5 cases and prednisolone alone (intolerance to methotrexate) in one case. At baseline, 3 patients presented with ventricular arrhythmias, 2 with atrioventricular block and 2 with heart failure. After a mean follow up of 21.2±15.5 months of being on infliximab, 5/6 CS patients had decreased myocardial uptake on PET (1 was awaiting a scan) which included complete resolution of FDG-PET signal in one patient (Table 2). A trend in improvement of mean LVEF [52.7±6.6% to 60.2±5.9%, p = 0.10] and reduction of mean prednisolone dose [19.2±6.6mg to 11.3±7.0mg, p = 0.08] was observed during Infliximab treatment. None of the patients had worsening of LVEF or admission with acute heart failure whilst being on infliximab. A total of 4/6 patients had an Implantable Cardioverter Defibrillator device in situ at the time of Infliximab initiation. No major arrhythmias were observed during follow up. One patient died following complications of patent foramen ovale repair. There were three new cases of infection (1 pneumonia and 2 COVID-19 pneumonitis) and one case of renal cell carcinoma diagnosis three years after Infliximab treatment initiation. The drug safety was overall satisfactory since none of the patients required hospitalisation (Table 2). Case 2 patient stopped infliximab after 13 months of treatment and was found to have disease relapse seven months later. During a 20 month follow up of being on infliximab again, he demonstrated complete resolution of FDG uptake on subsequent FDG-PET scan.

Conclusion

This study supports the use of infliximab in refractory CS by demonstrating improvement in clinical, functional and tissue characterization parameters. However, infliximab is associated with an increased risk of infections.
Influence of background therapy on efficacy of dapagliflozin in patients with heart failure and improved ejection fraction
Authors: Pabon Porras M A , Clagget B L , Chatur S , Bhatt A S , Vaduganathan M , Fang J , Desai A , Jhund P , Martinez F , De Boer R , Kosiborod M , Lam C , Mcmurray J , Solomon S , Vaderny O
Published: November 2023

Introduction

Heart failure with improved ejection fraction (HFimpEF), defined as prior reduced left ventricular EF (LVEF) ≤40% with a subsequent measurement LVEF >40%, is growing in prevalence, in part because of effective guideline directed medical therapy (GDMT) initiated when LVEF was ≤40%. These patients have been largely excluded from major HF clinical trials. The DELIVER trial demonstrated dapagliflozin to be beneficial in patients with symptomatic HFimpEF; whether this benefit differs by background medical therapy is unclear.

Purpose

We investigated the efficacy and safety of dapagliflozin in patients with HFimpEF by background HF GDMT (beta-blocker [BB], mineralocorticoid receptor antagonist [MRA], and ACEi/ARB/ARNI at baseline).

Methods

The DELIVER trial randomized patients with symptomatic heart failure and LVEF>40% to dapagliflozin or placebo. Treatment effects on the primary endpoint, worsening heart failure or cardiovascular (CV) death, and its components were assessed by a GDMT composite score. We assigned 1 point each for baseline use of ACEi/ARB, evidence-based BB, or MRA, and 2 points for sacubitril/valsartan. The composite GDMT score could range from 0 (no GDMT) to 4 (triple therapy inclusive of sacubitril/valsartan).

Results

Among the 6,263 patients randomized, 1,151 (18%) had HFimpEF. Of those, 2% of patients were on no GDMT, 14% were on 1 GDMT, 47% were on 2 GDMT therapies, and 37% were on triple therapy at baseline (Figure 1). Patients treated with triple therapy, compared to those on less than 3 therapies, were younger, more likely male, have a history of myocardial infarction, less likely to have diabetes, had a lower baseline LVEF and systolic blood pressure, and higher eGFR. During 2.2 years of median follow-up, the incidence rate was 9.8 per 100 person-years among those on 1 or no medications at baseline compared with 8.6 per 100 person-years among those on 2 or 3 therapies. Relative benefits of dapagliflozin on the primary outcome were not significantly modified by baseline GDMT score (Pinteraction = 0.11), but absolute benefits appeared more pronounced in those receiving 1 or no medications at baseline (Figure 2). Serious adverse events were well-balanced between treatment arms in the HFimpEF cohort, including among those already treated with triple therapy.

Conclusions

In patients with HFimpEF, the benefits of dapagliflozin are similar irrespective of background GDMT. Dapagliflozin was safe and did not lead to higher risk of adverse events among those with HFimpEF, including those already treated with triple therapy.Figure 1Figure 2
Efficacy of sodium-glucose cotransporter 2 inhibitors on cardiorenal outcomes in older patients: a systematic review and meta-analysis
Authors: Yamashita I , Fujisaki T , Romeo F J , Fujisue K , Sueta D , Usuku H , Yamamoto E , Tsujita K
Published: November 2023

Background

Recent randomized controlled trials (RCTs) showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiorenal outcomes in patients with increased risks of cardiovascular diseases. However, only limited data from subgroup analyses are available for older patients.

Methods

A systematic review was performed by searching PubMed, Cochran Central, and Embase through February 2023 for RCTs of SGLT2 inhibitors that were performed in adults and large (≥500 participants per group). Hazard ratios (HRs) and relative risk estimates in older subgroups ≥ 65 years were extracted from each study and were pooled using a random-effects meta-analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The secondary outcomes were heart failure exacerbation, adverse renal outcomes, and a composite outcome of cardiovascular death or heart failure exacerbation.

Results

This study included 10 RCTs. SGLT2 inhibitors decreased the primary outcome but it did not reach statistical significance in older subgroups (HR, 0.86; 95% CI, 0.73-0.1.00, p = 0.06). Whereas SGLT2 inhibitors were associated with decreased risks of heart failure exacerbation (HR, 0.76; 95% CI, 0.67-0.87), adverse renal outcome (HR, 0.58; 95% CI, 0.43-0.77), and a composite outcome of cardiovascular death or heart failure exacerbation (HR, 0.76; 95% CI, 0.70-0.83).

Conclusions

SGLT2 inhibitors were associated with improved cardiovascular outcomes in older patients. Further therapeutic data and sufficient long-term safety data are warranted in this population.
Effect of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction treated with beta-blockers: the DELIVER trial
Authors: Peikert A , Bart B A , Vardeny O , Vaduganathan M , Claggett B L , Desai A S , Jhund P S , Kosiborod M N , Lam C S P , Martinez F A , De Boer R A , Hernandez A F , Shah S J , Mc Murray J J V , Solomon S D
Published: November 2023

Background

While beta-blockers are not recommended for the treatment of HFpEF according to the latest ESC and AHA/ACC/HFSA guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers might adversely influence clinical outcomes by limiting chronotropic response in HFpEF.

Purpose

To examine the contemporary use and implications of beta-blocker use in patients with HFmrEF or HFpEF.

Methods

In the DELIVER trial, a total of 6,263 patients with symptomatic HF with LVEF >40% were randomized to dapagliflozin or placebo across 20 countries. Efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF.

Results

Overall, beta-blockers were used in 5,177 patients (83%), with wide variation ranging from Mexico (60%) to Poland (93%). Nearly all patients taking beta-blockers had at least 1 potential indication (n = 5,106 [99%]), such as hypertension (n = 4,623 [89%]), atrial fibrillation/flutter (n= 2,969 [57%]), coronary artery disease (n= 2,744 [53%]), or previous LVEF< = 40% that has since improved (n = 991 [19%]). Beta-blocker use was not associated with a higher risk of the primary outcome in covariate-adjusted models (HR 0.68 [95% CI 0.59-0.80]; Left Panel). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR 0.82 [95% CI 0.72- 0.94]) and those not taking beta-blockers (HR 0.79 [95% CI 0.61-1.03]; P for interaction = 0.85), with similar findings for key secondary endpoints (Right Panel). Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use.

Conclusions

In patients with HFmrEF or HFpEF enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker, with virtually all these patients having at least 1 potential indication for use. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use.
Clinician perceptions and reasons for non-use of guideline-directed medical therapy for heart failure with reduced ejection fraction in the United States
Authors: Gulea C , Coyle C R , Bash L D , Tebbs K W , Hancock L N , Greene S J
Published: November 2023

Background

Despite evidence that guideline-directed medical therapy (GDMT) improves outcomes in heart failure with reduced ejection fraction (HFrEF), many eligible patients remain untreated in the United States (US).

Purpose

To explore reasons why patients are not receiving GDMT and physician perceptions in management of their patients.

Methods

We conducted a cross-sectional survey of HF treatment practices (Adelphi Real World Heart Failure Disease Specific Programme) between August 2022 and February 2023, following publication of the 2022 US HF guidelines recommended that patients with HFrEF receive: angiotensin receptor/neprilysin inhibitors (ARNI), beta-blocker, mineralocorticoid receptor antagonists (MRA), and SGLT-2 inhibitors (SGLT2i). A total of 63 cardiologists and 39 primary care physicians in the US provided clinical and treatment patterns data on adult patients with HFrEF (ejection fraction ≤ 40%) and completed an attitudinal survey detailing reasons for treatment initiation.

Results

The study group included 323 patients with HFrEF (median age of 67 years [IQR 56-74]; 39% females) of which 59.4% were White, 19.8% African American and 9.6% Hispanic; half of the sample was insured by Medicare (50.2%), followed by commercial insurance (36.5%). GDMT prescription rates are presented in Table 1. Overall, 57.3% were not prescribed ARNI (185/323), 16.4% (53/323) were not prescribed a beta-blocker; 71.5% (231/323) were not prescribed MRA, and 65.3% (211/323) were not prescribed SGLT2i. Among patients not receiving GDMT, the most frequently reported physician reason for not prescribing ARNIs (54.1%), beta-blockers (43.4%), MRAs (54.5%) or SGLT-2is (53.6%) was physician deemed the patient to be clinically stable (Table 2).

Most physicians (93.5%) reported being satisfied with treatment for patients with HFrEF and most (80.3%) believed that their patients with HFrEF were fully compliant with their treatments. Most physicians (91.2%) stated that they based their treatment decisions on both clinical experience and laboratory tests, as opposed to laboratory tests/imaging only (9.8%) or personal judgement only (16.7%).

Conclusions

In this cohort of patients with HFrEF from the US, the most common primary reason physicians reported for their patients not receiving GDMT was that the patient was clinically stable. Patient medication costs, contraindications, and proven intolerance were each reported as primary reasons for non-treatment in only a small minority of cases. These data suggest a strong culture of clinical inertia and lack of therapeutic urgency as the dominant driver of large gaps in use of GDMT in the US.GDMT prescriptions in HFrEF (n = 323)Physician-reasons for no GDMT
Device-measured physical activity and cardiometabolic health: the Prospective Physical Activity, Sitting, and Sleep (ProPASS) consortium
Authors: Blodgett Joanna M , Ahmadi Matthew N , Atkin Andrew J , Chastin Sebastien , Chan Hsiu-Wen , Suorsa Kristin , Bakker Esmee A , Hettiarcachchi Pasan , Johansson Peter J , Sherar Lauren B , Rangul Vegar , Pulsford Richard M , Mishra Gita , Eijsvogels Thijs M H , Stenholm Sari , Hughes Alun D , Teixeira-Pinto Armando M , Ekelund Ulf , Lee I-Min , Holtermann Andreas , Koster Annemarie , Stamatakis Emmanuel , Hamer Mark ,   ProPASS Collaboration, Gupta Nidhi , Stehouwer Coen , Savelberg Hans , de Galan Bastiaan , van de Kallen Carla , Thijssen Dick H J
Published: November 2023

Background and Aims

Physical inactivity, sedentary behaviour (SB), and inadequate sleep are key behavioural risk factors of cardiometabolic diseases. Each behaviour is mainly considered in isolation, despite clear behavioural and biological interdependencies. The aim of this study was to investigate associations of five-part movement compositions with adiposity and cardiometabolic biomarkers.

Methods

Cross-sectional data from six studies (n = 15 253 participants; five countries) from the Prospective Physical Activity, Sitting and Sleep consortium were analysed. Device-measured time spent in sleep, SB, standing, light-intensity physical activity (LIPA), and moderate-vigorous physical activity (MVPA) made up the composition. Outcomes included body mass index (BMI), waist circumference, HDL cholesterol, total:HDL cholesterol ratio, triglycerides, and glycated haemoglobin (HbA1c). Compositional linear regression examined associations between compositions and outcomes, including modelling time reallocation between behaviours.

Results

The average daily composition of the sample (age: 53.7 ± 9.7 years; 54.7% female) was 7.7 h sleeping, 10.4 h sedentary, 3.1 h standing, 1.5 h LIPA, and 1.3 h MVPA. A greater MVPA proportion and smaller SB proportion were associated with better outcomes. Reallocating time from SB, standing, LIPA, or sleep into MVPA resulted in better scores across all outcomes. For example, replacing 30 min of SB, sleep, standing, or LIPA with MVPA was associated with −0.63 (95% confidence interval −0.48, −0.79), −0.43 (−0.25, −0.59), −0.40 (−0.25, −0.56), and −0.15 (0.05, −0.34) kg/m2 lower BMI, respectively. Greater relative standing time was beneficial, whereas sleep had a detrimental association when replacing LIPA/MVPA and positive association when replacing SB. The minimal displacement of any behaviour into MVPA for improved cardiometabolic health ranged from 3.8 (HbA1c) to 12.7 (triglycerides) min/day.

Conclusions

Compositional data analyses revealed a distinct hierarchy of behaviours. Moderate-vigorous physical activity demonstrated the strongest, most time-efficient protective associations with cardiometabolic outcomes. Theoretical benefits from reallocating SB into sleep, standing, or LIPA required substantial changes in daily activity.
Associations between occupational physical activity and left ventricular structure and function over 25 years in CARDIA
Authors: Quinn Tyler D , Lane Abbi , Pettee Gabriel Kelley , Sternfeld Barbara , Jacobs David R , Smith Peter , Barone Gibbs Bethany
Published: November 2023

Aims

Leisure time physical activity (LTPA) confers cardiovascular health benefits, while occupational physical activity (OPA) may have paradoxically negative health associations. This study tested the explanatory hypothesis that unfavourable cardiac remodelling may result from chronic OPA-induced cardiovascular strain.

Methods and results

Longitudinal associations of OPA and left ventricular (LV) structure and function were examined in 1462 participants {50.0% female, 56.4% White, aged 30.4 ± 3.4 years at baseline [Year 5 exam (1990–91)]} from the Coronary Artery Risk Development in Young Adults study. Left ventricular structure and function were measured as LV mass (LVMi), end-diastolic volume (LVEDVi), end-systolic volume (LVESVi), ejection fraction (LVEF), stroke volume (LVSVi), and e/a-wave ratio (EA ratio) via echocardiography at baseline and 25 years later. Occupational physical activity was reported at seven exams during the study period as months/year with ‘vigorous job activities such as lifting, carrying, or digging’ for ≥5 h/week. The 25-year OPA patterns were categorized into three trajectories: no OPA (n = 770), medium OPA (n = 410), and high OPA (n = 282). Linear regression estimated associations between OPA trajectories and echocardiogram variables at follow-up after adjusting for baseline values, individual demographic/health characteristics, and LTPA. Twenty-five-year OPA exposure was not significantly associated with LVMi, LVEDVi, LVSVi, or EA ratio (P > 0.05). However, higher LVESVi (β = 1.84, P < 0.05) and lower LVEF (β = −1.94, P < 0.05) were observed at follow-up among those in the high- vs. no-OPA trajectories.

Conclusion

The paradoxically adverse association of OPA with cardiovascular health was partially supported by null or adverse associations between high OPA and echocardiogram outcomes. Confirmation is needed using more precise OPA measures.
Identification of concealed cardiomyopathy using next-generation sequencing–based genetic testing in Korean patients initially diagnosed with idiopathic ventricular fibrillation
Authors: Jeong Joo Hee , Kim Yun Gi , Oh Suk-Kyu , Lee Hyoung Seok , Choi Yun Young , Min Kyongjin , Shim Jaemin , Park Yae Min , Kim Jun-Hyung , Oh Yong-Seog , Kim Nam-Ho , Pak Hui-Nam , On Young Keun , Park Hyung Wook , Hwang Gyo-Seung , Kim Dae-Kyeong , Park Young-Ah , Park Hyoung-Seob , Cho Yongkeun , Oh Seil , Choi Jong-Il , Kim Young-Hoon
Published: November 2023

Aims

Idiopathic ventricular fibrillation (IVF) is a disease in which the cause of ventricular fibrillation cannot be identified despite comprehensive clinical evaluation. This study aimed to investigate the clinical yield and implications of genetic testing for IVF.

Methods and results

This study was based on the multi-centre inherited arrhythmia syndrome registry in South Korea from 2014 to 2017. Next-generation sequencing–based genetic testing was performed that included 174 genes previously linked to cardiovascular disease. A total of 96 patients were clinically diagnosed with IVF. The mean age of the onset was 41.2 ± 12.7 years, and 79 patients were males (82.3%). Of these, 74 underwent genetic testing and four (5.4%) of the IVF probands had pathogenic or likely pathogenic variants (each having one of MYBPC3, MYH7, DSP, and TNNI3). All pathogenic or likely pathogenic variants were located in genes with definite evidence of a cardiomyopathy phenotype, either hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy.

Conclusion

Next-generation sequencing–based genetic testing identified pathogenic or likely pathogenic variants in 5.4% of patients initially diagnosed with IVF, suggesting that genetic testing with definite evidence genes of cardiomyopathy may enable molecular diagnosis in a minority of patients with IVF. Further clinical evaluation and follow-up of patients with IVF with positive genotypes are needed to unveil concealed phenotypes, such as the pre-clinical phase of cardiomyopathy.
Natural Canopy Disturbance Patterns and Ecological Silviculture in the Alabama Fall Line Hills
Authors: Baker Aurora C , Phillips David L , Goode J Davis , Hart Justin L
Published: November 2023

As a natural disturbance-based approach to silviculture is increasingly embraced by forest managers, quantitative reference conditions of natural disturbance patterns are paramount. We used LiDAR data to quantify resultant structural patterns from an EF3 tornado on the Oakmulgee Ranger District of Talladega National Forest in the Alabama Fall Line Hills, USA. We found the zone of catastrophic disturbance totaled 123 ha, had a mean width of 360 m, and residual trees were randomly distributed. This zone was buffered by an edge zone of intermediate-severity disturbance where trees were removed individually and in groups. The edge zone averaged 220 m in width. In total, the study area included seventy-nine stands and the percentage of stand area damaged ranged from < 1% to 94%. We suggest that clearcut, seed tree, and shelterwood with reserves regeneration methods may be appropriate analogs to natural canopy disturbance in the Fall Line Hills region. These catastrophic disturbance entries should be buffered from undisturbed neighborhoods by a system that retains mature forest structures and would constitute a zone of intermediate-severity disturbance. Our approach may be used as a template to expand our understanding of natural canopy disturbance patterns in other regions and forest types.

Study Implications: In regions where tornadoes are a natural component of the disturbance regime, including much of the southeastern United States, we suggest that clearcut, seed tree, or shelterwood with reserves regeneration methods may be used to approximate the zone of catastrophic disturbance that corresponds to the tornado track. We observed that reserve tree spatial patterns were random, but residual trees could be selected based on desired species or protection of important biophysical features such as seeps. Surrounding the catastrophic disturbance zone was an edge zone of intermediate-severity disturbance where trees were removed individually and in variably sized groups. We suggest that the structural patterns documented in this edge zone may be created through variable retention harvesting.
Transvection between nonallelic genomic positions in Drosophila
Authors: Blum Jacob A , Wells Michelle , Huxley-Reicher Zina , Johnson Justine E , Bateman Jack R
Published: November 2023

In Drosophila, pairing of maternal and paternal homologous chromosomes can permit trans-interactions between enhancers on one homolog and promoters on another, an example of transvection. Although trans-interactions have been observed at many loci in the Drosophila genome and in other organisms, the parameters that govern enhancer action in trans remain poorly understood. Using a transgenic reporter system, we asked whether enhancers and promoters at nonallelic, but nearby, genomic positions can communication in trans. Using one transgenic insertion carrying the synthetic enhancer GMR and another nearby insertion carrying the hsp70 promoter driving a fluorescent reporter, we show that transgenes separated by 2.6 kb of linear distance can support enhancer action in trans at the 53F8 locus. Furthermore, transvection between the nonallelic insertions can be augmented by a small deletion flanking one insert, likely via changes to the paired configuration of the homologs. Subsequent analyses of other insertions in 53F8 that carry different transgenic sequences demonstrate that the capacity to support transvection between nonallelic sites varies greatly, suggesting that factors beyond the linear distance between insertion sites play an important role. Finally, analysis of transvection between nearby nonallelic sites at other genomic locations shows evidence of position effects, where one locus supported GMR action in trans over a linear distance of over 10 kb, whereas another locus showed no evidence of transvection over a span <200 bp. Overall, our data demonstrate that transvection between nonallelic sites represents a complex interplay between genomic context, interallelic distance, and promoter identity.
Genetic analysis of pericarp pigmentation variation in Corn Belt dent maize
Authors: Schoemaker Dylan L , Qiu Yinjie , de Leon Natalia , Hirsch Candice N , Kaeppler Shawn M
Published: November 2023

The US standard for maize commercially grown for grain specifies that yellow corn can contain at maximum 5% corn of other colors. Inbred parents of commercial hybrids typically have clear pericarp, but transgressive segregants in breeding populations can display variation in pericarp pigmentation. We identified 10 doubled haploid biparental populations segregating for pigmented pericarp and evaluated qualitative genetic models using chi-square tests of observed and expected frequencies. Pigmentation ranged from light to dark brown color, and pigmentation intensity was quantitatively measured across 1,327 inbred lines using hue calculated from RGB pixel values. Genetic mapping was used to identify loci associated with pigmentation intensity. For 9 populations, pigmentation inheritance best fit a hypothesis of a 2- or 3-gene epistatic model. Significant differences in pigment intensity were observed across populations. W606S-derived inbred lines with the darkest pericarp often had clear glumes, suggesting the presence of a novel P1-rw allele, a hypothesis supported by a significant quantitative trait locus peak at P1. A separate quantitative trait locus region on chromosome 2 between 221.64 and 226.66 Mbp was identified in LH82-derived populations, and the peak near p1 was absent. A genome-wide association study using 416 inbred lines from the Wisconsin Diversity panel with full genome resequencing revealed 4 significant associations including the region near P1. This study supports that pericarp pigmentation among dent maize inbreds can arise by transgressive segregation when pigmentation in the parental generation is absent and is partially explained by functional allelic variation at the P1 locus.
Multidimensional Sleep Health Problems Across Middle and Older Adulthood Predict Early Mortality
Authors: Lee Soomi , Mu Christina X , Wallace Meredith L , Andel Ross , Almeida David M , Buxton Orfeu M , Patel Sanjay R
Published: November 2023

Background

Having multiple sleep problems is common in adulthood. Yet, most studies have assessed single sleep variables at one timepoint, potentially misinterpreting health consequences of co-occurring sleep problems that may change over time. We investigated the relationship between multidimensional sleep health across adulthood and mortality.

Methods

Participants from the Midlife in the United States Study reported sleep characteristics in 2004–2006 (MIDUS-2; M2) and in 2013–2014 (MIDUS-3; M3). We calculated a composite score of sleep health problems across 5 dimensions: Regularity, Satisfaction, Alertness, Efficiency, and Duration (higher = more problems). Two separate models for baseline sleep health (n = 5 140; median follow-up time = 15.3 years) and change in sleep health (n = 2 991; median follow-up time = 6.4 years) to mortality were conducted. Cox regression models controlled for sociodemographics and key health risk factors (body mass index, smoking, depressive symptoms, diabetes, and hypertension).

Results

On average, 88% of the sample reported having one or more sleep health problems at M2. Each additional sleep health problem at M2 was associated with 12% greater risk of all-cause mortality (hazard ratio [HR] = 1.12, 95% confidence interval [CI] = 1.04–1.21), but not heart disease-related mortality (HR = 1.14, 95% CI = 0.99–1.31). An increase in sleep health problems from M2 to M3 was associated with 27% greater risk of all-cause mortality (HR = 1.27, 95% CI = 1.005–1.59), and 153% greater risk of heart disease mortality (HR = 2.53, 95% CI = 1.37–4.68).

Conclusions

More sleep health problems may increase the risk of early mortality. Sleep health in middle and older adulthood is a vital sign that can be assessed at medical checkups to identify those at greater risk.
Multisectoral Collaborations to Increase Recruitment and Retention of Diverse Older Adults in Biomedical Research
Authors: Wong Roger , Grullon Jason R , McNamara Sarah E , Smith Nancy H , Dillenbeck Colleen A , Royal Kathy , Brangman Sharon A
Published: November 2023

Background

Older adults, especially minoritized racial-ethnic groups, are historically underrepresented in biomedical research. This study summarizes the development and assesses the impact of a review board involving a multisectoral group of stakeholders with the goal of increasing the diversity of older adults in biomedical research.

Methods

A 25-member board of community members, caregivers, researchers, and clinicians from Upstate New York reviewed 3 projects presented by researchers, clinician-scientists, and a pharmaceutical company between January and December 2022. For each biomedical research project, the reviews provided guidance to increase the recruitment and retention of diverse older adults engaged in the study. Review board members and presenters completed surveys to provide feedback on their experience in this collaboration.

Results

There was consistent positive feedback from all members and presenters. From member surveys, feedback trended positive in meetings throughout the year. Community members and caregivers initially indicated discomfort in expressing their views; however, these concerns subsided over time. Presenters had a very positive experience in the review board’s impact on their recruitment strategy and study design, and therefore very likely to use this service again. Recommendations were made to adjust membership criteria, presentation format, and funding to sustain this effort.

Conclusions

Lack of diversity for older adults represented in biomedical research contributes to ethical and generalizability ramifications. The positive feedback from all stakeholders in our multisectoral board of community members, caregivers, researchers, and clinicians offers a promising structure for developing similar strategies to increase diversity within and beyond biomedical aging research in other communities.
Gender Differences in Social Support Vary by Environment Among Older People With HIV in South Africa and Uganda
Authors: Kaufman Jennifer E , Brennan-Ing Mark , MacPhail Catherine , Minichiello Victor , Seeley Janet
Published: November 2023

Background and Objectives

Sub-Saharan Africa is home to 3.7 million older adults living with HIV, who experience high rates of comorbid conditions. Formal services other than HIV clinical care are largely unavailable. Overall, women are the mainstay of informal social support networks, and older women with HIV may face burdens due to family caregiving expectations. Thus, it is important to understand the extent of informal support provided to older adults living with HIV, and how this is affected by gender.

Research Design and Methods

We examined differences in social networks, needs, social support and caregiving, and perceptions of support adequacy among women and men aged 50 and older living with HIV in Uganda (n = 101) and South Africa (n = 108), mostly rural and suburban populations, respectively. We used multiple regression to determine whether there was an association between gender and the amount of social support received and whether that varied by research site.

Results

Men were more likely than women to receive support from a partner. Women were more likely to live with offspring, both providing and receiving care. In South Africa but not Uganda, women received more help from family than men did. There was no gender difference in getting help from friends, but it was more common in Uganda. Living alone was strongly associated with less family help and more help from friends.

Discussion and Implications

Older women with HIV in sub-Saharan Africa tend to be more heavily involved in social support exchanges—both providing and receiving care—than their male peers, but place matters. Interdependence is high in rural Uganda, where formal services are scarce and needs exceed resources. Given the projected growth in this population, stronger formal supports are needed for communities and older people with HIV, especially those who live alone.