Worsening Heart Failure Research Articles

Combining Recurrent and Terminal Events Into a Composite Endpoint May Be Problematic

In clinical trials for chronic heart failure (CHF), time to a composite of first hospitalization for worsening heart failure or death is a widely accepted primary efficacy measure. Motivated by lower event rates in recent CHF trials, there are proposals to use endpoints accounting for recurrent heart failure hospitalization (HFH) events (e.g. recurrent HFH events plus death as an additional event) as the primary endpoint to better quantify disease burden and to improve trial efficiency. However, analysis and interpretation of recurrent event endpoints may be complicated by the terminal event death. In a previous simulation study it was shown that the type I error rate was well-controlled for the analysis of the composite recurrent event endpoint using the negative binomial (NB) model and the Lin-Wei-Yang-Ying (LWYY) model. As these results were based on limited scenarios, we extended the previous simulation study and identified situations where the type I error rate is no longer controlled for the analysis of the composite recurrent event endpoint using the LWYY model, despite a neutral effect on HFH and a detrimental effect on death of the experimental treatment. Therefore, depending on clinical settings, the LWYY model should be applied and interpreted with more caution.

Pro-adrenomedullin associates with congestion in acute heart failure patients.

Congestion is a major determinant of outcomes in acute heart failure. Its assessment is complex, making sufficient decongestive therapy a challenge. Residual congestion is frequent at discharge, increasing the risk of re-hospitalization and death. Mid-regional pro-adrenomedullin mirrors vascular integrity and may therefore be an objective marker to quantify congestion and to guide decongestive therapies in patients with acute heart failure. Observational, prospective, single-centre study in unselected patients presenting with acute heart failure. This study aimed to assess adrenomedullin's association with congestion and clinical outcomes: in-hospital death, post-discharge mortality and in-hospital worsening heart failure according to RELAX-AHF-2 trial criteria. Pro-adrenomedullin was quantified at baseline and at discharge. Congestion was assessed applying clinical scores. Cox and logistic regression models with adjustment for clinical features were fitted. N=233, median age 77years (IQR 67, 83), 148 male (63.5%). Median pro-adrenomedullin 2.0nmol/L (IQR 1.4, 2.9). Eight patients (3.5%) died in hospital and 100 (44.1%) experienced in-hospital worsening heart failure. After discharge, 60 patients (36.6%) died over a median follow-up of 1.92years (95% CI: 1.76, 2.46). Pro-adrenomedullin concentrations (logarithmized) were significantly associated with congestion, both at enrolment (β=0.36 and 0.81 depending on score, each P<0.05) and at discharge (β=1.12, P<0.001). Enrolment of pro-adrenomedullin was associated with in-hospital worsening heart failure [OR 4.23 (95% CI: 1.87, 9.58), P<0.001], and pro-adrenomedullin at discharge was associated with post-discharge death [HR 3.93 (1.86, 8.67), P<0.001]. Elevated pro-adrenomedullin is associated with in-hospital worsening heart failure and with death during follow-up in patients with acute heart failure. Further research is needed to validate this finding and to explore the ability of pro-adrenomedullin to guide decongestive treatment.

Clinical impact of atrial fibrillation progression in patients with heart failure with preserved ejection fraction: A report from the CHART-2 Study.

Atrial fibrillation (AF) frequently coexists with heart failure with preserved ejection fraction (HFpEF), and clinical outcomes of patients with AF vary depending on its subtype. While AF progression characterized by the transition from paroxysmal AF to persistent AF is sometimes observed, the incidence and clinical impact of AF progression in patients with HFpEF remain to be explored. We enrolled patients with HFpEF and paroxysmal AF from the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. AF progression was defined as the transition from paroxysmal AF to persistent AF. A total of 718 patients (median age: 72 years, 36% were female) were enrolled. For a median follow-up of 6.0 years (interquartile range: 3.0-10.2 years), AF progression occurred in 105 patients (14.6%), with a cumulative incidence of 16.7% at 10 years. In the multivariable Cox proportional hazards model, previous hospitalization for heart failure [hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.16-2.60; P = 0.007] and left atrial diameter (per 5-mm increase) (HR 1.37, 95% CI 1.20-1.55; P < 0.001) were significantly associated with AF progression. Furthermore, AF progression was significantly linked to worsening heart failure (adjusted HR 1.68, 95% CI 1.18-2.40; P = 0.004). Notably, 27 cases (26%) of worsening heart failure occurred within 1 year following AF progression. In patients with HFpEF, AF progression is significantly associated with adverse outcomes, particularly worsening heart failure. An increased risk is observed in the early phases following progression to persistent AF. Clinical Trials.gov Identifier: NCT00418041.

From routine to rescue: Thyroidectomy for life-threatening thyrotoxicosis.

Thyroidectomies are routinely same-day elective procedures. The aim of this study was to investigate outcomes in patients who underwent uncommon urgent thyroidectomy. We retrospectively reviewed patients diagnosed with thyrotoxicosis at a quaternary medical center between 2011 and 2023. Included patients were admitted nonelectively with thyroidectomies performed during same hospital stay. Patient demographics, comorbidities, hospital course, and operative outcomes were analyzed. Thirty patients met the inclusion criteria. The majority were female (60%) and Black (60%) with a mean age of 41±14years. At admission, 76.6% had undetectable thyrotropin levels (<0.01µU/mL) and 26.7% were diagnosed with thyroid storm. Common presenting comorbidities included atrial fibrillation (53.3%), heart failure (40%), and liver failure (16.7%). Graves' disease was diagnosed in 83.3% of patients, while 13.3% had amiodarone-induced thyrotoxicosis. Median hospital stay before surgery was 8days (interquartile range: 4-16). Indications for surgery were adverse medication events (30%), inadequate therapeutic effect by medication (30%), and worsening heart failure (26.7%). Postoperatively, 6.7% required reoperation for neck hematoma, 13.3% experienced temporary hypoparathyroidism, and 6.7% had hoarseness. Following surgery, 50% of patients with atrial fibrillation experienced resolution and 50% with heart failure with reduced ejection fraction showed ultrasonic improvement. Within 30days, 20% visited the emergency department, none due to thyroidectomy complications, and 13.3% were readmitted for comorbidities. One patient (3.3%) died from liver failure. Patients who require an urgent thyroidectomy often have life-threatening comorbidities particularly cardiac disease. Performing thyroidectomy in these patients can potentially create clinical homeostasis for further management of their comorbidities.

Effectiveness of Vericiguat on right ventricle to pulmonary artery uncoupling associated with heart failure with reduced ejection fraction

BackgroundsA soluble guanylyl cyclase stimulator vericiguat has been shown to reduce cardiovascular mortality or hospitalization for heart failure in patients with worsening heart failure in the VICTORIA study. However, little is known about the effects of vericiguat on biventricular structure and function. Methods and resultsA retrospective analysis of 63 consecutive patients with heart failure with reduced ejection fraction (HFrEF) who were treated with vericiguat was performed. Clinical data and echocardiographic parameters were compared between baseline and follow-up after the initiation of vericiguat. The median follow-up duration was 266 days. Treatment with vericiguat significantly reduced the plasma BNP levels (log-transformed) compared to baseline (2.46 ± 0.51 vs. 2.14 ± 0.58, p < 0.0001). Left ventricular end-diastolic volume index and left ventricular end-systolic volume index were significantly reduced (LVEDVI, 113.5 ± 46.3 vs. 103.6 ± 51.0, p = 0.0056; LVESVI, 82.0 ± 41.9 vs. 72.8 ± 44.7, p = 0.0077; respectively). The tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio, an indicator of right ventricle-pulmonary artery (RV-PA) coupling, increased significantly after the treatment (0.56 ± 0.29 vs. 0.92 ± 1.09, p < 0.0001). Univariate and multivariate analyses showed that the treatment effects of vericiguat on BNP levels, LV reverse remodeling, and RV-PA coupling were not correlated with the achievement of the quadruple therapy with beta-blockers, renin-angiotensin system inhibitors, mineralocorticoid inhibitors, and sodium-glucose cotransporter-2 inhibitors, nor with worsening heart failure (WHF). ConclusionTreatment with vericiguat improved adverse LV remodeling and RV-PA uncoupling in HFrEF patients. These effects were independent of WHF and achieving the quadruple therapy. Patients with HFrEF may benefit from early initiation of vericiguat to prevent biventricular adverse remodeling.

Determinación aislada de sodio urinario en pacientes ambulatorios con insuficiencia cardiaca

Introduction and objectivesSpot determination of urinary sodium (UNa+) has emerged as a useful tool for monitoring diuretic response in patients with acute heart failure (AHF). However, the evidence in outpatients is scarce. We aimed to examine the relationship between spot UNa+ levels and the risk of mortality and worsening heart failure (WHF) events in individuals with chronic HF. MethodsThis observational and ambispective study included 1145 outpatients with chronic HF followed in a single center specialized HF clinic. UNa+ assessment was carried out 1-5 days before each visit. The endpoints of the study were the association between UNa+ and risk of a) long-term death and b) AHF-hospitalization and total WHF events (including AHF-hospitalization, emergency department visits or parenteral loop-diuretic administration in HF clinic), assessed by multivariate Cox and negative binomial regressions. ResultsThe mean±standard deviation of age was 73±11 years, 670 (58.5%) were men, 902 (78.8%) were on stable NYHA class II, and 595 (52%) had LFEF ≥50%. The median (interquartile range) UNa+ was 72 (51-94) mmol/L. Over a median follow-up of 2.63 (1.70-3.36) years, there were 293 (25.6%) deaths and 382 WHF events (244 AHF-admissions) in 233 (20.3%) patients. After multivariate adjustment, baseline UNa+ was inverse and linearly associated with the risk of total WHF (IRR, 1.07; 95%CI, 1.02-1.12; P=.007) and AHF-admissions (IRR, 1.08; 95%CI, 1.02-1.14; P=.012) and borderline associated with all-cause mortality (HR, 1.04; 95%CI, 0.99-1.09; P=.068). ConclusionsIn outpatients with chronic HF, lower UNa+ was associated with a higher risk of recurrent WHF events.

Association Between Late Gadolinium Enhancement with or Without Reverse Remodeling and Prognosis.

Late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (CMR) prevents left ventricular reverse remodeling (LVRR), resulting in a poor prognosis. However, the prognosis of patients who have LGE and achieve LVRR and patients who do not have LGE and do not achieve LVRR remains unknown. This study aimed to answer this question by sorting patients with heart failure based on the presence of LGE and LVRR and comparing their prognoses. Another aim was to identify useful factors for predicting LVRR.All patients were followed-up for 24 months. LVRR was defined as a ≥ 10% increase at the last follow-up at 12 ± 6 months from baseline, on echocardiography. The primary endpoint was a composite of cardiovascular death and hospitalization due to worsening heart failure within 18 ± 6 months. Baseline data and data from each outpatient visit were collected and analyzed. We enrolled 80 consecutive patients with heart failure and reduced left ventricular ejection fraction (< 50%) who underwent CMR.LGE was positive in 40 patients (50.0%) and LVRR was observed in 50 patients (63%). The incidence of the primary endpoint was significantly lower in the group that achieved LVRR, regardless of LGE status (LGE-positive group, P = 0.01; LGE-negative group, P = 0.02). In the multivariate analysis, the percentage change in NT-pro BNP levels at 3 months, NT-pro BNP levels at 6 months, and age were independent predictors of LVRR.LGE-positive patients may have a better prognosis if they achieve LVRR. Serial NT-pro BNP testing may be a valuable predictor of LVRR.

A Novel Model of Integrated Care of Older Patients With Atrial Fibrillation in Rural China

BackgroundAn integrated management approach is essential to improving outcomes for patients with atrial fibrillation (AF). China's rural health care system, primarily reliant on village doctors, falls short of providing optimal management of AF in rural populations with limited resources and access to health care. To support village doctors in providing integrated care for AF, we have developed a digital health support platform. ObjectivesThis study aims to evaluate the effectiveness of this telemedicine-based, village doctor–led, multifaceted care model. MethodsThe MIRACLE-AF (a novel Model of IntegRAted Care of oLdEr patients with Atrial Fibrillation in rural China) trial is a prospective cluster-randomized clinical trial. Thirty village clinics in Jiangdu County, Jiangsu Province, were randomly assigned to village doctor-led telemedicine integrated care or enhanced usual care in a 1:1 ratio. All the patients diagnosed with AF who resided in this rural area and were aged ≥65 years were eligible for enrollment. The primary outcome in stage 1 was the proportion of patients who met all 3 criteria for the atrial fibrillation better care pathway at 12 months, and in stage 2, a composite of cardiovascular death, all strokes including ischemic stroke and hemorrhagic stroke, worsening of heart failure or acute coronary syndrome, and emergency visits due to AF over 36 months. ResultsIn total, 1,039 participants were recruited from December 1, 2020, to May 9, 2022, with 524 in the telemedicine care arm and 515 in the enhanced usual care arm. All the enrolled patients are under scheduled follow-up. ConclusionsThe MIRACLE-AF trial will provide evidence for this novel integrated care model for treating rural older patients with AF. (New Model of Integrated Care of Older Patients with Atrial Fibrillation in Rural China; NCT04622514)

A Review of the Potential Role of Sotagliflozin: A Dual SGLT2 and SGLT1 Inhibitor-in the Treatment of Heart Failure.

Objective: This review provides an overview of the pharmacology, efficacy, and safety of sotagliflozin, a dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2), to reduce the risk of cardiovascular death and hospitalization in those with heart failure. Data sources: A search of Embase via Elsevier, PubMed, Web of Science-All Databases, and The Cochrane Library for clinical trials in CENTRAL, as well as the MedRxiv and BioRxiv pre-print servers, was conducted from inception through December 1, 2023. Search terms included sotagliflozin, lx 4211, lp 802034, sar 439954, and (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol. Study selection and data extraction: Published phase 1, phase 2, and phase 3 clinical trials, meta-analyses, and systematic reviews. Studies were included if they were published in English and evaluated sotagliflozin pharmacology, pharmacokinetics, efficacy, or safety. Data synthesis: The Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure (SOLOIST-WHF) and Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) phase 3 trials compared sotagliflozin with placebo in patients with type 2 diabetes mellitus. In both the SCORED and SOLOIST-WHF trials, treatment with sotagliflozin resulted in a statistically significant reduction in the primary composite outcome of death from cardiovascular causes, hospitalizations due to heart failure (HF), and urgent visits for HF. Conclusions: Dual SGLT1 and SGLT2 inhibition with sotagliflozin is efficacious in reducing myocardial infarction (MI), stroke, and HF hospitalizations and urgent visits in the SCORED and SOLOIST-WHF trials. However, its impact on reducing cardiovascular mortality remains uncertain due to premature study discontinuation. Owing to these factors and lack of generalizability, further studies are needed to establish its role in renal protection and cardiovascular mortality in broader populations. At this time, more evidence is warranted to definitively establish sotagliflozin in HF.

Efficacy and safety of hypertonic saline therapy in ambulatory patients with heart failure: The SALT-HF trial.

Combination of hypertonic saline solution (HSS) with intravenous loop diuretics has been suggested to improve diuretic response in patients hospitalized for heart failure (HF). The efficacy and safety of this approach in the ambulatory setting remain unexplored. In this multicentre, double-blind, randomized study, we allocated ambulatory patients with worsening heart failure (WHF) to a 1-h infusion of intravenous furosemide (ivFurosemide)-HSS versus ivFurosemide. The primary endpoint was the volume of diuresis at 3 h. Secondary endpoints included 3-h natriuresis and weight variation, 7-day congestion data, kidney function and electrolytes, and 30-day clinical events. Overall, 167 participants (median age: 81 years, 30.5% female) were randomized across 13 sites between December 2020 and March 2023. There were no differences in 3-h diuresis between treatments (ivFurosemide-HSS: 1099 ml vs. ivFurosemide: 1103 ml, p = 0.963), 3-h natriuresis (∆ +2.642 mEq/L, p = 0.559), or 3-h weight (∆ +0.012 kg, p = 0.920). Patients in the ivFurosemide-HSS arm experienced significant weight decrease at 7 days (Δ -0.586 kg, p = 0.048). There were no between-treatment differences in clinical congestion score, biomarkers, inferior vena cava diameter, or the presence of lung ultrasound B-lines. At 30 days, 26.5% of the patients in the ivFurosemide-HSS group versus 33.3% in the ivFurosemide group experienced WHF (hazard ratio 0.76, p = 0.330). The incidence of death from any cause or HF hospitalization was 6% of patients in the ivFurosemide-HSS group and 8.3% of patients in the ivFurosemide group (hazard ratio 0.69, p = 0.521). The incidence of worsening kidney function or metabolic derangements was not significantly different in the two arms. A single infusion of ivFurosemide-HSS did not improve 3-h diuresis or congestion parameters in patients with ambulatory WHF. This therapy showed an appropriate safety profile.

Bioimpedance analysis predicts worsening events in outpatients with heart failure and reduced ejection fraction.

Heart failure (HF) with reduced left ventricle ejection fraction (LVEF) is an entity with poor prognosis characterized by decompensations. Bioelectrical impedance analysis (BIA) is used to assess volume overload (VO) and may be useful to identify apparently stable HF outpatients at risk of decompensation. The aim of this study is to analyse whether VO assessed by BIA is associated with worsening heart failure (WHF) in stable outpatients with HF and reduced LVEF (HFrEF). This is a prospective single-centre observational study. Consecutive stable HF outpatients with LVEF below 40% underwent BIA, transthoracic echocardiography, blood sampling, and physical examination and were followed up for 3months. VO was defined as the difference between the measured weight and the dry weight assessed by BIA. Demographic, clinical, anthropometric, echocardiographic, and analytical parameters were recorded. The primary endpoint was WHF, defined by visits to the emergency department for HF or hospitalization for HF. A total of 100 patients were included. The median VO was 0.5L (interquartile range 0-1.6L). Eleven patients met the primary endpoint. Univariate binary logistic regression analysis showed that left ventricle filling pressures assessed by E/e', N-terminal pro B-type natriuretic peptide, inferior vena cava dilatation (≥21mm), signs of congestion, and VO were associated with the primary endpoint. Binary logistic regression multivariate analysis showed that VO was the only independent predictor for the primary endpoint (adjusted OR 2.7; 95% CI 1.30-5.63, P=0.008). Multivariate Cox regression analysis also showed an adjusted hazard ratio (HR) for VO of 2.03; 95% CI 1.37-3.02, P<0.001. Receiver-operating characteristic curve analysis showed an area under the curve for VO of 0.88 (95% CI 0.79-0.97, P<0.001) with an optimal cut-off of 1.2L. VO assessed by BIA is independently associated with WHF in stable outpatients with HFrEF at 3months.

Cardiac sarcoidosis treated with nonsteroidal immunosuppressive therapy

BackgroundNonsteroidal immunosuppressive therapy is a potential therapeutic strategy for cardiac sarcoidosis. However, it is not recommended as an established treatment option. This study aimed to demonstrate the clinical outcomes of patients with cardiac sarcoidosis using nonsteroidal immunosuppressants through the ILLUstration of the Management and PrognosIs of JapaNese PATiEnts with Cardiac Sarcoidosis multicenter retrospective registry. MethodsFrom a cohort of 512 patients, 426 who received corticosteroid therapy and 26 who received other immunosuppressive therapy were included for analysis. Clinical outcomes included all-cause death, fatal ventricular arrhythmic events (FVAE), and worsening heart failure with hospitalization. ResultsNonsteroidal immunosuppressants were used for retained fluorodeoxyglucose uptake in the heart (n = 14), corticosteroid side effects (n = 7), ventricular arrhythmia (n = 4), complete atrioventricular block (n = 2), worsened extracardiac sarcoidosis (n = 2), and other reasons (n = 2). They comprised of methotrexate (n = 20), cyclosporine (n = 2), cyclophosphamide (n = 2), and azathioprine (n = 3). After the addition of a nonsteroidal immunosuppressant, corticosteroids were reduced in 14 of 26 patients (5 [5–17] mg), although no patient discontinued corticosteroids. Of the 14 patients, decreased fluorodeoxyglucose uptake was observed in seven at follow-up. Clinical outcomes were observed in 11 patients (42.3 %). Detected events included all-cause death in five patients (19.2 %), FVAE in four (15.4 %), and worsening heart failure with hospitalization in five (19.2 %), with some overlap. ConclusionsNonsteroidal immunosuppressive therapy may be a possible treatment option for patients who are not stabilized with corticosteroids alone or develop corticosteroid side effects.

A review of novel endothelin antagonists and overview of non-steroidal mineralocorticoid antagonists for treating resistant hypertension: An update

Several agents are emerging from five different novel classes of antihypertensive medications. We will focus on endothelin antagonists and non-steroidal mineralocorticoid receptor antagonists. While several agents exist in this later class, only a couple have demonstrated superior efficacy in resistant hypertension management. Endothelin receptor antagonists are effective therapy for primary and resistant hypertension, but they are not widely used. This is due to side effects demonstrated in large clinical trials, specifically increased peripheral edema and worsening heart failure in some cases, as well as the availability of many alternative agents to manage blood pressure effectively. However, the relationship between endothelin and its close ties to hypertension is evolving. Recent pre-clinical work explores new applications of more selective endothelin receptor antagonists. They suggest that specific subtypes of hypertension may benefit more from endothelin receptor blockade than simply those with primary hypertension. We review this topic and other related data. Lastly, we also provide a brief overview of non-steroidal mineralocorticoid receptor antagonists as some in the class show promise as antihypertensive agents.

Role of spot urinary sodium in outpatients with heart failure

Introduction and objectivesSpot determination of urinary sodium (UNa+) has emerged as a useful tool for monitoring diuretic response in patients with acute heart failure (AHF). However, the evidence in outpatients is scarce. We aimed to examine the relationship between spot UNa+ levels and the risk of mortality and worsening heart failure (WHF) events in individuals with chronic HF. MethodsThis observational and ambispective study included 1145 outpatients with chronic HF followed in a single center specialized HF clinic. UNa+ assessment was carried out 1-5 days before each visit. The endpoints of the study were the association between UNa+ and risk of a) long-term death and b) AHF-hospitalization and total WHF events (including AHF-hospitalization, emergency department visits or parenteral loop-diuretic administration in HF clinic), assessed by multivariate Cox and negative binomial regressions. ResultsThe mean±standard deviation of age was 73±11 years, 670 (58.5%) were men, 902 (78.8%) were on stable NYHA class II, and 595 (52%) had LFEF ≥50%. The median (interquartile range) UNa+ was 72 (51-94) mmol/L. Over a median follow-up of 2.63 (1.70-3.36) years, there were 293 (25.6%) deaths and 382 WHF events (244 AHF-admissions) in 233 (20.3%) patients. After multivariate adjustment, baseline UNa+ was inverse and linearly associated with the risk of total WHF (IRR, 1.07; 95%CI, 1.02-1.12; P=.007) and AHF-admissions (IRR, 1.08; 95%CI, 1.02-1.14; P=.012) and borderline associated with all-cause mortality (HR, 1.04; 95%CI, 0.99-1.09; P=.068). ConclusionsIn outpatients with chronic HF, lower UNa+ was associated with a higher risk of recurrent WHF events.

New Therapeutics for Heart Failure Worsening: Focus on Vericiguat.

Heart failure (HF) is a syndrome characterized by signs and symptoms resulting from structural or functional cardiac abnormalities, confirmed by elevated natriuretic peptides or evidence of congestion. HF patients are classified according to left ventricular ejection fraction (LVEF). Worsening HF (WHF) is associated with increased short- and long-term mortality, re-hospitalization, and healthcare costs. The standard treatment of HF includes angiotensin-converting enzyme inhibitors, angiotensin receptor-neprilysin inhibitors, mineralocorticoid-receptor antagonists, beta-blockers, and sodium-glucose-co-transporter 2 inhibitors. To manage systolic HF by reducing mortality and hospitalizations in patients experiencing WHF, treatment with vericiguat, a direct stimulator of soluble guanylate cyclase (sGC), is indicated. This drug acts by stimulating sGC enzymes, part of the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway, regulating the cardiovascular system by catalyzing cGMP synthesis in response to NO. cGMP acts as a second messenger, triggering various cellular effects. Deficiencies in cGMP production, often due to low NO availability, are implicated in cardiovascular diseases. Vericiguat stimulates sGC directly, bypassing the need for a functional NO-sGC-cGMP axis, thus preventing myocardial and vascular dysfunction associated with decreased sGC activity in heart failure. Approved by the FDA in 2021, vericiguat administration should be considered, in addition to the four pillars of reduced EF (HFrEF) therapy, in symptomatic patients with LVEF < 45% following a worsening event. Cardiac rehabilitation represents an ideal setting where there is more time to implement therapy with vericiguat and incorporate a greater number of medications for the management of these patients. This review covers vericiguat's metabolism, molecular mechanisms, and drug-drug interactions.

A study to determine if the fluid heart tracker app supports patient decision-making at the onset of worsening heart failure

Abstract Background Delay in seeking early intervention for worsening heart failure (HF) can result in poorer patient outcomes, hospital admission and increased risk of mortality (Andersen 2017, Matsue et al. 2017, Mikami et al. 2021). Despite the availability of health-related mobile apps for HF self-care, no study has focused on whether apps designed for HF weight monitoring make a meaningful contribution to the decision-making process of HF self-care. The Fluid Heart Tracker App was developed as a simple app to support the patient in the identification of significant weight gain as a result of worsening HF. An Advanced Nurse Practitioner in HF proposed the concept of the app, and it was developed by an Open-Source Volunteer team. It has one feature which is weight monitoring. It does not require interpretation of symptoms. The app has CE approval. It does not have a backend. The Irish Heart Foundation (IHF) has championed the app and the National Heart Programme listed it as a patient resource in the National Model of Care for Heart Failure in Ireland. The app is free to download from play store and the app-store in Ireland and the UK. Pilot study An evaluative, cross-sectional pilot study was initially carried out in potential users from three acute general hospitals. to determine the acceptability and usefulness of the Fluid Heart Tracker-App for patients with HF. This to garner feedback to use to develop, alter or refine the app. Methods Participants downloaded the app and used it to monitor their daily weight for two weeks. A short bespoke questionnaire was developed for the survey. It comprised five valid questions with dichotomous answers and an option at the end for participants to add any additional six comments. Results 31 participations- 13 female. The average age was 72. All participants (N=31, 100%) used the app, found it useful and found it easy to use and all participants would recommend the app to other patients with heart failure. 30 participants used the app daily, while one used it on alternate days. Participants stated that it was easy or very easy to use. Based on these positive results a before and after, quasi-experimental study is currently being undertaken. Aim of current study The aim of this current study is to determine the impact, use and the effect of the Fluid Heart Tracker App on patient decision making in HF. Primary Outcomes 1) Compare if using the app improved previous engagement patterns for weight monitoring. 2) Determine which factors influence engagement with the app. 3) Determine the impact of an app alert to the patient on seeking medical attention for worsening heart failure. Progress to date 179 participants were recruited from 12 HF sites in Ireland. Data collection was completed November 2nd, 2023. Currently the data set is being cleaned prior to statistical analysis. This investigation has been undertaken as part of a PhD study.

Experiences of primary care nurses with using a handheld ultrasound device (Vscan) and a remote dielectric sensing (ReDS) device in the assessment of patients with heart failure

Abstract Background Early detection of increased lung fluids is vital to further prevent deterioration and treat worsening of heart failure (HF). However, nurses often face challenges in assessing the status of HF patients, especially in primary care, where specialized competence in cardiology may be lacking and many patients have co-morbidities. The handheld ultrasound device (Vscan) and remote dielectric sensing device (ReDS) have the potential to provide valuable support in these challenges. Purpose To describe the additional value of the information obtained with Vscan and ReDS in primary care, and to identify challenges encountered by nurses in relation to the measurements among HF patients. Methods One nurse in a Swedish primary healthcare centre used both devices on 17 separate occasions during January-June in 2023, involving a total of six patients (mean age 84.5 years, female 67%, NYHA II/III 33%/67%, lung disease 67%). The nurse made notes about the perceived value in the HF assessment and informativeness of the devices and any challenges encountered during the measurements using a self-administered questionnaire. Qualitative data was narratively reviewed and described. Results Information obtained from Vscan images such as pleural effusion and B-lines, and ReDS values contributed to the assessment of the HF status in patients, determining whether their condition worsened, remained stable or improved. These devices helped in verifying and confirming physical examination findings, including lung auscultation and subjective symptoms reported by the patient, such as shortness of breath and leg oedema. Additionally, the information (e.g., high ReDS value and the presence of B-lines) supported decisions on medication optimization, primarily through adjustments of diuretic dosages and initiation of new HF medications. It also helped to distinguish symptoms of asthma or chronic obstructive pulmonary diseases from worsening HF (e.g., presence of shortness of breath without B-lines and low ReDS value of 31). The nurse expressed uncertainty due to limited experience with using the devices, particularly when results from the two devises were not congruent. Trust in ReDS-data evolved over time and initial problems in managing the vest were resolved. Challenges associated with ReDS included difficulties in fitting the vest on patients with abnormal spine features and obesity, and issues arising from patient movements during measurements. Problems with Vscan included the generation and interpretation of ultrasound images, particularly in obese patients. Conclusion Our data suggests that both Vscan and ReDS have the potential to provide valuable information to primary care nurses in the daily management of HF patients, particularly for assessing HF status and optimizing medication. Further studies are needed to assess the effectiveness of these devices in improving patient outcomes in heart failure management in primary care.Handheld portable ultrasound (Vscan)ReDS device

Potential prognostic impact of left-ventricular global longitudinal strain in analysis of whole-heart myocardial mechanics in nonischemic dilated cardiomyopathy

Cardiac magnetic resonance (CMR) feature-tracking (FT) has an important diagnostic role in non-ischemic dilated cardiomyopathy (NIDCM). To date, the relationship between whole-heart myocardial mechanics by CMR and early primary outcomes in NIDCM has not been elucidated. patients with NIDCM were eligible for this study. CMR-FT was used to analyze whole-heart myocardial mechanics. The primary outcomes were a composite of heart failure (HF) death, heart transplantation (HT), and hospitalization for HF worsening (WHF) after 1-year since diagnosis. 98 patients were included. During a 1-year follow-up, a worse prognosis occurred in 32 patients (30 hospitalizations for WHF, 8 deaths, and 3 HT). The left ventricular (LV) global longitudinal systolic strain (GLS), left ventricular global circumferential strain (LV GCS), strains of right ventricle and both atria were significantly reduced in patients with events vs. those without (GLS − 8.0 ± 3.4 vs. − 12.1 ± 4.5, p < 0.001; GCS − 13.0 ± 6.4 vs. − 18.3 ± 7.1, p < 0.001; right ventricular (RV) GLS − 12.1 ± 4.9 vs. − 17.4 ± 6.4, p < 0.001; left atrial longitudinal strain 7.5 ± 3.8 vs. 15.1 ± 12.3, p < 0.001; right atrial longitudinal strain 11.0 ± 6.7 vs. 17.2 ± 8.0, p < 0.001). Left ventricular ejection fraction (LVEF) was significantly higher in patients with better prognosis (22.7 ± 8.7 vs. 33.56 ± 10.4, p < 0.001). Multivariate regression analysis revealed LV GLS as an independent predictor of a worse prognosis (OR 0.787, CI 95% 0.697–0.890, p < 0.001). reduction of LV GLS showed the strongest predictive value for the composite outcome of WHF, HT, and HF death.Graphical abstract

Disability and Recurrent Stroke Among Participants in Stroke Prevention Trials

Stroke secondary prevention trials have disproportionately enrolled participants with mild or no disability. The impact of this bias remains unclear. To investigate the association between poststroke disability and the rate of recurrent stroke during long-term follow up. This cohort study is a post hoc analysis of the Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) and Insulin Resistance Intervention After Stroke (IRIS) secondary prevention clinical trial datasets. PRoFESS enrolled patients from 2003 to 2008, and IRIS enrolled patients from 2005 to 2015. Data were analyzed from September 23, 2023, to May 16, 2024. The exposure was poststroke functional status at study baseline, defined as modified Rankin Scale (mRS; range, 0-5; higher score indicates more disability) score of 0 vs 1 to 2 vs 3 or greater. The primary outcome was recurrent stroke. The secondary outcome was major cardiovascular events (MACE), defined as recurrent stroke, myocardial infarction, new or worsening heart failure, or vascular death. A total of 20 183 PRoFESS participants (mean [SD] age, 66.1 [8.5] years; 12 931 [64.1%] male) and 3265 IRIS participants (mean [SD] age, 62.7 [10.6] years; 2151 [65.9%] male) were included. The median (IQR) follow-up was 2.4 (1.9-3.0) years in PRoFESS and 4.7 (3.2-5.0) years in IRIS. In PRoFESS, the recurrent stroke rate was 7.2%, among patients with an mRS of 0, 8.7% among patients with an mRS of 1 or 2, and 10.6% among patients with an mRS of 3 or greater (χ22 = 27.1; P < .001); in IRIS the recurrent stroke rate was 6.4% among patients with an mRS of 0, 9.0% among patients with an mRS of 1 or 2, and 11.7% among patients with an mRS of 3 or greater (χ22 = 11.1; P < .001). The MACE rate was 10.1% among patients with an mRS of 0, 12.2% among patients with an mRS of 1 or 2, and 17.2% among patients with an mRS of 3 or greater (χ22 = 103.4; P < .001) in PRoFESS and 10.9% among patients with an mRS of 0, 13.3% among patients with an mRS of 1 or 2, and 15.3% among patients with an mRS of 3 or greater (χ22 = 5.8; P = .06) in IRIS. Compared with patients with an mRS of 0, patients with an mRS of 3 or greater had increased hazard for recurrent stroke in PRoFESS (hazard ratio [HR], 1.63; 95% CI, 1.38-1.92; P < .001) and in IRIS (HR, 1.91; 95% CI, 1.28-2.86; P = .002). There was also increased hazard for MACE in PRoFESS (HR, 1.90; 95% CI, 1.66-2.18; P < .001) and in IRIS (HR, 1.45; 95% CI, 1.03-2.03; P = .03). This cohort study found that higher baseline poststroke disability was associated with increased rates of recurrent stroke and MACE. Including more patients with greater baseline disability in stroke prevention trials may improve the statistical power and generalizability of these studies.

REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy.

LMNA (lamin A/C)-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA-related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23-72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences (P>0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, -24.2 to 34.1]; P=0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; P=0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; P=0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; P=0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; P=0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; P=0.84) were similar between groups. No new safety findings were observed. Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA-related dilated cardiomyopathy. URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.