Phosphorylation is often used to promote protein ubiquitylation, yet we rarely understand quantitatively how ligase activation and ubiquitin (UB) chain assembly are integrated with phosphoregulation. ...Here we employ quantitative proteomics and live-cell imaging to dissect individual steps in the PINK1 kinase-PARKIN UB ligase mitochondrial control pathway disrupted in Parkinson’s disease. PINK1 plays a dual role by phosphorylating PARKIN on its UB-like domain and poly-UB chains on mitochondria. PARKIN activation by PINK1 produces canonical and noncanonical UB chains on mitochondria, and PARKIN-dependent chain assembly is required for accumulation of poly-phospho-UB (poly-p-UB) on mitochondria. In vitro, PINK1 directly activates PARKIN’s ability to assemble canonical and noncanonical UB chains and promotes association of PARKIN with both p-UB and poly-p-UB. Our data reveal a feedforward mechanism that explains how PINK1 phosphorylation of both PARKIN and poly-UB chains synthesized by PARKIN drives a program of PARKIN recruitment and mitochondrial ubiquitylation in response to mitochondrial damage.
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•PINK1-PARKIN pathway is dissected via quantitative proteomics and live-cell imaging•PINK1-activated PARKIN synthesizes multiple chain linkage types in vitro and in vivo•PINK1 phosphorylates PARKIN to activate E3 and poly-UB to promote their interaction•The data suggest feedforward PINK1 PARKIN activation and recruitment to mitochondria
Ordureau et al. describe a feedforward mechanism that explains how PINK1 phosphorylation of both PARKIN and PARKIN-synthesized ubiquitin chains drives PARKIN recruitment and mitochondrial ubiquitylation in response to mitochondrial damage, a process that is disrupted in Parkinson’s disease.
Objectives Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). Background Bone ...marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. Methods We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n = 53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. Results Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p = 0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p = 0.003) in the hMSC-treated patients. Global symptom score in all patients (p = 0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. Conclusions Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells MSC to Treat Acute Myocardial Infarction; NCT00114452 )
Sudden emotional distress, such as that caused by an unexpected death, can sometimes produce severe transient left ventricular dysfunction. This stress-induced cardiomyopathy appears to be a form of ...myocardial stunning associated with marked sympathetic stimulation.
Sudden emotional distress, such as that caused by an unexpected death, can sometimes produce severe transient left ventricular dysfunction.
The potentially lethal consequences of emotional stress are deeply rooted in folk wisdom, as reflected by phrases such as “scared to death” and “a broken heart.” In the past decade, cardiac contractile abnormalities and heart failure have been reported after acute emotional stress,
1
–
6
but the mechanism remains unknown. We evaluated 19 patients with “stress cardiomyopathy,” a syndrome of profound myocardial stunning precipitated by acute emotional stress, in an effort to identify the clinical features that distinguish this syndrome from acute myocardial infarction and the cause of transient stress-induced myocardial dysfunction.
Methods
Study Patients
Nineteen previously healthy patients were admitted . . .
A Middle-Aged Man With a Worrisome ECG Alfaddagh, Abdulhamied; Schulman, Steven P
Circulation (New York, N.Y.),
2020-May-12, 2020-05-12, Letnik:
141, Številka:
19
Journal Article
The incidence of complications and the outcomes of temporary transvenous pacemaker (TTP) placement in the modern era are not well established.
To determine the current incidence of pericardial ...complications and the outcomes of patients undergoing TTP, we performed an analysis using the National Inpatient Sample (NIS), which is a US national database of hospital admissions. All patients who underwent TTP were identified by using International Classification of Diseases, Ninth Revision, Clinical Modification codes. A multivariate logistic regression model was constructed for a primary outcome of pericardial tamponade and another for a primary outcome of in-hospital mortality.
A total of 360,223 patients underwent TTP placement in the United States between 2004 and 2014. In-hospital mortality was 14.1%, and 37.9% later underwent permanent pacemaker implantation. Potential procedural complications included pericardial tamponade in 0.6% of patients, pneumothorax in 0.9% of patients, and non-pericardial bleeding in 2.4% of patients. In adjusted models, female sex (OR, 1.33 95% CI, 1.09-1.64; P = .005), in-hospital cardiac arrest (OR, 3.52 95% CI, 2.76-4.48; P < .001), teaching hospital status (OR, 1.91 95% CI, 1.53-2.40; P < .001), and previous coronary artery bypass grafting (OR, 0.26 95% CI, 0.14-0.49; P < .001) were associated with tamponade. Following multivariate adjustment, pericardial tamponade complicating TTP insertion was associated with a fivefold increase in risk for in-hospital death (OR, 5.00 95% CI, 2.51-9.96; P < .001).
TTP placement is generally safe with low pericardial complication rates. Clinicians should be mindful of infrequent but serious complications of TTP, and strategies to mitigate pericardial tamponade and other complications should be sought and implemented.
To characterize patient profile and hemodynamic profile of those undergoing intra-aortic balloon pump (IABP) for cardiogenic shock and define predictors of hemodynamic failure of IABP support.
...Clinical characteristics of IABP support in cardiogenic shock not related to acute myocardial infarction (AMI) remain poorly characterized.
We retrospectively studied a cohort of 74 patients from 2010 to 2015 who underwent IABP insertion for cardiogenic shock complicating acute decompensated heart failure not due to AMI.
In the overall cohort, which consisted primarily of patients with chronic systolic heart failure (89%), IABP significantly augmented cardiac index and lowered systemic vascular resistance (P<.05). Despite this improvement, 28% of these patients died (24%) or require urgent escalation in mechanical circulatory support (MCS) (4%). Multivariable regression revealed that baseline left ventricular cardiac power index (LVCPI), a measure of LV power output derived from cardiac index and mean arterial pressure (P=.01), and history of ischemic cardiomyopathy (P=.003) were significantly associated with the composite adverse-event endpoint of death or urgent MCS escalation. An IABP Failure risk score using baseline LVCPI <0.28 W/m2 and ischemic history predicted 28-day adverse events with excellent discrimination.
Despite hemodynamic improvements with IABP support, patients with non-AMI cardiogenic shock still suffer poor outcomes. Patients with ischemic cardiomyopathy and low LVPCI fared significantly worse. These patients may warrant closer observation or earlier consideration of more advanced hemodynamic support.
Abstract With potent analgesic properties, perceived hemodynamic benefits and limited alternatives, morphine is the analgesic mainstay for patients with nitrate resistant chest pain due to acute ...Myocardial Infarction (MI). However, observational data suggest that morphine administration during MI may have negative ramifications. While vomiting, hypotension and respiratory depression are established side effects, recent reports have demonstrated attenuated and delayed oral anti-platelet agent absorption, as well as suboptimal reperfusion after MI, all of which may translate into adverse cardiovascular outcomes. These data have resulted in reduced support for morphine in recent European and U.S. clinical practice guidelines for MI; despite the absence of any prospective randomized outcomes trials addressing this question. As such, randomized trials are now necessary to confirm whether or not morphine, which is administered in up to 30% of MI cases, causes adverse clinical outcomes in these patients. However, given that placebo-controlled randomized trial designs evaluating morphine in MI are limited by an ethical requirement for appropriate analgesia, alternative investigational approaches are now necessary. In this article we review the updated evidence for morphine in MI and outline novel strategies that may facilitate future investigation of this clinical dilemma.
Abstract
Morphine delays oral P2Y
12
platelet inhibitor absorption and is associated with adverse outcomes after myocardial infarction. Consequently, many physicians and first responders are now ...considering fentanyl as an alternative. We conducted a single-centre trial randomizing cardiac patients undergoing coronary angiography to intravenous fentanyl or not. All participants received local anaesthetic and intravenous midazolam. Those requiring percutaneous coronary intervention (PCI) with stenting received 180 mg oral ticagrelor intra-procedurally. The primary outcome was area under the ticagrelor plasma concentration–time curve (AUC
0–24 hours
). The secondary outcomes were platelet function assessed at 2 hours after loading, measured by P2Y
12
reaction units (PRUs) and light transmission platelet aggregometry. Troponin-I was measured post-PCI using a high-sensitivity troponin-I assay (hs-TnI). All participants completed a survey of pain and anxiety. Of the 212 randomized, 70 patients required coronary stenting and were loaded with ticagrelor. Two participants in the no-fentanyl arm crossed over to receive fentanyl for pain. In as-treated analyses, ticagrelor concentrations were higher in the no-fentanyl arm (AUC
0–24 hours
70% larger,
p
= 0.03). Platelets were more inhibited by 2 hours in the no-fentanyl arm (71 vs. 113 by PRU,
p
= 0.03, and 25% vs. 41% for adenosine diphosphate response by platelet aggregation,
p
< 0.01). Mean hs-TnI was higher with fentanyl at 2 hours post-PCI (11.9 vs. 7.0 ng/L,
p
= 0.04) with a rate of enzymatic myocardial infarction of 11% for fentanyl and 0% for no-fentanyl (
p
= 0.08). No statistical differences in self-reported pain or anxiety were found. In conclusion, fentanyl administration can impair ticagrelor absorption and delay platelet inhibition, resulting in mild excess of myocardial damage. This newly described drug interaction should be recognized by physicians and suggests that the interaction between opioids and oral P2Y
12
platelet inhibitors is a drug class effect associated with all opioids.
Clinical Trial Registration:
https://clinicaltrials.gov/ct2/show/NCT02683707
(
NCT02683707).
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