Heart Failure Clinical Trials Research Articles

Sex differences in heart failure

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20-25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.

Monitoring of iron status in patients with heart failure.

The 2016 ESC/HFA heart failure (HF) guidelines emphasize the importance of identifying and treating iron deficiency (ID) in patients with HF. Iron deficiency can occur in half or more of HF sufferers, depending on age and the phase of the disease. Iron deficiency can be a cause of anaemia, but it is also common even without anaemia, meaning that ID is a separate entity, which should be screened for within the HF population. Although assessment of iron stores in bone marrow samples is the most accurate method to investigate iron status, it is not practical in most HF patients. Levels of circulating iron biomarkers are an easily available alternative; especially, ferritin and transferrin saturation (Tsat). In patients with HF serum ferritin level <100 µg/L (regardless of Tsat value) or between 100 and 299 µg/L with Tsat <20% are considered as recommended criteria for the diagnosis of ID, criteria which have been used in the clinical trials in HF that have led to a recommendation to treat ID with intravenous iron. We discuss the optimal measures of iron biomarkers in patients with HF in order to screen and monitor iron status and introduce some novel ways to assess iron status.

Representativeness of a Heart Failure Trial by Race and Sex: Results From ASCEND-HF and GWTG-HF

ObjectivesThis study sought to determine the degree to which U.S. patients enrolled in a heart failure (HF) trial represent patients in routine U.S. clinical practice according to race and sex. BackgroundBlack patients and women are frequently under-represented in HF clinical trials. However, the degree to which black patients and women enrolled in trials represent such patients in routine practice is unclear. MethodsThe ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized patients hospitalized for HF to receive nesiritide or placebo from May 2007 to August 2010 and was neutral for clinical endpoints. This analysis compared non-Hispanic white (n = 1,494) and black (n = 1,012) patients enrolled in ASCEND-HF from the U.S. versus non-Hispanic white and black patients included in a U.S. hospitalized HF registry (i.e., Get With The Guidelines–Heart Failure [GWTG-HF]) during the ASCEND-HF enrollment period and meeting trial eligibility criteria. ResultsAmong 79,291 white and black registry patients, 49,063 (62%) met trial eligibility criteria (white, n = 37,883 [77.2%]; black, n = 11,180 [22.8%]). Women represented 35% and 49% of the ASCEND-HF and trial-eligible GWTG-HF cohorts, respectively. Compared with trial-enrolled patients, trial-eligible GWTG-HF patients tended to be older with higher blood pressure and higher ejection fraction. Trial-eligible patients had higher in-hospital mortality (2.3% vs. 1.3%), 30-day readmission (20.2% vs. 16.8%), and 180-day mortality (21.2% vs. 18.6%) than those enrolled in the trial (all p < 0.02), with consistent mortality findings by race and sex. After propensity score matching, mortality rates were similar; however, trial-eligible patients continued to have higher rates of 30-day readmission (23.1% vs. 17.3%; p < 0.01), driven by differences among black patients and women (all p for interaction ≤0.02). ConclusionsPatients with HF seen in U.S. practice and eligible for the ASCEND-HF trial had worse clinical outcomes than those enrolled in the trial. After accounting for clinical characteristics, trial-eligible real-world patients continued to have higher rates of 30-day readmission, driven by differences among black patients and women. Social, behavioral, and other unmeasured factors may impair representativeness of patients enrolled in HF trials, particularly among racial/ethnic minorities and women. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852)

P6300Endothelial cell activation by pro-inflammatory cytokines exerts novel paracrine effects on co-cultured cardiomyocytes

Abstract Background Anti-inflammatory therapies have failed to meet expectations in recent clinical trials for heart failure, despite the number of studies demonstrating pro-fibrotic, arrhythmogenic and hypertrophic effects of inflammation. To enlighten this, we sought to examine the contribution of non-myocytes in the cardiac inflammatory response. Endothelial cells (EC) can regulate cardiomyocyte (CM) function with multiple soluble factors. While many studies have shown the effects of pro-inflammatory cytokines on EC or CM separately, it is still unclear how the activation of EC can affect CM function. Purpose We studied the effect of pro-inflammatory pre-conditioning of EC on CM in indirect co-culture systems and in an ex vivo model of cardiac tissue. We hypothesised that pro-inflammatory activation of EC would alter the contractility of co-cultured CM. Methods Human cardiac microvascular EC were first pre-conditioned for 24h with Cytomix (1 ng/ml TNF-α, 1 ng/ml IL-1β, 25 ng/ml IL-6 Rα/IL-6 chimera) and co-cultured in a transwell system (pore size: 0.4μm) with adult rat ventricular CM. Co-culture supernatants were screened using a Cytokine Profiler Array. In vitro analysis of calcium handling in CM utilised the optical mapping technique and Fluo-4. Contractility of cardiac tissue was measured ex vivo using myocardial slices of 300 μm, prepared from left ventricles of adult rat and cultured for 24h with field stimulation and a fixed stretch producing a sarcomeric length of 2.2 μm. Results Treatment of EC by Cytomix prior to co-cultures induced a release of CC and CXC chemokines, G-/GM-CSF, ST2 and the adhesion molecule ICAM-1. Using published RNAseq datasets we noticed that adult CM do not constitutively express the receptors for the chemokines identified with the Profiler Array. However, duration of calcium transients in CM was significantly reduced from 454 to 322 ms in co-cultures with EC pre-conditioned by Cytomix, compared to untreated EC. Amplitude and time to peak were unchanged. In contrast, myocardial slices treated with Cytomix demonstrated a significant increase in contractility compared to control (from 3.3 to 5.3 mN/mm2) but no significant change in the duration of contraction (from 467 to 434 ms) or the rate of relaxation. Conclusions Pre-conditioned EC exert paracrine effects on the calcium handling of isolated CM, suggesting pro-inflammatory activation of proximal EC can affect CM function. In myocardial slices, pro-inflammatory stimulation provoked an inotropic response. The divergence of effect with findings in isolated cells may reflect differences in experimental design and multicellularity. Future work will aim to characterise the soluble mediators involved, and selectively target EC in slices to contextualise the effects described in co-cultures. Ultimately, this may inform the development of novel anti-inflammatory strategies for clinical use. Acknowledgement/Funding British Heart Foundation

What causes sudden death in patients with chronic heart failure and a reduced ejection fraction?

Sudden death characterizes the mode of demise in 30–50% of patients with chronic heart failure and a reduced ejection fraction. Occasionally, these events have an identifiable pathophysiological trigger, e.g. myocardial infarction, catecholamine surges, or electrolyte imbalances, but in most circumstances, there is no acute precipitating mechanism. Instead, adverse left ventricular remodelling and fibrosis creates an exceptionally fragile and highly vulnerable substrate, which can be characterized using the model developed in theoretical physics of ‘self-organizing criticality’. This framework has been applied to describe the genesis of avalanches, nodes of traffic congestion unrelated to an accident, the abrupt system-wide failure of electrical grids, and the initiation of cancer and neurodegenerative diseases. Self-organizing criticality within the ventricular myocardium relies on complex adaptations to progressive stress and stretch, which evolve inevitably to an abrupt end (termed ‘cascading failure’), even though the rate of deterioration of the underlying disease process has not changed. The result is acute circulatory collapse (i.e. sudden death) in the absence of an identifiable triggering event. Cascading failure in a severely remodelled or fibrotic heart can become manifest electrically as a first-time ventricular tachyarrhythmia that is responsive to the shock delivered by an implantable cardioverter-defibrillator (ICD). Alternatively, it may present as an acute mechanical failure, which is manifest as (i) asystole, bradyarrhythmia, or electromechanical dissociation; or (ii) incessant ventricular fibrillation that persists despite repetitive ICD discharges; in both instances, the sudden deaths cannot be prevented by an ICD. This conceptual framework explains why anti-remodelling and antifibrotic interventions (i.e. neurohormonal antagonists and cardiac resynchronization) reduce the risk of sudden death in patients with heart failure in the absence of an ICD and provide incremental benefits in those with an ICD. The adoption of anti-remodelling and antifibrotic treatments may explain why the incidence of sudden death in clinical trials of heart failure has declined dramatically over the past 10–15 years, independent of the use of ICDs.

Differences between Academic and Non-Academic Institutions in Heart Failure Clinical Trials in North America: Insights from the HFSA Research Network Survey

Background The conduct of rigorous HF clinical trials requires participation from a wide variety of institutions and partnerships across academic, non-academic, Veterans Affairs, and industry. We aimed to examine differences between academic and non-academic centers in the conduct of HF clinical trials in North America. Methods HFSA distributed an electronic survey to examine the current state of HF clinical trial activity. Surveys were distributed to current or past HFSA members and affiliates, HF members of AHA and ACC. Pearson's chi-squared test was applied to categorical data. Results A total of615 surveys were returned. Of these, 410 respondents reported being currently active in the conduct of HF trials and were included in this analysis. Respondents represented 45 states and 331 distinct institutions. Most respondents were physicians (n=269, 66%), followed by nurses or nurse practitioners (n=83, 20%) and pharmacists (n=20, 5%). The majority of respondents were from academic centers (n=311, 75.5%), followed by non-academic (n=59, 14%), industry (n=22, 5%), and Veterans Affairs (n=18, 4%). Academic and non-academic institutions participated in a similar number of trials per year and reported similar numbers of subjects enrolled per year (Table). In addition, regulatory and staff resources including time to Institutional Review Board (IRB) approval, access to a central IRB, timeline for execution of contracts and number of study coordinators were not different between academic and non-academic institutions. Respondents from academic institutions did report more publications per year than those from non-academic institutions and participation differed in types of trials. Involvement as a lead national primary investigator or co-investigator for multi-centered trials was higher in academic institutions than non-academic institutions (40% vs 29%). Conclusion Academic and non-academic institutions contributed similarly to the conduct of HF clinical trials across North America. Regulatory and staff resources were also comparable. Opportunities exist to better engage non-academic investigators in publications and other leadership opportunities within multi-centered HF clinical trials.

Guideline Directed Medical Therapy in Heart Failure Trials: A New Proposed Scoring System

Background Current guidelines recommend multiple drugs titrated to maximally-tolerated dose as Guideline Directed Medical Therapy (GDMT) for chronic heart failure (HF). In clinical trials, background therapy at randomization is often stated as being “optimized” but objective criteria supporting such assertion are lacking. We propose a simple scoring system to define GDMT, set thresholds for optimal therapy, and standardize comparisons across HF clinical trials. Methods We evaluated current ACC/AHA/HFSA and ESC HF guidelines and the GDMT definition in 8 HF drug and device trials. We created a score based on strength of evidence, literature review, and data regarding dose effects. The score was tested in 10 hypothetical clinical scenarios based on likely drug combinations in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) Trial. Results Figure 1 shows the proposed score. Of the 10 clinical scenarios based on COAPT, 3 patients were not optimized according to the proposed score. The score performed well in defining GDMT in most of these clinical scenarios. Conclusion We propose a simple score for measuring GDMT, which validates well in clinical scenarios from a modern clinical trial. Utilizing this system will help establish a quality threshold for background therapy according to guideline recommendations, and provide standards for comparison across clinical trials. Further research should be conducted to determine whether the proposed score correlates with clinical outcomes.

BAOXIN Granules Protected Mouse Model With Elevated Afterload From Cardiac Hypertrophy by Suppressing Both Inflammatory Reaction and Collagen Deposition.

BAOXIN Pill was reported to be effective clinically for chronic heart failure based on the principles of traditional Chinese medicine (TCM), invigorating qi and activating blood. The present study evaluated preclinically the effects of the improved dosage form, BAOXIN Granules, on cardiac hypertrophy. Transverse aortic constriction (TAC) was performed in mice to model cardiac hypertrophy by aortic stenosis for 4 weeks. The sham and TAC group were intragastrically administrated with saline as the controls. Two treatment groups were administrated orally with 10 mg/kg⋅d Enalapril (positive control) or 0.77 g/kg⋅d BAOXIN Granules for 4 weeks respectively. The effects were evaluated by echocardiography, morphology, and biological markers for cardiac function. The specific genes involved in inflammation and fibrosis were also examined for their expressions to investigate the pathways involved in early heart failure. Just as Enalapril, BAOXIN Granules administration markedly attenuated left ventricular hypertrophy and improved heart function as evidenced by echo cardiography, morphology. Accordingly, the biomarkers of the early stage heart failure, ANP, BNP and β-MHC, were decreased in the two treatment groups. We also found that mRNA expressions of some inflammatory factors and fibrosis associated genes were down-regulated in the tissue of heart after treatment. BAOXIN Granules may protect the heart from myocardial hypertrophy caused by increasing left ventricular afterload. It can suppress both inflammatory reaction and collagen deposition during pressure overload. BAOXIN Granules is advised to be tested in clinical trials for heart failure in the future.

Update in recent clinical trials in heart failure.

Heart failure represents a major growing health problem in developed world. This article aims to review recent heart failure trials that have significantly impacted the management of heart failure. Despite advances in heart failure, mortality and morbidity remains elevated amongst patients. Recent clinical trials demonstrate promising treatment strategies that likely impact clinical practice; including heart failure prevention with the use of SGLT2-inhibitors in patients with diabetes and cardiovascular risk, new treatments that may abrogate disease progression in cardiac amyloidosis, intravenous iron therapy in iron deficiency anemia in chronic systolic heart failure, predischarge treatment with angiotensin receptor blocker with neprilysin inhibition (ARNi) in patients hospitalized for acute decompensated heart failure, and newer continuous flow left ventricular assist device with increased durability and efficacy in patients with Stage D heart failure. Recent clinical trials with SGLT2 inhibitors, therapies targeting transthyretin cardiac amyloidosis, iron, angiotensin receptor blocker with neprilysin inhibition and newer mechanical circulatory support devices are very promising as practice changing new treatment strategies in prevention and treatment of heart failure. This article presents a summary of important trials and should be of practical value to both clinicians and researchers.

Evidence-based drug therapy for heart failure-an update

Chronic heart failure affects millions of people worldwide and is associated with high morbidity and mortality. Because of steadily increasing ageing populations and improved survival rates after myocardial infarction, the incidence of chronic heart failure is rising. As acute decompensated heart failure is one of the leading causes for hospitalization in Germany, heart failure imposes ahuge economic burden on its health care system. Guideline directed therapy is important to improve prognosis. In the following, we give an overview about novel heart failure clinical trial results and point to important comorbidities.

The modifying effects of social support on psychological outcomes in patients with heart failure.

We examined the modifying effects of social support on depressive symptoms and health-related quality of life (QoL) in patients receiving coping skills training (CST). We considered the modifying effects of social support in the Coping Effectively with Heart Failure clinical trial, which randomized 179 heart failure (HF) patients to either 4 months of CST or usual care enhanced by HF education (HFE). CST involved training in specific coping techniques, whereas HFE involved education about HF self-management. Social support was assessed by the Enhancing Recovery in Coronary Heart Disease (ENRICHD) Social Support Inventory, QoL was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), and depression was assessed with the Beck Depression Inventory-II (BDI-II). Linear regression models revealed a significant Intervention Group × Baseline Social Support interaction for change in KCCQ total scores (p = .006) and BDI-II scores (p < .001). Participants with low social support assigned to the CST intervention showed large improvements in KCCQ scores (M = 11.2, 95% CI [5.7, 16.8]), whereas low-social-support patients assigned to the HFE controls showed no significant change (M = -0.8, 95% CI [-7.2, 5.6]). Similarly, BDI-II scores in participants with low social support in the CST group showed large reductions (M = -8.7, 95% CI [-11.3, -6.1]) compared with low-social-support HFE participants (M = -3.0, 95% CI [-6.0, -0.1]). HF patients with low social support benefit substantially from telephone-based CST interventions. Targeting HF patients with low social support for behavioral interventions could prove to be a cost-effective strategy for improving QoL and reducing depression. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Cardiovascular risk prediction in the elderly.

Heart failure (HF) in the elderly, besides being a leading cause of mortality and morbidity, is rapidly increasing in prevalence with patients aged 65 and older accounting for more than 75% of heart failure hospitalizations. Elderly patients have historically been unrepresented in clinical HF trials and often present with multiple comorbidities, including frailty, depression, nutritional, functional and cognitive impairments. Additionally, pharmacologic challenges such as adherence to therapy, polypharmacy, altered drug pharmacokinetics and/or renal derangements make them less likely to receive guideline-directed medical therapies for HF. Recognition of these various interrelated domains is key and should prompt a multidisciplinary, holistic management approach so as to optimize prognosis in this vulnerable subset of the population.

Editorial introductions

Current Opinion in Cardiology was launched in 1985. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of cardiology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Ali J. MarianAli J. MarianDr Ali J. Marian joined the faculty at the Department of Medicine (Cardiology) at Baylor College of Medicine, USA, in 1992 and was recruited to The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at UTHealth, USA, in 2006. His colleagues nationally and internationally recognize him for his research achievements and expertise in genetics of cardiomyopathies. He received the Young Investigator Award from the American College of Cardiology, the Junior Faculty Award for research from the American Federation of Medical Research, the Award for Excellence in Research at Baylor College of Medicine, the Established Investigator Award by the American Heart Association, the Clinician-Scientist Award in Translational Research from Burroughs Wellcome Fund and the Best Editor Award from the American Heart Association. Dr Marian is a Deputy Editor for Circulation Research. He is an Associate Editor for European Journal of Clinical Investigation, Section Editor on Genetics for Current Opinion in Cardiology and Current Atherosclerosis Reports and a former Associate Editor for Circulation. Dr Marian has co-authored over 180 manuscripts in peer-reviewed journals. He has served as a reviewer for > 100 National Institute of Health, American Heart Association and other organization's study sections. Dr Marian's research is supported by grants from NHLBI-NIH, Leducq Foundation Trans-Atlantic Network of Excellence and local foundations. Rebecca CogswellRebecca CogswellDr Cogswell completed internal medicine residency, chief residency, and cardiology fellowship at the University of California, San Francisco, USA. While at UCSF, she also completed a year of advanced clinical research training. She then went on to complete Advanced Heart Failure fellowship at the University of Minnesota, USA. She has been on faculty at the University of Minnesota since 2013 and is presently the Medical Director of Mechanical Circulatory Support Program. Dr Cogswell's research focus is the skeletal muscle changes that occur in end stage heart failure. Specifically, she is interested in what these changes can reveal about optimal timing of advanced heart failure therapies and using these measures to predict outcomes after mechanical circulatory support. She has built a left ventricular assist device database at the University of Minnesota and is collaborating with other centers towards answering several clinical questions in the contemporary continuous flow LVAD population. She is presently the Advanced Heart Failure fellowship director and is an active reviewer for Journal of Heart Lung Transplant and Circulation Heart Failure. She is a principle investigator for several heart failure and LVAD related clinical trials. In 2017, she was appointed to the Medtronic Heart Failure Advisory Board. In addition, she developed and directs to the Infiltrative Cardiomyopathies Clinic at the University of Minnesota. Gene KimGene KimDr Kim is a cardiologist with the Advanced heart failure, Cardiac transplant, and Mechanical Circulatory Support Program at the University of Chicago Medicine, USA. He is an Assistant Professor of Medicine and the Advanced Heart Failure Fellowship Program Director. His medical school, residency, and fellowship training were completed at the University of Chicago. Dr Kim's research interests include the genetic and epigenetic regulation of heart failure and arrhythmogenesis with publications on the role of microRNAs in cardiomyopathy. His interests also include myocardial recovery, extracellular matrix in failing myocardium, and the role of inflammation and angiogenesis in LVAD patients. He has published over 80 articles and book chapters and is an investigator in numerous clinical trials.

Heart Failure Site-Based Research in the United States: Results of the Heart Failure Society of America Research Network Survey

ObjectivesThis study sought to determine clinician and scientist involvement in heart failure (HF) clinical research and to describe the challenges of conducting clinical trials in the United States. BackgroundImprovements in the current capability, potential, and deficiencies of the HF clinical research infrastructure in the United States are needed in order to enhance efficiency and impact. MethodsThe Heart Failure Society of America (HFSA) distributed an electronic survey regarding HF clinical trial activity for the purpose of understanding the barriers that exist to conducting high-quality HF clinical research. ResultsOverall, 1,794 HFSA members were queried, and 434 members (24%) completed surveys, whereas a total of 7,589 individuals with interest in HF were queried, and 615 completed surveys. Of the respondents, 410 (67%) were actively engaged in HF research and 120 (20%) were interested in research. Most respondents, 270, were physicians (44%); 311 of the total (76% of the total and 80% of physicians) practiced in academic institutions; 333 respondents (81%) had served as principal investigators and 73 (18%) as site coordinators. Respondents active in clinical research usually participated in 1 to 5 trials and enrolled 1 to 20 patients annually. Institutional review board (IRB) approval typically required 3 months, and contract completion required 3 to 6 months per site. The greatest barriers to research were insufficient site budgets, delay in contracting, inability to find participants meeting trial entry criteria, and unavailability of qualified study coordinators. ConclusionsMany U.S. clinical research sites are constrained by budgetary, staffing, and contractual issues. The HFSA Research Network seeks to unify interested sites and deconstruct barriers to permit high-value HF research.

Soluble Guanylate Cyclase Activators Increase cGMP Expression and Improve Vascular Function and Placental Ischemia‐Induced Hypertension

Preeclampsia (PE) is a pregnancy specific disorder associated with maternal hypertension and endothelial dysfunction caused by the release of anti‐angiogenic and pro‐inflammatory factors from the ischemic placenta. In addition, nitric oxide (NO), which typically binds to soluble guanylate cyclase (sGC), and synthesizes cGMP, to facilitate vasodilation, is depleted in PE and contributes to vascular dysfunction. A novel class of drug, sGC activators, which are in clinical trials for pulmonary hypertension and heart failure, have been shown to bind to the sGC molecule and increase cGMP activity independently of NO. However, the therapeutic potential of sGC activators during PE is not known. We tested the hypothesis that sGC activators attenuate blood pressure in a placental ischemic rat model of PE by increasing cGMP production and improving vascular function. Sprague‐Dawley rats underwent Sham or RUPP (Reduced Uterine Perfusion Pressure) surgery on gestational day (GD) 14, where silver clips were placed on the abdominal aorta and branches of the ovarian artery to induce placental ischemia. Animals were then placed on placebo (P) or sGC activator (sGC‐A, 16 ppm, BAY 60‐2770) ‐supplemented diets, ad libitum, from GD14–19. On GD19, blood pressure was measured via indwelling catheter and uterine arteries were harvested to determine endothelium‐dependent vasorelaxation and cGMP expression. To determine the effect of sGC activator treatment on vascular function, uterine arteries from placebo or sGC activator‐supplemented rats were mounted on a wire myograph and pre‐constricted, followed by endothelium‐dependent vasorelaxation. A subset of uterine arteries from these rats were also prepared to determine expression of cGMP. RUPP surgery significantly increased mean arterial blood pressure (Sham+P, n=20, 105±9 mmHg; RUPP+P, n=19, 126±13 mmHg; P&lt;0.05), and this was attenuated by treatment with the sGC activator (RUPP+sGC‐A, n=11, 107±8 mmHg; P&lt;0.05). RUPP surgery induced endothelial dysfunction in uterine arteries (% relaxation, Sham+P, n=6, 92±2 %; RUPP+P, n=5, 34±12%, P&lt;0.05), which was restored in the sGC activator treated group (RUPP+sGC‐A, n=5, 103±2%, P&lt;0.05). Finally, cGMP was reduced in uterine arteries of RUPP‐operated animals (Sham+P, n=3, 0.11±0.009 pmol/mg; RUPP+P, n=3, 0.033±0.009 pmol/mg, P&lt;0.05); however, sGC activation significantly increased cGMP production in the treated group (RUPP+sGC‐A, n=3, 0.127±0.013 pmol/mg, P&lt;0.05). The results of this study demonstrate that activating sGC can reduce blood pressure by restoring cGMP production and improving vascular function in the RUPP rat. In conclusion, these findings suggest there could be a therapeutic potential for treating PE with sGC activators.Support or Funding InformationThis research was supported by the American Heart Association (18POST33990293) and the National Institutes of Health (P01HL051971, P20GM104357).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Noninvasive Quantification of Pressure-Volume Loops From Brachial Pressure and Cardiovascular Magnetic Resonance.

Pressure-volume (PV) loops provide a wealth of information on cardiac function but are not readily available in clinical routine or in clinical trials. This study aimed to develop and validate a noninvasive method to compute individualized left ventricular PV loops. The proposed method is based on time-varying elastance, with experimentally optimized model parameters from a training set (n=5 pigs), yielding individualized PV loops. Model inputs are left ventricular volume curves from cardiovascular magnetic resonance imaging and brachial pressure. The method was experimentally validated in a separate set (n=9 pig experiments) using invasive pressure measurements and cardiovascular magnetic resonance images and subsequently applied to human healthy controls (n=13) and patients with heart failure (n=28). There was a moderate-to-excellent agreement between in vivo-measured and model-calculated stroke work (intraclass correlation coefficient, 0.93; bias, -0.02±0.03 J), mechanical potential energy (intraclass correlation coefficient, 0.57; bias, -0.04±0.03 J), and ventricular efficiency (intraclass correlation coefficient, 0.84; bias, 3.5±2.1%). The model yielded lower ventricular efficiency ( P<0.0001) and contractility ( P<0.0001) in patients with heart failure compared with controls, as well as a higher potential energy ( P<0.0001) and energy per ejected volume ( P<0.0001). Furthermore, the model produced realistic values of stroke work and physiologically representative PV loops. We have developed the first experimentally validated, noninvasive method to compute left ventricular PV loops and associated quantitative measures. The proposed method shows significant agreement with in vivo-derived measurements and could support clinical decision-making and provide surrogate end points in clinical heart failure trials.

Key Considerations For Integrating Sacubitril/Valsartan Into Chronic Heart Failure Management

Heart failure with reduced ejection fraction remains a prevalent clinical syndrome associated with significant morbidity and mortality. Despite significant advances in heart failure with reduced ejection fraction pharmacotherapy, 5-year mortality remains 50%. Sacubitril/valsartan is a first-in-class angiotensin-receptor-neprilysin inhibitor, Food and Drug Administration–approved to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure with reduced ejection fraction. Sacubitril/valsartan is recognized as a significant therapeutic advancement and endorsed by national guidelines, yet adoption into clinical practice has lagged across the United States. Recommendations for use differ greatly between the Prospective Comparison of Angiotensin-Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure clinical trial, international guidelines, and the Food and Drug Administration-approved labeling, which can lead to uncertainty with prescribing. It is essential to establish an evidence-based, pragmatic approach to patient selection and management of sacubitril-valsartan facilitate integration into clinical practice. This review summarizes the pharmacology of sacubitril/valsartan, its known benefits and risks, and important considerations for incorporating sacubitril/valsartan into chronic heart failure management.

Sex Differences in the Management of Advanced Heart Failure.

Heart failure (HF) is prevalent among women and remains a leading cause of morbidity and mortality in the United States. Currently, 3million women live with HF and the prevalence is projected to continue to increase. The purpose of this review is to highlight sex differences in the use and response to evidence-based pharmacological, device, and advanced HF therapies, as well as explore emerging areas of research in sex differences in the treatment of HF. Under-representation of women in clinical HF trials has limited our understanding of sex-related differences in the treatment and outcomes of HF. Important sex differences exist in the use of evidence-based HF therapies and clinical response among women with HF. In general, women tend to obtain the same clinical benefit from evidence-based HF drug and device therapies, but the utilization rates of guideline-directed medical therapies remain poor compared to men. Future research efforts should focus on increasing the enrollment of women in HF trials to help gain helpful insight into sex-specific differences in treatment effects and subsequent clinical outcomes.

A Critical Appraisal of Short-Term End Points in Acute Heart Failure Clinical Trials

The prevalence of heart failure continues to grow, and this is accompanied by an increase in hospitalization for acute heart failure. Hospitalization for heart failure results in a trajectory shift of the syndrome and is associated with worsening outcomes, increased mortality risk, and high costs. Numerous clinical trials over the past 2 decades have had limited success, with no single agent shown to improve mortality risk. The lack of success is multifactorial and in part related to inadequate targets and end points selected for intervention, underscoring the need to better understand and define the pathophysiology of acute heart failure. To better inform future drug development, this review critically explores the short-term end points and outcomes that previous phase III acute heart failure trials have examined.

Enrollment of Older Patients, Women, and Racial and Ethnic Minorities in Contemporary Heart Failure Clinical Trials

Despite the importance of age, sex, and race/ethnicity representativeness in clinical trials, limited data exist regarding the enrollment trends of these groups in contemporary heart failure (HF) trials. To characterize the representation of older patients, women, and racial and ethnic minorities in HF trials. We performed a systematic search of HF trials enrolling more than 400 participants published between January 2001 and December 2016 using PubMed/Medline and ClinicalTrials.gov. A total of 118 trials enrolling a cumulative 215 508 patients were included. Trial findings were compared with large epidemiologic studies indexed to hospitalization status and ejection fraction. Median number of participants per trial was 994 (interquartile range [IQR], 543-1899), enrolled from a median of 82 (IQR, 28-171) study sites. Overall, 94 trials (80%) enrolled patients with HF with reduced ejection fraction (HFrEF) exclusively. Mean (SD) age of trial participants was 65 (11) years (from 64 years in 2001 to 2004 to 65 years in 2013 to 2016), and 58 873 of 215 508 were women (27%; from 26% in 2001 to 2004 to 29% in 2013 to 2016); no significant temporal trends were observed (P ≥ .60 for both). Chronic HF with preserved ejection fraction (HFpEF) trials enrolled older participants (mean [SD] age, 71 [7] years compared with 65 [11] years for HFrEF and 66 [12] years for acute HF [AHF] trials; P = .01). Corresponding mean ages in US epidemiologic studies were 69 years for HFrEF and 73 years for both patients with HFpEF and patients with AHF. The HFpEF trials had a higher proportion of women (n = 4940 of 8845 [56%]) compared with HFrEF (n = 34 397 of 143 538 [24%]) or AHF (n = 11 013 of 34 633 [32%]) (P < .001). Corresponding weighted proportions of women in HFpEF, HFrEF, and AHF trials in epidemiologic studies were 62%, 29%, and 50%, respectively. Distribution of racial/ethnic groups was reported in 55% (47%) of the trials; 22% of the participants were not white (n = 27 463 of 124 980), with significant increase over time from 13% in 2001 to 2004 (n = 5606 of 44 616) to 30% in 2013 to 2016 (8421 of 28 073) (P = .01). In contemporary HF trials, older patients and women are consistently underrepresented. Race/ethnicity data are reported in less than half of trials; when reported, such data show that enrollment of nonwhite patients increased over time.