Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials.

Current pharmacological therapies for heart failure with reduced ejection fraction are largely either repurposed anti-hypertensives that blunt overactivation of the neurohormonal system or diuretics that decrease congestion. However, they do not address the symptoms of heart failure that result from reductions in cardiac output and reserve. Over the last few decades, numerous attempts have been made to develop and test positive cardiac inotropes that improve cardiac haemodynamics. However, definitive clinical trials have failed to show a survival benefit. As a result, no positive inotrope is currently approved for long-term use in heart failure. The focus of this state-of-the-art review is to revisit prior clinical trials and to understand the causes for their findings. Using the learnings from those experiences, we propose a framework for future trials of such agents that maximizes their potential for success. This includes enriching the trials with patients who are most likely to derive benefit, using biomarkers and imaging in trial design and execution, evaluating efficacy based on a wider range of intermediate phenotypes, and collecting detailed data on functional status and quality of life. With a rapidly growing population of patients with advanced heart failure, the epidemiologic insignificance of heart transplantation as a therapeutic intervention, and both the cost and morbidity associated with ventricular assist devices, there is an enormous potential for positive inotropic therapies to impact the outcomes that matter most to patients

Impurity and strain effects on the magnetotransport of La1.85Sr0.15Cu(1-y)Zn(y)O4 films

The influence of zinc doping and strain related effects on the normal state transport properties(the resistivity, the Hall angle and the orbital magneto- resistance(OMR) is studied in a series of La1.85Sr0.15Cu(1-y)Zn(y)O4 films with values of y between 0 and 0.12 and various degrees of strain induced by the mismatch between the films and the substrate. The zinc doping affects only the constant term in the temperature dependence of cotangent theta but the strain affects both the slope and the constant term, while their ratio remains constant.OMR is decreased by zinc doping but is unaffected by strain. The ratio delta rho/(rho*tan^2 theta) is T-independent but decreases with impurity doping. These results put strong constraints on theories of the normal state of high- temperature superconductors

In-hospital Initiation and Up-titration of Guideline-directed Medical Therapies for Heart Failure with Reduced Ejection Fraction

Implementation of guideline-directed medical therapy for patients with heart failure is suboptimal. The use of guideline-directed medical therapy improves minimally after heart failure hospitalisation, despite this event clearly indicating increased risk of further hospitalisation and death. In-hospital initiation and titration of guideline-directed medical therapies is one potential strategy to fill these gaps in care, both in the acute vulnerable period after hospital discharge and in the long term. The purpose of this article is to review the knowledge gaps in best practices of in-hospital initiation and up-titration of guideline-directed medical therapies, the benefits and risks of in-hospital initiation and post-discharge focused titration of guideline-directed medical therapies, the recent literature evaluating these practices, and propose strategies to apply these principles to the care of patients with heart failure with reduced ejection fraction

Self-Care for the Prevention and Management of Cardiovascular Disease and Stroke: A Scientific Statement for Healthcare Professionals from the American Heart Association

Self‐care is defined as a naturalistic decision‐making process addressing both the prevention and management of chronic illness, with core elements of self‐care maintenance, self‐care monitoring, and self‐care management. In this scientific statement, we describe the importance of self‐care in the American Heart Association mission and vision of building healthier lives, free of cardiovascular diseases and stroke. The evidence supporting specific self‐care behaviors such as diet and exercise, barriers to self‐care, and the effectiveness of self‐care in improving outcomes is reviewed, as is the evidence supporting various individual, family‐based, and community‐based approaches to improving self‐care. Although there are many nuances to the relationships between self‐care and outcomes, there is strong evidence that self‐care is effective in achieving the goals of the treatment plan and cannot be ignored. As such, greater emphasis should be placed on self‐care in evidence‐based guidelines

Clinical outcomes and healthcare expenditures in the real world with left ventricular assist devices - The CLEAR-LVAD study

BACKGROUND: Several distinctly engineered left ventricular assist devices (LVADs) are in clinical use. However, contemporaneous real world comparisons have not been conducted, and clinical trials were not powered to evaluate differential survival outcomes across devices. OBJECTIVES: Determine real world survival outcomes and healthcare expenditures for commercially available durable LVADs. METHODS: Using a retrospective observational cohort design, Medicare claims files were linked to manufacturer device registration data to identify de-novo, durable LVAD implants performed between January 2014 and December 2018, with follow-up through December 2019. Survival outcomes were compared using a Cox proportional hazards model stratified by LVAD type and validated using propensity score matching. Healthcare resource utilization was analyzed across device types by using nonparametric bootstrap analysis methodology. Primary outcome was survival at 1-year and total Part A Medicare payments. RESULTS: A total of 4,195 de-novo LVAD implants were identified in fee-for-service Medicare beneficiaries (821 HeartMate 3; 1,840 HeartMate II; and 1,534 Other-VADs). The adjusted hazard ratio for mortality at 1-year (confirmed in a propensity score matched analysis) for the HeartMate 3 vs HeartMate II was 0.64 (95% CI; 0.52-0.79, p\u3c 0.001) and for the HeartMate 3 vs Other-VADs was 0.51 (95% CI; 0.42-0.63, p \u3c 0.001). The HeartMate 3 cohort experienced fewer hospitalizations per patient-year vs Other-VADs (respectively, 2.8 vs 3.2 EPPY hospitalizations, p \u3c 0.01) and 6.1 fewer hospital days on average (respectively, 25.2 vs 31.3 days, p \u3c 0.01). The difference in Medicare expenditures, conditional on survival, for HeartMate 3 vs HeartMate II was -$10,722, p \u3c 0.001 (17.4$17,947, p \u3c 0.001 (26.1% reduction). CONCLUSIONS: In this analysis of a large, real world, United States. administrative dataset of durable LVADs, we observed that the HeartMate 3 had superior survival, reduced healthcare resource use, and lower healthcare expenditure compared to other contemporary commercially available LVADs

What’s Next for Acute Heart Failure Research?

Each year over one million patients with acute heart failure (AHF) present to a United States emergency department (ED). The vast majority are hospitalized for further management. The length of stay and high postdischarge event rate in this cohort have changed little over the past decade. Therapeutic trials have failed to yield substantive improvement in postdischarge outcomes; subsequently, AHF care has changed little in the past 40 years. Prior research studies have been fragmented as either “inpatient” or “ED-based.” Recognizing the challenges in identification and enrollment of ED patients with AHF, and the lack of robust evidence to guide management, an AHF clinical trials network was developed. This network has demonstrated, through organized collaboration between cardiology and emergency medicine, that many of the hurdles in AHF research can be overcome. The development of a network that supports the collaboration of acute care and HF researchers, combined with the availability of federally funded infrastructure, will facilitate more efficient conduct of both explanatory and pragmatic trials in AHF. Yet many important questions remain, and in this document our group of emergency medicine and cardiology investigators have identified four high-priority research areas

Soluble guanylate cyclase stimulators in patients with heart failure with reduced ejection fraction across the risk spectrum

Patients with heart failure with reduced ejection fraction (HFrEF) have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Soluble guanylate cyclase (sGC) stimulators have the potential to lower this risk by modifying the nitric oxide–sGC–cyclic guanosine monophosphate cascade – a pathophysiological pathway that has been targeted with limited success in HFrEF previously. Vericiguat, an sGC stimulator, was shown to improve outcomes in patients with HFrEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. However, this trial included patients with recently worsening disease. In this brief review, we discuss the rationale of evaluating sGC stimulators in lower-risk HFrEF patients. First, all key HFrEF medications have been evaluated in both higher- and lower-risk populations, and the treatment effect is not always consistent across the risk spectrum. Second, pre-clinical studies and post-hoc studies of the VICTORIA trial have suggested that sGC stimulators may have cardioprotective effects – these effects may be more apparent when the medication is initiated earlier in the disease process. Third, the effect of vericiguat on cardiovascular mortality remains uncertain and a trial with a longer follow-up in a lower-risk population may allow better assessment of its effect on cardiovascular mortality. Therefore, there is a pertinent need to investigate the effects of vericiguat in optimally treated, low-risk HFrEF patients (i.e. those without recently worsening heart failure).</p

Clinical and Research Considerations for Patients with Hypertensive Acute Heart Failure

Management approaches for patients in the emergency department (ED) who present with acute heart failure (AHF) have largely focused on intravenous diuretics. Yet, the primary pathophysiologic derangement underlying AHF in many patients is not solely volume overload. Patients with hypertensive AHF (H-AHF) represent a clinical phenotype with distinct pathophysiologic mechanisms that result in elevated ventricular filling pressures. To optimize treatment response and minimize adverse events in this subgroup, we propose that clinical management be tailored to a conceptual model of disease based on these mechanisms. This consensus statement reviews the relevant pathophysiology, clinical characteristics, approach to therapy, and considerations for clinical trials in ED patients with H-AHF

Magnetotransport in the Normal State of La1.85Sr0.15Cu(1-y)Zn(y)O4 Films

We have studied the magnetotransport properties in the normal state for a series of La1.85Sr0.15Cu(1-y)Zn(y)O4 films with values of y, between 0 and 0.12. A variable degree of compressive or tensile strain results from the lattice mismatch between the substrate and the film, and affects the transport properties differently from the influence of the zinc impurities. In particular, the orbital magnetoresistance (OMR) varies with y but is strain-independent. The relations for the resistivity and the Hall angle and the proportionality between the OMR and tan^2 theta are followed about 70 K. We have been able to separate the strain and impurity effects by rewriting the above relations, where each term is strain-independent and depends on y only. We also find that changes in the lattice constants give rise to closely the same fractional changes in other terms of the equation.The OMR is more strongly supressed by the addition of impurities than tan^2 theta. We conclude that the relaxation ratethat governs Hall effect is not the same as for the magnetoresistance. We also suggest a correspondence between the transport properties and the opening of the pseudogap at a temperature which changes when the La-sr ratio changes, but does not change with the addition of the zinc impurities

Differential mortality association of loop diuretic dosage according to blood urea nitrogen and carbohydrate antigen 125 following a hospitalization for acute heart failure

AimsRecent observations in chronic stable heart failure suggest that high-dose loop diuretics (HDLDs) have detrimental prognostic effects in patients with high blood urea nitrogen (BUN), but recent findings have also indicated that diuretics may improve renal function. Carbohydrate antigen 125 (CA125) has been shown to be a surrogate of systemic congestion. We sought to explore whether BUN and CA125 modulate the mortality risk associated with HDLDs following a hospitalization for acute heart failure (AHF).Methods and resultsWe analysed 1389 consecutive patients discharged for AHF. CA125 and BUN were measured at a mean of 72 ± 12 h after admission. HDLDs (≥120 mg/day in furosemide equivalent dose) were interacted to a four-level variable according to CA125 (>35 U/mL) and BUN (above the median), and related to all-cause mortality. At a median follow-up of 21 months, 561 (40.4%) patients died. The use of HDLDs was independently associated with increased mortality [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.01–1.50], but this association was not homogeneous across CA125–BUN categories (P for interaction <0.001). In patients with normal CA125, use of HDLDs was associated with high mortality if BUN was above the median (HR 2.29, 95% 1.51–3.46), but not in those with BUN below the median (HR 1.22, 95% CI 0.73–2.04). Conversely, in patients with high CA125, HDLDs showed an association with increased survival if BUN was above the median (HR 0.73, 95% CI 0.55–0.98) but was associated with increased mortality in those with BUN below the median (HR 1.94, 95% CI 1.36–2.76).ConclusionThe risk associated with HDLDs in patients after hospitalization for AHF was dependent on the levels of BUN and CA125. The information provided by these two biomarkers may be helpful in tailoring the dose of loop diuretics at discharge for AHF