Single-Centre Registry Analysis of Patients Who Underwent Percutaneous Coronary Intervention on Their Coronary Bypass Grafts.

Background: The study assessed the outcomes of patients undergoing percutaneous coronary intervention (PCI) to bypass grafts, focusing on all-cause mortality and target vessel failure (TVF) rates. Methods: A single-centre registry analysis included 364 patients who underwent PCI on coronary bypass grafts between 2008 and 2019. The study analyzed all-cause mortality and TVF, which encompassed target lesion revascularization, target vessel revascularization, and medically treated occluded target graft post-PCI. Results: The median age of the patients was 71 years (interquartile range: [IQR] 65-78), with 82.1% being male. Most patients (94.8%) received PCI on saphenous vein grafts, and the median graft age was 13.0 years (IQR: 8.4-17.6). Drug-eluting stents were used more frequently (54.4%) than bare-metal stents (45.6%), with a median stent diameter of 3.5 mm (IQR: 3-4) and length of 19 mm (IQR: 18-28). Outcome differences were not significant for PCI sites (aorto-ostial, graft body, anastomosis), use of drug-eluting stents, or use of protection devices. The 1-year mortality rate was 3.3%, whereas the combined rate of TVF or death was 20.3%. After 5 years, the mortality rate increased to 14.9%, and the combined TVF or death rate rose to 40.3%. Multivariable analyses revealed that chronic kidney disease was independently associated with mortality (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.16-2.61, P = 0.007), whereas hypertension (HR 2.42, 95% CI 1.32-4.42, P = 0.004) and increased stent length (HR 1.01, 95% CI 1.00-1.02, P = 0.007) were independently associated with the TVF-or-mortality outcome. Conclusions: Patients undergoing PCI to bypass grafts experience considerable adverse outcomes over a 5-year period, highlighting the need for further strategies in managing this high-risk population.

Contexte: L'étude visait à évaluer l'issue des patients ayant subi une intervention coronarienne percutanée (ICP) sur un greffon coronarien, en mettant l'accent sur le taux de mortalité toutes causes confondues et le taux d'échecs de revascularisation du vaisseau cible (EVC). Méthodologie: Une analyse du registre d'un seul établissement a porté sur 364 patients ayant subi une ICP sur un greffon coronarien de 2008 à 2019. L'étude a analysé la mortalité toutes causes confondues et les EVC, qui comprenaient la revascularisation de la lésion cible, la revascularisation du vaisseau cible et le traitement médical de l'occlusion du greffon coronarien cible après l'ICP. Résultats: L'âge médian des patients était de 71 ans (intervalle interquartile [IIQ] de 65 à 78) et 82,1 % d'entre eux étaient de sexe masculin. La plupart des patients (94,8 %) avaient subi une ICP sur un greffon de veine saphène; l'âge médian des greffons était de 13,0 ans (IIQ de 8,4 à 17,6). Les endoprothèses médicamentées avaient été utilisées plus fréquemment (54,4 %) que les endoprothèses non médicamentées (45,6 %), le diamètre médian de l'endoprothèse étant de 3,5 mm (IIQ de 3 à 4) et sa longueur, de 19 mm (IIQ de 18 à 28). Les différences pour ce qui est de l'issue clinique n'étaient pas significatives à l'égard des sites d'ICP (aorto-ostial, corps du greffon, anastomose), de l'utilisation d'une endoprothèse médicamentée, ou encore de l'utilisation de dispositifs de protection. Le taux de mortalité à 1 an était de 3,3 %, alors que le taux combiné d'EVC ou de décès était de 20,3 %. Après 5 ans, le taux de mortalité avait augmenté à 14,9 %, alors que le taux combiné d'EVC ou de décès s'élevait à 40,3 %. Les analyses multivariables ont révélé que la néphropathie chronique était indépendamment associée au décès (rapport des risques instantanés [RRI] de 1,74, intervalle de confiance [IC] à 95 % de 1,16 à 2,61, p = 0,007), alors que l'hypertension (RRI de 2,42, IC à 95 % de 1,32 à 4,42, p = 0,004) et une longueur accrue de l'endoprothèse (RRI de 1,01, IC à 95 % de 1,00 à 1,02, p = 0,007) étaient indépendamment associées à une issue d'EVC ou de décès. Conclusions: Les patients qui ont subi une ICP sur un greffon coronarien présentent des complications considérables sur une période de 5 ans, ce qui souligne le besoin de mettre en place davantage de stratégies de prise en charge pour cette population à risque élevé.

Medium-Term Outcomes of Stent Therapy for Aortic Coarctation in Children Under 30 kg with New Generation Low-Profile Stents: A Follow-Up Study of a Single Centre Experience.

We previously reported short-term outcomes for stenting of aortic coarctation (CoA) (native or re-coarctation) with newer generation low-profile stents (Valeo, Formula, and Begraft stents) in children under 30 kg. We present here the medium-term outcomes of this procedure. Retrospective review of patients weighing under 30 kg who had percutaneous stent treatments for coarctation between 2012 and 2021 was performed. Clinical and procedural data were collected; 19 patients were included. The median age at the time of procedure was 5.1 [4.1-6.4] years and median weight 21.0 [17.3-22.3] kg. One patient had a history of re-coarctation. Thirteen (68%) patients were on anti-hypertensives pre-procedure. Different types of stents were used (14 Valeo™, 4 Formula® 535, 1 BeGraft), which can all be dilated to 18 mm or larger. One patient required a 9 F sheath, all others required a 7 F sheath. The narrowest diameter in the aorta increased from a median of 3.5 [3.0-4.5] to 9.4 [8.9-9.8] mm, p < 0.001; there was a reduction in the median pressure gradient across the coarctation from 35.0 [30.0-43.0] to 5.0 [0-10.0] mmHg, p < 0.001. There were no intra-procedural complications. Follow-up was for a median of 56.0 [13.0-65.0] months. Five (26%) of patients underwent re-intervention after a median time frame of 40.0 [39.5-52.0] months; four had balloon dilation, one had repeat stent implantation. Five (26%) patients were on anti-hypertensive agent(s) post-intervention. Our single centre experience demonstrates that percutaneous stenting for coarctation of aorta in children under 30 kg, with low-profile stents, had no significant complications during the median follow-up time of 56 months. This study demonstrated that the procedure is safe and effective for short and medium-term therapy in this group of patients with a 26% re-intervention rate. A quarter of patients remained on anti-hypertensive medication post stenting, emphasizing the importance of long-term follow-up.

Takotsubo cardiomyopathy findings on cardiac magnetic resonance imaging following immersion pulmonary oedema.

Immersion pulmonary oedema (IPO) can affect sea swimmers, snorkelers, and scuba divers. It can be fatal and cases are often mistaken for drowning. There has been an association between IPO and the development of takotsubo cardiomyopathy. We present a case study of a diver rescued from the water with IPO, who was subsequently found to have takotsubo cardiomyopathy on cardiac magnetic resonance imaging (CMR). This case demonstrates CMR findings as well as follow- up investigation results. The diver's and instructor's perspective during the initial dive incident are also described.

Post-infarction ventricular septal defect: percutaneous or surgical management in the UK national registry.

AIMS: Post-infarction ventricular septal defect (PIVSD) is a mechanical complication of acute myocardial infarction (AMI) with a poor prognosis. Surgical repair is the mainstay of treatment, although percutaneous closure is increasingly undertaken. METHODS AND RESUTS: Patients treated with surgical or percutaneous repair of PIVSD (2010-2021) were identified at 16 UK centres. Case note review was undertaken. The primary outcome was long-term mortality. Patient groups were allocated based upon initial management (percutaneous or surgical). Three-hundred sixty-two patients received 416 procedures (131 percutaneous, 231 surgery). 16.1% of percutaneous patients subsequently had surgery. 7.8% of surgical patients subsequently had percutaneous treatment. Times from AMI to treatment were similar [percutaneous 9 (6-14) vs. surgical 9 (4-22) days, P = 0.18]. Surgical patients were more likely to have cardiogenic shock (62.8% vs. 51.9%, P = 0.044). Percutaneous patients were substantially older [72 (64-77) vs. 67 (61-73) years, P < 0.001] and more likely to be discussed in a heart team setting. There was no difference in long-term mortality between patients (61.1% vs. 53.7%, P = 0.17). In-hospital mortality was lower in the surgical group (55.0% vs. 44.2%, P = 0.048) with no difference in mortality after hospital discharge (P = 0.65). Cardiogenic shock [adjusted hazard ratio (aHR) 1.97 (95% confidence interval 1.37-2.84), P < 0.001), percutaneous approach [aHR 1.44 (1.01-2.05), P = 0.042], and number of vessels with coronary artery disease [aHR 1.22 (1.01-1.47), P = 0.043] were independently associated with long-term mortality. CONCLUSION: Surgical and percutaneous repair are viable options for management of PIVSD. There was no difference in post-discharge long-term mortality between patients, although in-hospital mortality was lower for surgery.

Transcatheter pulmonary valve implant in a patient with a previous pulmonary valve-in-valve.

Increasing numbers of patients with congenital heart disease now survive well into adulthood. Often, these patients already had surgery to correct their congenital lesions from early life. Patients with tetralogy of Fallot commonly require several pulmonary valve replacements in their lifetime. This report highlights the utility of percutaneous pulmonary valve implant inside the two prior prosthetic valves avoiding a third sternotomy, in a young adult patient who developed severe prosthetic pulmonary valve stenosis. Learning objective: To understand the potential therapeutic option of transcatheter pulmonary valve implant inside a dilatable stented surgical bioprosthesis with an existing valve-in-valve in situ as part of lifetime management.

A Novel Frameshift Mutation, KCNH2 [p.Asp896ArgfsX79], Leading to Malignant Ventricular Arrhythmia, Identified After Treatment of Gastrointestinal Bleeding.

A novel frameshift mutation in the KCNH2 gene for long QT syndrome type 2 (LQTS2) was identified after torsades des pointes ventricular tachycardia in a 49-year-old patient managed with octreotide and nadolol for an acute variceal bleed. In spite of removal of offending medications, and correction of underlying electrolyte abnormalities, the patient's QT interval remained prolonged-at 521 ms-raising the suspicion of an underlying channelopathy. Genetic studies confirmed heterozygosity for a novel frameshift mutation for the KCNH2 gene, D896Rfs X79. We explore the pathogenicity and clinical impact of this variant mutation.

Une nouvelle mutation de changement de phase du gène KCNH2 impliqué dans le syndrome du QT long de type 2 (SQTL2) a été trouvée après une tachycardie ventriculaire à torsades de pointes chez un patient de 49 ans traité par octréotide et nadolol en raison d'un saignement variqueux en phase aiguë. En dépit du retrait des médicaments mis en cause et de la correction des anomalies électrolytiques sous-jacentes, l'intervalle du QT du patient qui demeurait prolongé (à 521 ms) a suscité la suspicion d'une canalopathie sous-jacente. Des études génétiques ont permis de confirmer l'hétérozygosité d'une nouvelle mutation de changement de phase du gène KCNH2, D896Rfs X79. Nous examinons la pathogénicité et les répercussions cliniques de cette mutation du variant.

Altered endoribonuclease activity of apurinic/apyrimidinic endonuclease 1 variants identified in the human population.

Apurinic/apyrimidinic endonuclease 1 (APE1) is the major mammalian enzyme in the DNA base excision repair pathway and cleaves the DNA phosphodiester backbone immediately 5' to abasic sites. APE1 also has 3'-5' DNA exonuclease and 3' DNA phosphodiesterase activities, and regulates transcription factor DNA binding through its redox regulatory function. The human APE1 has recently been shown to endonucleolytically cleave single-stranded regions of RNA. Towards understanding the biological significance of the endoribonuclease activity of APE1, we examined eight different amino acid substitution variants of APE1 previously identified in the human population. Our study shows that six APE1 variants, D148E, Q51H, I64V, G241R, R237A, and G306A, exhibit a 76-85% reduction in endoribonuclease activity against a specific coding region of the c-myc RNA, yet fully retain the ability to cleave apurinic/apyrimidinic DNA. We found that two APE1 variants, L104R and E126D, exhibit a unique RNase inhibitor-resistant endoribonuclease activity, where the proteins cleave c-myc RNA 3' of specific single-stranded guanosine residues. Expression of L104R and E126D APE1 variants in bacterial Origami cells leads to a 60-80% reduction in colony formation and a 1.5-fold increase in cell doubling time, whereas the other variants, which exhibit diminished endoribonuclease activity, had no effect. These data indicate that two human APE1 variants exhibit a unique endoribonuclease activity, which correlates with their ability to induce cytotoxicity or slow down growth in bacterial cells and supports the notion of their biological functionality.

Characterization of the endoribonuclease active site of human apurinic/apyrimidinic endonuclease 1.

Apurinic/apyrimidinic endonuclease 1 (APE1) is the major mammalian enzyme in DNA base excision repair that cleaves the DNA phosphodiester backbone immediately 5' to abasic sites. Recently, we identified APE1 as an endoribonuclease that cleaves a specific coding region of c-myc mRNA in vitro, regulating c-myc mRNA level and half-life in cells. Here, we further characterized the endoribonuclease activity of APE1, focusing on the active-site center of the enzyme previously defined for DNA nuclease activities. We found that most site-directed APE1 mutant proteins (N68A, D70A, Y171F, D210N, F266A, D308A, and H309S), which target amino acid residues constituting the abasic DNA endonuclease active-site pocket, showed significant decreases in endoribonuclease activity. Intriguingly, the D283N APE1 mutant protein retained endoribonuclease and abasic single-stranded RNA cleavage activities, with concurrent loss of apurinic/apyrimidinic (AP) site cleavage activities on double-stranded DNA and single-stranded DNA (ssDNA). The mutant proteins bound c-myc RNA equally well as wild-type (WT) APE1, with the exception of H309N, suggesting that most of these residues contributed primarily to RNA catalysis and not to RNA binding. Interestingly, both the endoribonuclease and the ssRNA AP site cleavage activities of WT APE1 were present in the absence of Mg(2+), while ssDNA AP site cleavage required Mg(2+) (optimally at 0.5-2.0 mM). We also found that a 2'-OH on the sugar moiety was absolutely required for RNA cleavage by WT APE1, consistent with APE1 leaving a 3'-PO(4)(2-) group following cleavage of RNA. Altogether, our data support the notion that a common active site is shared for the endoribonuclease and other nuclease activities of APE1; however, we provide evidence that the mechanisms for cleaving RNA, abasic single-stranded RNA, and abasic DNA by APE1 are not identical, an observation that has implications for unraveling the endoribonuclease function of APE1 in vivo.

RNA-cleaving properties of human apurinic/apyrimidinic endonuclease 1 (APE1).

We have recently identified apurinic/apyrimidinic endonuclease 1 (APE1) as an endoribonuclease that cleaves c-myc mRNA in vitro and regulates c-myc mRNA levels and half-life in cells. This study was undertaken to further unravel the RNA-cleaving properties of APE1. Here, we show that APE1 cleaves RNA in the absence of divalent metal ions and, at 2 mM, Zn(2+), Ni(2+), Cu(2+), or Co(2+) inhibited the endoribonuclease activity of APE1. APE1 is able to cleave CD44 mRNA, microRNAs (miR-21, miR-10b), and three RNA components of SARS-corona virus (orf1b, orf3, spike) suggesting that, when challenged, it can cleave any RNAs in vitro. APE1 does not cleave strong doublestranded regions of RNA and it has a strong preference for 3' of pyrimidine, especially towards UA, CA, and UG sites at single-stranded or weakly paired regions. It also cleaves RNA weakly at UC, CU, AC, and AU sites in single-stranded or weakly paired regions. Finally, we found that APE1 can reduce the ability of the Dicer enzyme to process premiRNAs in vitro. Overall, this study has revealed some previously unknown biochemical properties of APE1 which has implications for its role in vivo.

The role of mammalian ribonucleases (RNases) in cancer.

Ribonucleases (RNases) are a group of enzymes that cleave RNAs at phosphodiester bonds resulting in remarkably diverse biological consequences. This review focuses on mammalian RNases that are capable of, or potentially capable of, cleaving messenger RNA (mRNA) as well as other RNAs in cells and play roles in the development of human cancers. The aims of this review are to provide an overview of the roles of currently known mammalian RNases, and the evidence that associate them as regulators of tumor development. The roles of these RNases as oncoproteins and/or tumor suppressors in influencing cell growth, apoptosis, angiogenesis, and other cellular hallmarks of cancer will be presented and discussed. The RNases under discussion include RNases from the conventional mRNA decay pathways, RNases that are activated under cellular stress, RNases from the miRNA pathway, and RNases with multifunctional activity.

Identification of Apurinic/apyrimidinic endonuclease 1 (APE1) as the endoribonuclease that cleaves c-myc mRNA.

Endonucleolytic cleavage of the coding region determinant (CRD) of c-myc mRNA appears to play a critical role in regulating c-myc mRNA turnover. Using (32)P-labeled c-myc CRD RNA as substrate, we have purified and identified two endoribonucleases from rat liver polysomes that are capable of cleaving the transcript in vitro. A 17-kDa enzyme was identified as RNase1. Apurinic/apyrimidinic (AP) DNA endonuclease 1 (APE1) was identified as the 35-kDa endoribonuclease that preferentially cleaves in between UA and CA dinucleotides of c-myc CRD RNA. APE1 was further confirmed to be the 35-kDa endoribonuclease because: (i) the endoribonuclease activity of the purified 35-kDa native enzyme was specifically immuno-depleted with APE1 monoclonal antibody, and (ii) recombinant human APE1 generated identical RNA cleavage patterns as the native liver enzyme. Studies using E96A and H309N mutants of APE1 suggest that the endoribonuclease activity for c-myc CRD RNA shares the same active center with the AP-DNA endonuclease activity. Transient knockdown of APE1 in HeLa cells led to increased steady-state level of c-myc mRNA and its half-life. We conclude that the ability to cleave RNA dinucleotides is a previously unidentified function of APE1 and it can regulate c-myc mRNA level possibly via its endoribonuclease activity.