The changing landscape of interventional cardiology: A survival guide in the era of health system consolidation: The Society of Cardiovascular Angiography and Interventions affirms the value of this manuscript.

Practice environments for interventional cardiologists have evolved dramatically and now include small independent practices, large cardiology groups, multispecialty groups, and large integrated health systems. Increasingly, cardiologists are employed by hospitals or health systems. Data from MedAxiom and the American College of Cardiology (ACC) demonstrate an exponential increase in the percentage of cardiologists in employed positions from 10% in 2009 to 87% in 2020. This white paper explores these profound changes, considers their impact on interventional cardiologists, and offers guidance on how interventional cardiologists can best navigate this challenging environment. Finally, the paper offers a potential model to improve the employed physician experience through greater physician involvement in decision making, which may increase jobs satisfaction.

SCAI position statement on the performance of percutaneous coronary intervention in ambulatory surgical centers.

The Centers for Medicare & Medicaid Services (CMS) began reimbursement for percutaneous coronary intervention (PCI) performed in ambulatory surgical centers (ASC) in January 2020. The ability to perform PCI in an ASC has been made possible due to the outcomes data from observational studies and randomized controlled trials supporting same day discharge (SDD) after PCI. In appropriately selected patients for outpatient PCI, clinical outcomes for SDD or routine overnight observation are comparable without any difference in short-term or long-term adverse events. Furthermore, a potential for lower cost of care without a compromise in clinical outcomes exists. These studies provide the framework and justification for performing PCI in an ASC. The Society for Cardiovascular Angiography and Interventions (SCAI) supported this coverage decision provided the quality and safety standards for PCI in an ASC were equivalent to the hospital setting. The current position paper is written to provide guidance for starting a PCI program in an ASC with an emphasis on maintaining quality standards. Regulatory requirements and appropriate standards for the facility, staff and physicians are delineated. The consensus document identified appropriate patients for consideration of PCI in an ASC. The key components of an ongoing quality assurance program are defined and the ethical issues relevant to PCI in an ASC are reviewed.

Inducible cardiac-specific overexpression of cyclooxygenase-2 (COX-2) confers resistance to ischemia/reperfusion injury.

The role of cyclooxygenase-2 (COX-2) in cardiovascular biology remains controversial. Although COX-2 has been reported to mediate the protective actions of late preconditioning, other studies show that it is also an important mediator of inflammation, toxic shock, and apoptosis, resulting in significant dysfunction and injury in several tissues. To determine whether increased myocardial COX-2, in itself, is protective, cardiac-specific, inducible (Tet-off) COX-2 transgenic (iCOX-2 TG) mice were generated by crossbreeding α-MyHC-tTA transgenic mice (tetracycline transactivator [tTA]) with CMV/TRE-COX-2 transgenic mice. Three months after COX-2 induction, mice were subjected to a 30-min coronary occlusion and 24 h of reperfusion. Three different lines (L5, L7, and L8) of iCOX-2 TG mice were studied; in all three lines, infarct size was markedly reduced compared with WT mice: L5 TG/TG 23.4 ± 5.8 vs. WT/WT 48.5 ± 6.1% of risk region; L7 TG/TG 23.2 ± 6.2 vs. WT/WT 53.3 ± 3.6%; and L8 TG/TG 23.5 ± 2.8 vs. WT/WT 52.7 ± 4.6% (P < 0.05 for each). COX-2 inhibition with NS-398 completely abolished the cardioprotection provided by COX-2 overexpression. This study for the first time utilizes an inducible cardiac-specific COX-2 overexpression system to examine the role of this enzyme in ischemia/reperfusion injury in vivo. We demonstrate that induced cardiac-specific overexpression of COX-2 exerts a potent cardioprotective effect against myocardial infarction in mice, and that chronic COX-2 overexpression is not associated with any apparent deleterious effects. We also show that PGE2 levels are upregulated in COX-2 overexpressing cardiac tissue, confirming increased enzyme activity. Finally, we have developed a valuable genetic tool to further our understanding of the role of COX-2 in ischemia/reperfusion injury and other settings. The concept that COX-2 is chronically protective has important therapeutic implications for studies of long-term gene therapy aimed at increasing myocardial COX-2 content as well as other COX-2- based strategies.

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules.

The multidrug ATP-binding cassette, subfamily G, 2 (ABCG2) transporter was recently identified as an important human urate transporter, and a common mutation, a Gln to Lys substitution at position 141 (Q141K), was shown to cause hyperuricemia and gout. The nature of the Q141K defect, however, remains undefined. Here we explore the Q141K ABCG2 mutation using a comparative approach, contrasting it with another disease-causing mutation in an ABC transporter, the deletion of Phe-508 (ΔF508) in the cystic fibrosis transmembrane conductance regulator (CFTR). We found, much like in ΔF508 CFTR, that the Q141K mutation leads to instability in the nucleotide-binding domain (NBD), a defect that translates to significantly decreased protein expression. However, unlike the CFTR mutant, the Q141K mutation does not interfere with the nucleotide-binding domain/intracellular loop interactions. This investigation has also led to the identification of critical residues involved in the protein-protein interactions necessary for the dimerization of ABCG2: Lys-473 (K473) and Phe-142 (F142). Finally, we have demonstrated the utility of using small molecules to correct the Q141K defect in expression and function as a possible therapeutic approach for hyperuricemia and gout.

The GAP portion of Pseudomonas aeruginosa type III secreted toxin ExoS upregulates total and surface levels of wild type CFTR.

BACKGROUND: Pseudomonas aeruginosa (PA) infections account for a large percentage of fatal hospital acquired pneumonias. One of the PA Type III secreted toxin (TTST) ExoS, a bifunctional protein with N-terminal GTPase activating protein (GAP) and C-terminal ADP rybosyl transferase (ADPRT) activities, significantly contributes to PA virulence by targeting small molecular weight G-proteins (SMWGP). In this study, we have looked at one of the mechanisms by which the GAP portion of ExoS (ExoS-GAP) mediates cellular toxicity. METHODS: The effects of ExoS-GAP on CFTR trafficking were studied in CFBE41o- Kir 2.2 and MDCK cell lines stably expressing CFTR using a transient transfection system. RESULTS: Transient transfection of ExoS-GAP increased the total and surface protein levels of mature wild type CFTR in epithelial cells stably expressing wild type (WT) CFTR. The effect of ExoS-GAP was specific to CFTR in bronchial epithelial cells since it did not affect the total protein levels of Na(+)/K(+)ATPase, another membrane protein. A point mutation in the ExoS GAP domain (R146K), known to disrupt its catalytic GAP activity, abolished the effect of ExoS-GAP on WT CFTR. Lysosomal inhibition studies with Bafilomycin A1 indicate that ExoS-GAP decreased lysosomal degradation of the mature WT CFTR with concomitant increase in the total levels of mature WT CFTR. However, ExoS-GAP did not increase the total protein levels of ∆F508CFTR. CONCLUSION: The GAP portion of the PA TTST ExoS increases the total and surface levels of wild type CFTR in vitro mammalian cell system. The effect of ExoS-GAP on WT CFTR total protein levels provides new insight into understanding the virulent pathophysiology of PA infections.

Advocacy 101 for Interventional Cardiologists: A Society for Cardiovascular Angiography & Interventions Policy Statement.

Advocacy is a core mission of the Society for Cardiovascular Angiography & Interventions (SCAI). SCAI advocates on behalf of interventional cardiologists and our patients. This document provides foundational information and a toolkit for grassroots advocacy by interventional cardiologists. The first half of the document summarizes how health care laws are made, how medical devices are approved, and how procedure reimbursement is determined. The second half of the document is a playbook of advocacy strategies: legislative advocacy, judicial advocacy, advocacy with regulators and payors, advocacy in the media, and participation in SCAI advocacy initiatives, such as the Government Relations Committee and SCAI Political Action Committee. Equipped with this toolbox, interventional cardiologists must increase our advocacy activities with government, payors, and industry.

Endosomal Na+ (K+)/H+ exchanger Nhx1/Vps44 functions independently and downstream of multivesicular body formation.

The multivesicular body (MVB) is an endosomal intermediate containing intralumenal vesicles destined for membrane protein degradation in the lysosome. In Saccharomyces cerevisiae, the MVB pathway is composed of 17 evolutionarily conserved ESCRT (endosomal sorting complex required for transport) genes grouped by their vacuole protein sorting Class E mutant phenotypes. Only one integral membrane protein, the endosomal Na+ (K+)/H+ exchanger Nhx1/Vps44, has been assigned to this class, but its role in the MVB pathway has not been directly tested. Herein, we first evaluated the link between Nhx1 and the ESCRT proteins and then used an unbiased phenomics approach to probe the cellular role of Nhx1. Select ESCRT mutants (vps36Δ, vps20Δ, snf7Δ, and bro1Δ) with defects in cargo packaging and intralumenal vesicle formation shared multiple growth phenotypes with nhx1Δ. However, analysis of cellular trafficking and ultrastructural examination by electron microscopy revealed that nhx1Δ cells retain the ability to sort cargo into intralumenal vesicles. In addition, we excluded a role for Nhx1 in Snf7/Bro1-mediated cargo deubiquitylation and Rim101 response to pH stress. Genetic epistasis experiments provided evidence that NHX1 and ESCRT genes function in parallel. A genome-wide screen for single gene deletion mutants that phenocopy nhx1Δ yielded a limited gene set enriched for endosome fusion function, including Rab signaling and actin cytoskeleton reorganization. In light of these findings and the absence of the so-called Class E compartment in nhx1Δ, we eliminated a requirement for Nhx1 in MVB formation and suggest an alternative post-ESCRT role in endosomal membrane fusion.

Small nuclear RNAs U11 and U12 modulate expression of TNR-CFTR mRNA in mammalian kidneys.

TNR-CFTR, discovered as a splice variant of CFTR (Cystic Fibrosis Transmembrane conductance Regulator), is distributed in different tissues such as human and rat kidney, trachea, lungs etc and is a functional chloride channel. In Kidneys, our findings show TNR-CFTR to have an unique distribution pattern with low levels of expression in renal cortex and high levels of expression in renal medulla. As shown by us previously, TNR-CFTR mRNA lacks 145 bp corresponding to segments of exons 13 and 14. This deletion causes a frame shift mutation leading to reading of a premature termination codon in exon 14. Premature termination of translation produces a functional half molecule of CFTR; TNR-CFTR. Our analysis of TNR mRNA has shown that the putative alternatively spliced intron has in its 5' and 3' conserved element CT and AC, respectively, that can be recognized by snRNAs U11 and U12. With these findings, we hypothesize that TNR-CFTR mRNA alternative splicing is probably mediate by splicing pathways utilizing U11 and U12 snRNAs. In this study, we have determined sequences of snRNAs U11 and U12 derived from rat kidney, which show significant homology to human U11 and U12 snRNAs. We show that there is significantly lower expression of U11 and U12 snRNAs in renal cortex compared to renal medulla in both humans and rats. This renal pattern of distribution of U11 and U12 snRNAs in both humans and rats closely follows distribution pattern of renal TNR-CFTR. Further, we have shown that blocking U11 and/or U12 mRNAs, by using antisense probes transfected in Immortalized Rat Proximal Tubule Cell line (IRPTC), decreases TNR-CFTR mRNA expression but not wild-type CFTR mRNA expression. Our results suggest that expression of U11 and/or U12 snRNAs is important for non-conventional alternative splicing process that gives rise to mRNA transcript coding for TNR-CFTR.

The yeast endosomal Na+K+/H+ exchanger Nhx1 regulates cellular pH to control vesicle trafficking.

The relationship between endosomal pH and function is well documented in viral entry, endosomal maturation, receptor recycling, and vesicle targeting within the endocytic pathway. However, specific molecular mechanisms that either sense or regulate luminal pH to mediate these processes have not been identified. Herein we describe the use of novel, compartment-specific pH indicators to demonstrate that yeast Nhx1, an endosomal member of the ubiquitous NHE family of Na+/H+ exchangers, regulates luminal and cytoplasmic pH to control vesicle trafficking out of the endosome. Loss of Nhx1 confers growth sensitivity to low pH stress, and concomitant acidification and trafficking defects, which can be alleviated by weak bases. Conversely, weak acids cause wild-type yeast to present nhx1Delta trafficking phenotypes. Finally, we report that Nhx1 transports K+ in addition to Na+, suggesting that a single mechanism may responsible for both pH and K+-dependent endosomal processes. This presents the newly defined family of eukaryotic endosomal NHE as novel targets for pharmacological inhibition to alleviate pathological states associated with organellar alkalinization.

Venous thromboembolism in cancer patients: risk assessment, prevention and management.

Thrombosis and thromboembolic events contribute to significant morbidity in cancer patients. Venous thrombosis embolism (which includes deep vein thrombosis and pulmonary embolism) accounts for a large percentage of thromboembolic events. Appropriate identification of cancer patients at high risk for venous thromboembolism and management of thromboembolic event is crucial in improving the quality of care for cancer patients. However, thromboembolism in cancer patients is a complex problem and the management has to be tailored to each individual. The focus of this review is to understand the complex pathology, physiology and risk factors that drive the process of venous thrombosis and embolism in cancer patients and the current guidelines in management.

Paradoxical Thromboembolism/ST-Elevation Myocardial Infarction via a Patent Foramen Ovale in Sub-Massive Pulmonary Embolism Following an Upper Extremity Deep Venous Thrombosis: Is It Time for a Change in the Standard of Care?

The objective of this case study is to discuss a rare case of proven paradoxical thromboembolism captured in-transit. A 23-year-old female with a diagnosis of right internal jugular deep vein thrombus who developed acute onset chest pain, dyspnea and hypotension, was selected for the study. Sub-massive PE and STEMI were diagnosed. Transthoracic echocardiogram revealed a left ventricular (LV) mass moving across the aortic valve. Soon after, the patient developed numbness of right extremities with non-palpable pulses. A transesophageal echocardiogram revealed absent LV mass, PFO, left atrial mass entering through the PFO and emboli in bilateral pulmonary arteries. We report a case of sub-massive PE and paradoxical proven coronary and upper extremity embolism, captured in-transit, following destabilization of an UEDVT in a patient with PFO.

The COX-2/PGI2 receptor axis plays an obligatory role in mediating the cardioprotection conferred by the late phase of ischemic preconditioning.

BACKGROUND: Pharmacologic studies with cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by COX-2. However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only relative. Furthermore, the specific prostaglandin (PG) receptors responsible for the salubrious actions of COX-2-derived prostanoids remain unclear. OBJECTIVE: To determine the role of COX-2 and prostacyclin receptor (IP) in late PC by gene deletion. METHODS: COX-2 knockout (KO) mice (COX-2(-/-)), prostacyclin receptor KO (IP(-/-)) mice, and respective wildtype (WT, COX-2(+/+) and IP(+/+)) mice underwent sham surgery or PC with six 4-min coronary occlusion (O)/4-min R cycles 24 h before a 30-min O/24 h R. RESULTS: There were no significant differences in infarct size (IS) between non-preconditioned (non-PC) COX-2(+/+), COX-2(-/-), IP(+/+), and IP(-/-) mice, indicating that neither COX-2 nor IP modulates IS in the absence of PC. When COX-2(-/-) or IP(-/-) mice were preconditioned, IS was not reduced, indicating that the protection of late PC was completely abrogated by deletion of either the COX-2 or the IP gene. Administration of the IP selective antagonist, RO3244794 to C57BL6/J (B6) mice 30 min prior to the 30-min O had no effect on IS. When B6 mice were preconditioned 24 h prior to the 30-min O, IS was markedly reduced; however, the protection of late PC was completely abrogated by pretreatment of RO3244794. CONCLUSIONS: This is the first study to demonstrate that targeted disruption of the COX-2 gene completely abrogates the infarct-sparing effect of late PC, and that the IP, downstream of the COX-2/prostanoid pathway, is a key mediator of the late PC. These results provide unequivocal molecular genetic evidence for an essential role of the COX-2/PGI2 receptor axis in the cardioprotection afforded by the late PC.

Absence of ClC5 in knockout mice leads to glycosuria, impaired renal glucose handling and low proximal tubule GLUT2 protein expression.

Glycosuria is one of the well-documented characteristics in ClC-5 knockout (KO) mice and patients with Dent's disease. However, the underlying pathophysiology of its occurrence is unknown. In this study, we have compared ClC-5 KO mice with age and gender matched wild-type (WT) control mice to investigate if the underlying cause of manifested glycosuria is an impairment of glucose homeostasis and/or an alteration in expression levels of proximal tubule (PT) glucose transporters. We observed that, the blood glucose concentration (n=12, p<0.01) and the fractional excretion of glucose and insulin (n=6, p<0.05) were higher in KO mice. In contrast, the fasting blood glucose levels (n=7) were not significantly different in the two groups. Plasma glucose increased to a greater extent in KO mice (n=7, p<0.05) when challenged by an intraperitoneal injection of glucose. However, no peripheral tissue insulin resistance was observed following an intraperitoneal injection of insulin (n=9) in the KO mice. ELISA analysis demonstrated low plasma insulin concentrations after a 12 hour fasting period and also following glucose injection in KO mice. The total insulin released during a 2 hour period following glucose challenge was significantly lower in KO mice (n=6, p<0.05). By western blot, we observed a significant decrease in GLUT2 protein expression levels in isolated PT ((n=10, p<0.01)) of KO mice. This decrease in protein levels was corroborated by a significant decrease in GLUT2 mRNA levels estimated semi quantitatively by RT-PCR in isolated PT (n=10, p<0.01). No significant changes in mRNA expression levels of SGLT2, SGLT1 and GLUT1, as analyzed by RT-PCR, could be detected in the isolated PT (n=10). Also, we have shown by western blot analysis that expression of megalin is lower in the renal cortex of KO mice when compared to WT mice (n=3, p<0.05). Our results suggest that low plasma insulin concentration together with renal function changes observed in KO mice significantly contribute towards the glucose intolerance and documented glycosuria observed in this animal.