The Impact of Acute Exercise on Hemostasis and Angiogenesis Mediators in Patients With Continuous-Flow Left Ventricular Assist Devices: A Prospective Observational Pilot Study.

Impaired primary hemostasis and dysregulated angiogenesis, known as a two-hit hypothesis, are associated with gastrointestinal (GI) bleeding in patients with continuous-flow left ventricular assist devices (CF-LVADs). Exercise is known to influence hemostasis and angiogenesis in healthy individuals; however, little is known about the effect in patients with CF-LVADs. The objective of this prospective observational study was to determine whether acute exercise modulates two-hit hypothesis mediators associated with GI bleeding in patients with a CF-LVAD. Twenty-two patients with CF-LVADs performed acute exercise either on a cycle ergometer for approximately 10 minutes or on a treadmill for 30 minutes. Blood samples were taken pre- and post-exercise to analyze hemostatic and angiogenic biomarkers. Acute exercise resulted in an increased platelet count (p < 0.00001) and platelet function (induced by adenosine diphosphate, p = 0.0087; TRAP-6, p = 0.0005; ristocetin, p = 0.0009). Additionally, high-molecular-weight vWF multimers (p < 0.00001), vWF collagen-binding activity (p = 0.0012), factor VIII (p = 0.034), angiopoietin-1 (p = 0.0026), and vascular endothelial growth factor (p = 0.0041) all increased after acute exercise. This pilot work demonstrates that acute exercise modulated two-hit hypothesis mediators associated with GI bleeding in patients with CF-LVADs.

Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (-)-noradrenaline.

Omecamtiv mecarbil (OM) is a novel medicine for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. To assist translation to clinical practice we investigated OMs effect on explanted human failing hearts, specifically; contractile dynamics, interaction with the ß1 -adrenoceptor (AR) agonist (-)-noradrenaline and spontaneous contractions. Left and right ventricular trabeculae from 13 explanted failing hearts, and trabeculae from 58 right atrial appendages of non-failing hearts, were incubated with or without a single concentration of OM for 120 min. Time to peak force (TPF) and 50% relaxation (t50% ) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration-effect curves were established to (-)-noradrenaline at ß1 -ARs in the absence or presence of OM. OM prolonged TPF and t50% in ventricular trabeculae (600 nM, 2 µM, p < .001). OM had no significant inotropic effect but reduced time dependent deterioration in contractile strength compared to control (p < .001). OM did not affect the generation of spontaneous contractions. The potency of (-)-noradrenaline (pEC50 6.05 ± 0.10), for inotropic effect, was unchanged in the presence of OM 600 nM or 2 µM. Co-incubation with (-)-noradrenaline reduced TPF and t50% , reversing the negative diastolic effects of OM. OM, at both 600 nM and 2 µM, preserved contractile force in left ventricular trabeculae, but imparted negative diastolic effects in trabeculae from human failing heart. (-)-Noradrenaline reversed the negative diastolic effects, co-administration may limit the titration of inotropes by reducing the threshold for ischemic side effects.

Hypophosphatemia Is Common After Intravenous Ferric Carboxymaltose Infusion Among Patients With Symptomatic Heart Failure With Reduced Ejection Fraction.

Administration of intravenous ferric carboxymaltose (FCM) for iron-deficient patients suffering heart failure with reduced ejection fraction (HFrEF) has been associated with transient hypophosphatemia. We sought to investigate and model the effect of intravenous FCM on phosphate levels in iron-deficient patients with HFrEF. In this single-center retrospective study, serum phosphate levels, recorded for clinical reasons, were collected out to 60 days following intravenous FCM. Hypophosphatemia was defined as a nadir serum phosphate level <0.64 mmol/L. This was further categorized as severe (0.4 to <0.64 mmol/L) and extreme (<0.4 mmol/L). Factors associated with hypophosphatemia and change in serum phosphate over time were explored. Of 173 patients included, 47 (27%) experienced hypophosphatemia, 44 (25%) were classified as severe, and 3 (2%) extreme. Risk of hypophosphatemia was increased for patients with a creatinine clearance between 60 and <90 mL/min (odds ratio, 2.3; 95% confidence interval, 1.0-5.5), while <60 mL/min was protective. The median time to nadir in patients who experienced hypophosphatemia was 8 (interquartile range, 4-16) days, with a return to baseline levels at 6 weeks. Biochemically relevant hypophosphatemia is common following a single dose of intravenous FCM. The median time to nadir was 8 days, and creatinine clearance may influence phosphate levels following intravenous FCM. These observations support the need to increase awareness among clinicians administering intravenous FCM to iron-deficient patients with HFrEF.

Correction to "Understanding How Phosphorylation and Redox Modifications Regulate Cardiac Ryanodine Receptor Type 2 Activity to Produce an Arrhythmogenic Phenotype in Advanced Heart Failure".

[This corrects the article DOI: 10.1021/acsptsci.0c00003.].

Understanding How Phosphorylation and Redox Modifications Regulate Cardiac Ryanodine Receptor Type 2 Activity to Produce an Arrhythmogenic Phenotype in Advanced Heart Failure.

Heart failure (HF) is a global pandemic with significant mortality and morbidity. Despite current medications, 50% of individuals die within 5 years of diagnosis. Of these deaths, 30-50% will be a result of sudden cardiac death from ventricular arrhythmias. This review discusses two stress-induced mechanisms, phosphorylation from chronic ß-adrenoceptor (ß-AR) stimulation and thiol modifications from oxidative stress, and how they modulate the cardiac ryanodine receptor type 2 (RyR2) and foster an arrhythmogenic phenotype. Calcium (Ca2+) is the ubiquitous secondary messenger of excitation-contraction coupling and provides a common pathway for contractile dysfunction and arrhythmia genesis. In a healthy heart, Ca2+ is released from the sarcoplasmic reticulum (SR) by RyR2. The open probability of RyR2 is under the dynamic influence of co-proteins, ions, and kinases that are in strict balance to ensure normal physiological functioning. In HF, chronic ß-AR activity and production of reactive oxygen species and reactive nitrogen species provide two stress-induced mechanisms uncoupling RyR2 control, resulting in pathological diastolic SR Ca2+ leak. This increased cytosolic [Ca2+] promotes Ca2+ extrusion via the local Na+/Ca2+ exchanger, resulting in net sarcolemmal depolarization, delayed after depolarization and ventricular arrhythmia. Experimental models researching oxidative stress and phosphorylation have aimed to identify how post-translational modifications to the RyR2 macromolecular complex, and the associated Na+/Ca2+ cycling proteins, result in pathological Ca2+ handling and diastolic leak. However, the causative molecular changes remain controversial and undefined. Through understanding the molecular mechanisms that produce an arrhythmic phenotype, novel therapeutic targets to treat HF and prevent its malignant course can be identified.

Sarcoplasmic reticulum calcium mishandling: central tenet in heart failure?

Excitation-contraction coupling links excitation of the sarcolemmal surface membrane to mechanical contraction. In the heart this link is established via a Ca2+-induced Ca2+ release process, which, following sarcolemmal depolarisation, prompts Ca2+ release from the sarcoplasmic reticulum (SR) though the ryanodine receptor (RyR2). This substantially raises the cytoplasmic Ca2+ concentration to trigger systole. In diastole, Ca2+ is removed from the cytoplasm, primarily via the sarcoplasmic-endoplasmic reticulum Ca2+-dependent ATPase (SERCA) pump on the SR membrane, returning Ca2+ to the SR store. Ca2+ movement across the SR is thus fundamental to the systole/diastole cycle and plays an essential role in maintaining cardiac contractile function. Altered SR Ca2+ homeostasis (due to disrupted Ca2+ release, storage, and reuptake pathways) is a central tenet of heart failure and contributes to depressed contractility, impaired relaxation, and propensity to arrhythmia. This review will focus on the molecular mechanisms that underlie asynchronous Ca2+ cycling around the SR in the failing heart. Further, this review will illustrate that the combined effects of expression changes and disruptions to RyR2 and SERCA2a regulatory pathways are critical to the pathogenesis of heart failure.

Impact of Patient and Model of Care Factors on Titration and Tolerability of Sacubitril/Valsartan: An Early Australian Real-World Experience.

BACKGROUND: Sacubitril/valsartan was shown to be superior to enalapril in the Prospective Comparison of angiotensin receptor neprilysin inhibitor with an angiotensin converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study. However, the study design raised uncertainty about the potential real-world tolerability amongst less well selected cohorts. We aimed to examine the real-world tolerability and factors associated with successful titration of sacubitril/valsartan. METHODS: We performed a retrospective single centre analysis in a tertiary referral centre of 235 consecutive patients prescribed sacubitril/valsartan between August 2016 and January 2018. RESULTS: At baseline, our patients were younger, had lower baseline systolic blood pressure (SBP), reduced ischaemic aetiology and a higher rate of mineralocorticoids receptor antagonist compared to PARADIGM-HF. At last assessment, 120 patients (51%) reached target dose (97/103 mg bi-daily [BD]), 67 patients (29%) were stable on a mid-range dose (≥49/51 mg BD), 22 patients (9%) tolerated the low dose (24/26 mg BD) and 26 patients (11%) discontinued, comparable to PARADIGM-HF. Adverse effects were similar to PARADIGM-HF and hypotension remained the primary reason of sub-maximal titration. Several baseline characteristics were associated with successful titration to target dose including; higher baseline body mass index, systolic blood pressure (SBP) and sodium, male gender and treatment coordinated by multidisciplinary heart failure (HF) clinic. CONCLUSION: Comparable results to PARADIGM-HF in attaining target dose of sacubitril/valsartan and tolerability profile can be achieved in a real-world setting. Several baseline characteristics involving patient factors, markers of disease severity and systems of care predict successful titration to the target dose 97/103 mg BD.

A Rare Case of Severe Nontropical Isolated Right Ventricular Endomyocardial Fibrosis.

We present a case of late presentation nontropical endomyocardial fibrosis isolated to the right ventricle and tricuspid valve (TV). In response to deteriorating hemodynamics, surgical debulking and TV removal were performed before initiation of centralized venoarterial extracorporeal membrane oxygenation support. Definitive endomyocardial resection with a TV prosthesis was then successfully completed. (Level of Difficulty: Advanced.).

Use of a Three-Stent Technique for a Case of Spontaneous Coronary Artery Dissection.

A 78-year-old woman presented with acute inferior ST-segment-elevation myocardial infarction and complete heart block. Angiography revealed spontaneous coronary artery dissection (SCAD) of her right coronary artery. Given her ongoing instability, we proceeded to primary coronary intervention. A strategy of sealing the distal lesion edge followed by the proximal edge containing the intramural hematoma before placing a final stent to the midsegment was decided on (3-stent strategy). Our case represents the second such "sequential stent-sandwiching" report and provides a strategy for percutaneous coronary intervention in hemodynamically unstable patients with SCAD.

IGF-I abuse in sport.

It is widely believed that growth hormone (GH) is abused by athletes for its anabolic and lipolytic effects. Many of the physiological effects of GH are mediated by the production of insulin-like growth factor-I (IGF-I). Both GH and IGF-I appear on the World Anti-Doping Agency list of prohibited substances. Little is known, however, about the prevalence of abuse with exogenous IGF-I. IGF-I has effects on carbohydrate, lipid and protein metabolism and some of these actions could prove beneficial to competitive athletes. No studies have demonstrated a positive effect of IGF-I on physical performance in healthy individuals but this has not yet been studied in appropriately designed trials. Two pharmaceutical preparations of IGF-I have recently become available for the treatment of growth disorders in children. This availability is likely to increase the prevalence of IGF-I abuse. Combining IGF-I with its binding protein IGFBP-3 in one preparation has the potential to reduce the side-effect profile but the adverse effects of long term IGF-I abuse are currently unknown. Detection of abuse with IGF-I is a major challenge for anti-doping authorities. It is extremely difficult to distinguish the exogenous recombinant form of the hormone from endogenously-produced IGF-I. One approach currently being investigated is based on measuring markers of GH and IGF-I action. This has already proved successful in the fight against GH abuse and, it is hoped, will subsequently lead to a similar test for detection of IGF-I abuse.