A Patient in His 50s With Chest Tightness and Left Arm and Neck Tingling.

This case report describes a diagnosis of aortic dissection after a patient presentation of chest tightness, light-headedness, and a tingling sensation in the left arm and neck.

Combined Coronary Orbital Atherectomy and Intravascular Lithotripsy for the Treatment of Severely Calcified Coronary Stenoses: The First Case Series.

OBJECTIVE: Severely calcified coronary stenoses remain a significant challenge during contemporary percutaneous coronary intervention (PCI), often requiring advanced therapies to circumvent suboptimal lesion preparation and major adverse cardiac events (MACEs). Recent reports suggest combined coronary atherectomy and intravascular lithotripsy (IVL) may achieve superior preparation of severely calcified coronary stenoses during PCI. We sought to evaluate the safety and utility of combined orbital atherectomy (OA) and IVL for the modification of coronary artery calcification (CAC) prior to drug-eluting stent (DES) implantation in PCI. METHODS: We performed a retrospective review of all patients who underwent coronary OA and IVL within a single PCI procedure at our institution. The primary outcome was procedural success, defined as successful DES implantation with a residual percent diameter stenosis of <30% and Thrombolysis in Myocardial Infarction (TIMI) 3 flow following PCI without occurrence of in-hospital MACE (cardiac death, myocardial infarction, or target-vessel revascularization). MACE was additionally assessed at 30 days post intervention. RESULTS: Eight patients underwent combined coronary OA and IVL within a single PCI procedure. The mean percent diameter stenosis prior to intervention was 80.5 ± 8.3%, with a mean calcific arc of 338 ± 42°. Procedural success was achieved in 7 of 8 cases (87.5%). Both in-hospital and 30-day MACE rates were 0%. CONCLUSION: We report the safe and effective use of combined coronary OA and IVL for the preparation of severely calcified coronary stenoses during PCI. Through their distinct yet complementary mechanisms of action, the combined use of these therapies may achieve superior preparation of severely calcified coronary stenoses during PCI.

The Utility of Peripheral Intravascular Lithotripsy in Calcific Coronary Artery Disease: A Case Series.

BACKGROUND: Coronary intravascular lithotripsy (IVL) is an emerging therapy for the modification of coronary artery calcification (CAC). Data on its use in several clinical and lesion subsets are limited due to their exclusion from preapproval trials. METHODS: We performed a retrospective review of patients who were excluded from preapproval trials of coronary IVL and underwent CAC modification with the off-label use of a peripheral IVL system. The primary outcome was a composite of procedural success, defined as residual stenosis <10%, and no major adverse cardiac event (MACE), ie, cardiac death, myocardial infarction, or target- vessel revascularization, in hospital and at 30 days. RESULTS: Between June 2019 and April 2020, a total of 9 patients who underwent off-label coronary IVL were identified. Exclusion criteria from preapproval trials included a target lesion within an unprotected left main coronary artery (ULMCA; n = 3) and/or ostial location (n = 5), a target lesion involving in-stent restenosis (n = 3), a second target-vessel lesion with >50% stenosis (n = 1), and/or New York Heart Association class III/IV heart failure (n = 5). The primary outcome was achieved in 8 patients. MACE rate was 0% in hospital and at 30 days. For ULMCA lesions (n = 3), residual stenosis was 0% in 2 patients and 10% in 1 patient. For right coronary artery lesions (n = 3), residual stenosis was 0% in 2 patients and 40% in 1 patient. For left anterior descending coronary artery lesions (n = 3), residual stenosis was 0% in all patients. CONCLUSION: Coronary IVL with a peripheral IVL system may be an effective therapy for CAC modification within ULMCA disease, ostial disease, in-stent restenosis, and New York Heart Association class III/IV heart failure.

Improving cardiology fellow education of right heart catheterization using a simulation based curriculum.

BACKGROUND: Medical procedures are traditionally taught informally at patients' bedside through observation and practice using the adage "see one, do one, teach one." This lack of formalized training can cause trainees to be unprepared to perform procedures independently. Simulation based education (SBE) increases competence, reduces complications, and decreases costs. We developed, implemented, and evaluated the efficacy of a right heart catheterization (RHC) SBE curriculum. METHODS: The RHC curriculum consisted of a pretest, video didactics, deliberate practice, and a posttest. Pre-and posttest skills examinations consisted of a dichotomous 43-item checklist on RHC skills and a 14-item hemodynamic waveform quiz. We enrolled two groups of fellows: 6 first-year, novice cardiology fellows at Northwestern University in their first month of training, and 11 second- and third-year fellows who had completed traditional required, level I training in RHC. We trained the first-year fellows at the beginning of the 2018-2019 year using the SBE curriculum and compared them to the traditionally-trained cardiology fellows who did not complete SBE. RESULTS: The SBE-trained fellows significantly improved RHC skills, hemodynamic knowledge, and confidence from pre- to posttesting. SBE-trained fellows performed similarly to traditionally-trained fellows on simulated RHC skills checklists (88.4% correct vs. 89.2%, p = .84), hemodynamic quizzes (94.0% correct vs. 86.4%, p = .12), and confidence (79.4 vs. 85.9 out of 100, p = .15) despite less clinical experience. CONCLUSIONS: A SBE curriculum for RHC allowed novice cardiology fellows to achieve level I skills and knowledge at the beginning of fellowship and can train cardiology fellows before patient contact.

Risk Differences in Secondary Prevention Patients Who Present With Acute Coronary Syndrome and Implications of Guideline-Directed Cholesterol Management.

The 2018 American College of Cardiology/American Heart Association cholesterol guidelines for secondary prevention identified a group of "very high risk" (VHR) patients, those with multiple major atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk features. A second group, "high risk" (HR), was defined as patients without any of the risk features in the VHR group. The incidence and relative risk differences of these 2 groups in a nontrial population has not been well characterized. Using the Northwestern Medicine Enterprise Data Warehouse, we compared the incidence of VHR and HR patients as well as their relative risk for cardiovascular morbidity and mortality in a single-center, large, academic, retrospective cohort study. Total 1,483 patients with acute coronary events from January 2014 to December 2016 were risk stratified into VHR and HR groups. International Classification of Diseases versions 9 and 10 were used to assess for composite events of unstable angina pectoris, non-ST elevation myocardial infarction, or ST-elevation myocardial infarction, ischemic stroke, or all-cause death with a median follow-up of 3.3 years. VHR patients were found to have 87 ± 5.4 composite events per 1,000 patient-years compared with HR patients who had 33 ± 5.1 events per 1,000 patient-years (p <0.001). VHR group had increased risk of future events as compared to the HR group (multivariable adjusted hazard ratio 1.66 [1.01 to 2.74], p = 0.047). In conclusion, these results support the stratification of patients into the VHR and HR risk groups for secondary prevention.

High Risk Coronary Atherectomy, Perforation, and Successful Percutaneous Treatment: When Impella Support Prevents Catastrophe.

We report a case of coronary perforation during high-risk percutaneous coronary intervention with Impella (Abiomed, Danvers, Massachusetts) support that resulted in cessation of pulsatile arterial flow. Maintenance of systemic perfusion due to antecedent placement of Impella 2.5 allowed for successful treatment with pericardiocentesis and covered stent placement, early discharge, and complication-free follow-up. (Level of Difficulty: Intermediate.).

A Comparative Analysis of Current Lipid Treatment Guidelines: Nothing Stands Still.

Lipid treatment guidelines have continued to evolve as new evidence emerges. We sought to review similarities and differences of 5 lipid treatment guidelines from the American College of Cardiology/American Heart Association, Canadian Cardiovascular Society, European Society for Cardiology/European Atherosclerosis Society, U.S. Preventive Services Task Force, and U.S. Veterans Affairs/Department of Defense. All guidelines utilize rigorous evidentiary review, highlight statin therapy for primary and secondary prevention of atherosclerotic cardiovascular disease, and emphasize a clinician-patient risk discussion. However, there are differences in statin intensities, use of risk estimators, treatment of specific patient subgroups, and consideration of safety concerns. Clinicians should understand these similarities and differences in current and future guideline recommendations when considering if and how to treat their patients with statin therapy.

Late neurologic events after surgery for atrial fibrillation: rare but relevant.

BACKGROUND: The classic cut and sew maze is thought to reduce stroke, in part because of left atrial appendage (LAA) elimination. Multiple LAA elimination techniques have evolved with the introduction of new surgical treatment options for atrial fibrillation (AF), but the impact on stroke remains unknown. We studied the rate of late neurologic event (LNE) in the era of contemporary AF surgery. METHODS: From April 21, 2004, to June 30, 2011, 773 patients underwent surgery for AF. In 131 patients, the LAA was excised. In 579, alternative elimination techniques were used (97 external ligation, 313 internal ligation, 126 stapled excision, 23 stapled excision plus internal ligation, 5 internal plus external ligations, and 15 that did not fit into any category); 63 LAAs were left intact and excluded from analyses. Complete follow-up was obtained by medical record review and phone call. Median survival follow-up was 3.3 years (first and third quartiles, 1.6 and 5.0). An LNE was defined as either a documented stroke or transient ischemic attack 30 or more days after surgery. Baseline characteristics and outcomes between LAA techniques were compared using χ(2), Fisher's exact tests, and Student's t tests. RESULTS: There were 25 LNEs (3.5%) overall; the median occurrence time was 3.6 years (first and third quartiles, 1.9 and 5.4) after surgery. There were 17 strokes and 8 transient ischemic attacks. Of 45 demographic and surgical variables, only age, aortic valve surgery, and perioperative neurologic event (<30 days after cardiac surgery) independently predicted LNE (p = 0.003, 0.021, and 0.010, respectively). Late neurologic events occurred with an annual rate of 1.13% in patients with alternative elimination techniques, and 0.20% in patients with excised LAA (p = 0.001). Patients in AF at any time were more likely to have LNE, but this was not an independent predictor. CONCLUSIONS: After surgery for AF ablation, there is ongoing low risk of LNE even when the LAA is surgically excised. Further investigation should be pursued to clarify whether a difference exists with alternative elimination techniques and in patients in whom AF is successfully eliminated.

The G protein-coupled taste receptor T1R1/T1R3 regulates mTORC1 and autophagy.

Cells continually assess their energy and nutrient state to maintain growth and survival and engage necessary homeostatic mechanisms. Cell-autonomous responses to the fed state require the surveillance of the availability of amino acids and other nutrients. The mammalian target of rapamycin complex 1 (mTORC1) integrates information on nutrient and amino acid availability to support protein synthesis and cell growth. We identify the G protein-coupled receptor (GPCR) T1R1/T1R3 as a direct sensor of the fed state and amino acid availability. Knocking down this receptor, which is found in most tissues, reduces the ability of amino acids to signal to mTORC1. Interfering with this receptor alters localization of mTORC1, downregulates expression of pathway inhibitors, upregulates key amino acid transporters, blocks translation initiation, and induces autophagy. These findings reveal a mechanism for communicating amino acid availability through a GPCR to mTORC1 in mammals.

Reconstitution of the nuclear transport of the MAP kinase ERK2.

The nuclear-cytoplasmic distribution of ERK2 is regulated in response to various stimuli and changes in cell context. Furthermore, the nuclear flux of ERK2 occurs by several energy- and carrier-dependent and -independent mechanisms. ERK2 has been shown to translocate into and out of the nucleus by facilitated diffusion through the nuclear pore, interacting directly with proteins within the nuclear pore complex, as well as by karyopherin-mediated transport. Nuclear export has been suggested to be CRM1- and MEK1/2-dependent. Here, we describe a general nuclear import assay of wild-type ERK2 that can be employed to identify different mechanisms governing nuclear entry of the protein kinase, adapted to evaluate ERK2 mutants that impair nuclear entry to dissect energy- and carrier-dependent and -independent mechanisms, and extended to characterize export mechanisms.

Radial spoke protein 3 is a mammalian protein kinase A-anchoring protein that binds ERK1/2.

Initially identified in Chlamydomonas, RSP3 (radial spoke protein 3) is 1 of more than 20 identified radial spoke structural components of motile cilia and is required for axonemal sliding and flagellar motility. The mammalian orthologs for this and other radial spoke proteins, however, remain to be characterized. We found mammalian RSP3 to bind to the MAPK ERK2 through a yeast two-hybrid screen designed to identify interacting proteins that have a higher affinity for the phosphorylated, active form of the protein kinase. Consistent with the screening result, the human homolog, RSPH3, interacts with and is a substrate for ERK1/2. Moreover, RSPH3 is a protein kinase A-anchoring protein (AKAP) that scaffolds the cAMP-dependent protein kinase holoenzyme. The binding of RSPH3 to the regulatory subunits of cAMP-dependent protein kinase, RIIalpha and RIIbeta, is regulated by ERK1/2 activity and phosphorylation. Here we describe an ERK1/2-interacting AKAP and suggest a mechanism by which cAMP-dependent protein kinase-AKAP binding can be modulated by the activity of other enzymes.

The roles of MAPKs in disease.

MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.

Structural basis of androgen receptor binding to selective androgen response elements.

Steroid receptors bind as dimers to a degenerate set of response elements containing inverted repeats of a hexameric half-site separated by 3 bp of spacer (IR3). Naturally occurring selective androgen response elements have recently been identified that resemble direct repeats of the hexameric half-site (ADR3). The 3D crystal structure of the androgen receptor (AR) DNA-binding domain bound to a selective ADR3 reveals an unexpected head-to-head arrangement of the two protomers rather than the expected head-to-tail arrangement seen in nuclear receptors bound to response elements of similar geometry. Compared with the glucocorticoid receptor, the DNA-binding domain dimer interface of the AR has additional interactions that stabilize the AR dimer and increase the affinity for nonconsensus response elements. This increased interfacial stability compared with the other steroid receptors may account for the selective binding of AR to ADR3 response elements.

Structure of the N-terminal domain of GRP94. Basis for ligand specificity and regulation.

GRP94, the endoplasmic reticulum (ER) paralog of the chaperone Hsp90, plays an essential role in the structural maturation or secretion of a subset of proteins destined for transport to the cell surface, such as the Toll-like receptors 2 and 4, and IgG, respectively. GRP94 differs from cytoplasmic Hsp90 by exhibiting very weak ATP binding and hydrolysis activity. GRP94 also binds selectively to a series of substituted adenosine analogs. The high resolution crystal structures at 1.75-2.1 A of the N-terminal and adjacent charged domains of GRP94 in complex with N-ethylcarboxamidoadenosine, radicicol, and 2-chlorodideoxyadenosine reveals a structural mechanism for ligand discrimination among hsp90 family members. The structures also identify a putative subdomain that may act as a ligand-responsive switch. The residues of the charged region fold into a disordered loop whose termini are ordered and continue the twisted beta sheet that forms the structural core of the N-domain. This continuation of the beta sheet past the charged domain suggests a structural basis for the association of the N-terminal and middle domains of the full-length chaperone.