Patients Aged 90 Years and Above With Acute Coronary Syndrome in the Cardiac Intensive Care Unit: Management and Outcomes.

Limited data exist regarding outcomes after coronary angiography (CAG) and percutaneous coronary intervention (PCI) in patients aged ≥90 years admitted to the cardiac intensive care unit (CICU) with acute coronary syndrome (ACS). We studied sequential CICU patients ≥90 years admitted with ACS from 2007 to 2018. Three therapeutic approaches were defined: (1) No CAG; (2) CAG without PCI (CAG/No PCI); and (3) CAG with PCI (CAG/PCI). In-hospital mortality was evaluated using multivariable logistic regression. All-cause 1-year mortality was evaluated using Kaplan-Meier and multivariable Cox proportional hazards analysis. The study included 239 patients with a median age of 92 (range 90 to 100) years (57% females; 45% ST-elevation myocardial infarction; 8% cardiac arrest; 16% shock). The No CAG group had higher Day 1 Sequential Organ Failure Assessment scores, more co-morbidities, worse kidney function, and fewer ST-elevation myocardial infarctions. In-hospital mortality was 20.8% overall and did not differ between the No CAG (n = 103; 21.4%), CAG/No PCI (n = 47; 21.3%), and CAG/PCI (n = 90; 20.0%) groups, before or after adjustment. Overall 1-year mortality was 52.5% and did not differ between groups before or after adjustment. Median survival was 6.9 months overall and 41.2% of hospital survivors died within 1 year of CICU admission. CICU patients aged ≥90 years with ACS have a substantial burden of illness with high in-hospital and 1-year mortality that was not lower in those who underwent CAG or PCI. These results suggest that careful patient selection for invasive coronary procedures is essential in this vulnerable population.

Acute coronary occlusion and percutaneous coronary intervention after out-of-hospital cardiac arrest.

OBJECTIVES: Early coronary angiography (CAG) has been recommended in selected patients following out-of-hospital-cardiac-arrest (OHCA). We aimed to identify clinical features associated with acute coronary occlusion (ACO) and evaluate the associations between ACO, successful percutaneous coronary intervention (PCI) and outcomes in this population. METHODS: We included comatose OHCA patients treated with targeted temperature management (TTM) between December 2005 and September 2016 who underwent early CAG within 24 hours. The co-primary outcomes were all-cause 30-day mortality and good neurological outcome (modified Rankin Score [mRS] ≤2) at hospital discharge. RESULTS: Among 155 patients (93% shockable arrest rhythm, 55% with ST elevation), 133 (86%) had coronary artery stenosis ≥50% and 65 (42%) had ACO. ST elevation (sensitivity 74%, specificity 59%, OR 4.0, 95% CI 2.0-8.1) and elevated first troponin (sensitivity 88%, specificity 26%, OR 2.5, 95% CI 1.1-6.1) had limited sensitivity and specificity for ACO. Unadjusted 30-day mortality did not differ significantly by coronary disease severity or ACO. Successful PCI was associated with a lower risk of 30-day mortality (adjusted HR 0.5, 95% CI 0.2-0.9, P=.03), especially among patients with ACO (adjusted HR 0.4, 95% CI 0.1-0.9, P=0.03). After adjustment, ACO and PCI were not associated with the probability of good neurological outcome. CONCLUSIONS: In this select cohort of resuscitated OHCA patients undergoing CAG, unstable coronary disease is highly prevalent and successful PCI was associated with a higher probability of 30-day survival, especially among those with ACO. Neither ACO nor successful PCI were independently associated with good neurological outcome.

Indications for Cardiac Catheterization and Percutaneous Coronary Intervention in Patients with Resuscitated Out-of-Hospital Cardiac Arrest.

PURPOSE OF REVIEW: The role of emergent cardiac catheterization after resuscitated out-of-hospital cardiac arrest (OHCA) has evolved based on recent randomized evidence. This review aims to discuss the latest evidence and current indications for emergent coronary angiography (CAG) and mechanical circulatory support (MCS) use following OHCA. RECENT FINDINGS: In contrast to previous observational data, recent RCTs evaluating early CAG in resuscitated OHCA patients without ST elevation have uniformly demonstrated a lack of benefit in terms of survival or neurological outcome. There is currently no randomized evidence supporting MCS use specifically in patients with resuscitated OHCA and cardiogenic shock. Urgent CAG should be considered in all patients with ST elevation, recurrent electrical or hemodynamic instability, those who are awake following resuscitated OHCA, and those receiving extracorporeal cardiopulmonary resuscitation (ECPR). Recent evidence suggests that CAG may be safely delayed in hemodynamically stable patients without ST-segment elevation following resuscitated OHCA.

Dipyridamole and vascular healing following stent implantation.

Introduction: Patients undergoing coronary stent implantation incur a 2% annual rate of adverse events, largely driven by in-stent restenosis (ISR) due to neointimal (NI) tissue proliferation, a process in which smooth muscle cell (SMC) biology may play a central role. Dipyridamole (DP) is an approved therapeutic agent with data supporting improved vascular patency rates. Pre-clinical data supports that DP may enact its vasculoprotective effects via adenosine receptor-A2B (ADOR-A2B). We sought to evaluate the efficacy of DP to mitigate ISR in a pre-clinical rabbit stent model. Methods & Results: 24 New Zealand White Rabbits were divided into two cohorts-non-atherosclerosis and atherosclerosis (n = 12/cohort, 6 male and 6 female). Following stent implantation, rabbits were randomized 1:1 to control or oral dipyridamole therapy for 6 weeks followed by optical coherence tomography (OCT) and histology assessment of NI burden and stent strut healing. Compared to control, DP demonstrated a 16.6% relative reduction in NI volume (14.7 ± 0.8% vs. 12.5 ± 0.4%, p = 0.03) and a 36.2% relative increase in optimally healed stent struts (37.8 ± 2.8% vs. 54.6 ± 2.5%, p < 0.0001). Atherosclerosis demonstrated attenuated effect with no difference in NI burden (15.2 ± 1.0% vs. 16.9 ± 0.8%, p = 0.22) and only a 14.2% relative increase in strut healing (68.3 ± 4.1% vs. 78.7 ± 2.5%, p = 0.02). DP treated rabbits had a 44.6% (p = 0.045) relative reduction in NI SMC content. In vitro assessment of DP and coronary artery SMCs yielded dose-dependent reduction in SMC migration and proliferation. Selective small molecule antagonism of ADOR-A2B abrogated the effects of DP on SMC proliferation. DP modulated SMC phenotypic switching with ADOR-A2B siRNA knockdown supporting its role in the observed effects. Conclusion: Dipyridamole reduces NI proliferation and improves stent healing in a preclinical model of stent implantation with conventional antiplatelets. Atherosclerosis attenuates the observed effect. Clinical trials of DP as an adjunctive agent may be warranted to evaluate for clinical efficacy in stent outcomes.

Cardiogenic shock: a major challenge for the clinical trialist.

PURPOSE OF REVIEW: Cardiogenic shock (CS) results in persistently high short-term mortality and a lack of evidence-based therapies. Several trials of novel interventions have failed to show an improvement in clinical outcomes despite promising preclinical and physiologic principles. In this review, we highlight the challenges of CS trials and provide suggestions for the optimization and harmonization of their design. RECENT FINDINGS: CS clinical trials have been plagued by slow or incomplete enrolment, heterogeneous or nonrepresentative patient cohorts, and neutral results. To achieve meaningful, practice-changing results in CS clinical trials, an accurate CS definition, a pragmatic staging of its severity for appropriate patient selection, an improvement in informed consent process, and the use of patient-centered outcomes are required. Future optimizations include the use of predictive enrichment using host response biomarkers to unravel the biological heterogeneity of the CS syndrome and identify subphenotypes most likely to benefit from individualized treatment to allow a personalized medicine approach. SUMMARY: Accurate characterization of CS severity and its pathophysiology are crucial to unravel heterogeneity and identify the patients most likely to benefit from a tested treatment. Implementation of biomarker-stratified adaptive clinical trial designs (i.e., biomarker or subphenotype-based therapy) might provide important insights into treatment effects.

Pathogenesis, Evaluation, and Management of Pulmonary Vein Stenosis: JACC Review Topic of the Week.

Pulmonary vein stenosis (PVS) can arise from several etiologies, including congenital, acquired, and iatrogenic sources. PVS presents insidiously, leading to significant delays in diagnosis. A high index of suspicion and dedicated noninvasive evaluation are key to diagnosis. Once diagnosed, both noninvasive and invasive evaluation may afford further insights into the relative contribution of PVS to symptoms. Treatment of underlying reversible pathologies coupled with transcatheter balloon angioplasty and stenting for persistent severe stenoses are established approaches. Ongoing refinements in diagnostic modalities, interventional approaches, postintervention monitoring, and medical therapies hold promise to further improve patient outcomes.

Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells.

In prostate cancer, loss of the tumour suppressor gene, Retinoblastoma (Rb), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that upon mating, binucleate secondary cells (SCs) of the Drosophila melanogaster male accessory gland (AG), which share some similarities with prostate epithelial cells, switch their growth regulation from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control. This physiological change induces genome endoreplication and allows SCs to rapidly replenish their secretory compartments, even when ecdysone levels are low because the male has not previously been exposed to females. Here, we test whether the Drosophila Rb homologue, Rbf, and E2F1 regulate this switch. Surprisingly, we find that excess Rbf activity reversibly suppresses binucleation in adult SCs. We also demonstrate that Rbf, E2F1 and the cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key regulators of mating-dependent SC endoreplication, as well as SC growth in both virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and endoreplication-associated growth in SCs, mirroring changes seen in CRPC. Furthermore, Bone Morphogenetic Protein (BMP) signalling, mediated by the BMP ligand Decapentaplegic (Dpp), intersects with CycD/Rbf/E2F1 signalling to drive endoreplication in these fly cells. Overall, our work reveals a signalling switch, which permits rapid growth of SCs and increased secretion after mating, independently of previous exposure to females. The changes observed share mechanistic parallels with the pathological switch to hormone-independent AR signalling seen in CRPC, suggesting that the latter may reflect the dysregulation of a currently unidentified physiological process.

Evaluation of a Rabbit Model of Vascular Stent Healing: Application of Optical Coherence Tomography.

Percutaneous coronary intervention (PCI) is a management strategy for symptomatic obstructive coronary artery disease (CAD). Despite advancements, in-stent restenosis (ISR) still imparts a 1-2% annual rate of repeat revascularization-a focus of ongoing translational research. Optical coherence tomography (OCT) provides high resolution virtual histology of stents. Our study evaluates the use of OCT for virtual histological assessment of stent healing in a rabbit aorta model, enabling complete assessment of intraluminal healing throughout the stent. ISR varies based on intra-stent location, stent length, and stent type in a rabbit model-important considerations for translational experimental design. Atherosclerosis leads to more prominent ISR proliferation independent of stent-related factors. The rabbit stent model mirrors clinical observations, while OCT-based virtual histology demonstrates utility for pre-clinical stent assessment. Pre-clinical models should incorporate clinical and stent factors as feasible to maximize translation to clinical practice.

Urine Output and Mortality in Patients Resuscitated from out of Hospital Cardiac Arrest.

BACKGROUND: Limited data exist regarding urine output (UO) as a prognostic marker in out-of-hospital-cardiac-arrest (OHCA) survivors undergoing targeted temperature management (TTM). METHODS: We included 247 comatose adult patients who underwent TTM after OHCA between 2007 and 2017, excluding patients with end-stage renal disease. Three groups were defined based on mean hourly UO during the first 24 h: Group 1 (<0.5 mL/kg/h, n = 73), Group 2 (0.5-1 mL/kg/h, n = 81) and Group 3 (>1 mL/kg/h, n = 93). Serum creatinine was used to classify acute kidney injury (AKI). The primary and secondary outcomes respectively were in-hospital mortality and favorable neurological outcome at hospital discharge (modified Rankin Scale [mRS]<3). RESULTS: In-hospital mortality decreased incrementally as UO increased (adjusted OR 0.9 per 0.1 mL/kg/h higher; p = 0.002). UO < 0.5 mL/kg/h was strongly associated with higher in-hospital mortality (adjusted OR 4.2 [1.6-10.8], p = 0.003) and less favorable neurological outcomes (adjusted OR 0.4 [0.2-0.8], p = 0.007). Even among patients without AKI, lower UO portended higher mortality (40% vs 15% vs 9% for UO groups 1, 2, and 3 respectively, p < 0.001). CONCLUSION: Higher UO is incrementally associated with lower in-hospital mortality and better neurological outcomes. Oliguria may be a more sensitive early prognostic marker than creatinine-based AKI after OHCA.

Pulmonary Vein Stenosis-Balloon Angioplasty Versus Stenting: A Systematic Review and Meta-Analysis.

Pulmonary vein stenosis (PVS) may arise from a variety of conditions and result in major morbidity and mortality. In some patients, pharmacologic therapy may help, but more often in advanced stages, mechanical treatment must be considered. Transcatheter approaches, both balloon angioplasty (BA) and stent implantation, have been applied. Although both are effective, they continue to be limited by restenosis. In this systematic review and meta-analysis, Ovid MEDLINE, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus were searched for English-language studies in humans published between January 1, 2010, and August 2, 2021. Two independent reviewers screened for studies in which BA or stenting was performed for PVS with reporting of restenosis outcomes, and data were independently extracted. A systematic review was performed, and overall restenosis rates were reported across all 34 included studies. Meta-analysis was then performed using RevMan version 5.4, assessing rates of restenosis and restenosis requiring reintervention in those studies with available data reported. For restenosis rates, 4 studies treated a total of 340 patients with 579 pulmonary vein interventions (225 with BA and 354 with stenting, mean follow-up 13-69 months). Restenosis requiring repeat intervention was reported in 3 studies, including 301 patients with 495 pulmonary vein interventions (157 with BA and 338 with stenting). Compared with BA, stenting was associated with both a lower risk for restenosis (risk ratio: 0.36; 95% CI: 0.18-0.73; P = 0.005) and a lower risk for restenosis requiring reintervention (RR: 0.36; 95% CI: 0.15-0.86; P = 0.02). For PVS intervention, restenosis and reintervention rates may be improved by stent implantation compared with BA.

Society for cardiovascular angiography and intervention shock classification predicts mortality after out-of-hospital cardiac arrest.

BACKGROUND: Shock is common in patients resuscitated from out-of-hospital-cardiac arrest (OHCA). Shock severity can be classified using the Society for Cardiovascular Angiography and Intervention (SCAI) Shock Classification. We aimed to examine the association of SCAI Shock Stage with in-hospital mortality and neurological outcome in comatose OHCA patients undergoing targeted temperature management (TTM). METHODS: This study included 213 comatose adult patients who underwent TTM after OHCA between January 2007 and December 2017. SCAI shock stage (A through E) was assigned using data from the first 24 hours, with shock defined as SCAI shock stage C/D/E. Good neurological outcome was defined as a modified Rankin Scale (mRS) less than 3. RESULTS: In-hospital mortality was higher in the 144 (67.6%) patients with shock (46.5% v. 23.2%, unadjusted OR 2.88, 95% CI 1.51-5.51, p = 0.001). After multivariable adjustment, each SCAI shock stage was incrementally associated with an increased risk of in-hospital mortality (adjusted OR 1.80 per stage, 95% CI 1.20-2.71, p = 0.003). Good neurological outcome was less likely in patients with shock (31.9% vs. 53.6%, unadjusted OR 0.41, 95% CI 0.23-0.73, p = 0.002) and a higher SCAI shock stage was incrementally associated with a lower likelihood of good neurological outcome after multivariable adjustment (adjusted OR 0.67 per stage, 95% CI 0.48-0.93, p = 0.015). CONCLUSION: Higher shock severity, defined using the SCAI Shock Classification, was associated with increased in-hospital mortality and a lower likelihood of good neurological outcome in OHCA patients treated with TTM.

Retrograde Transseptal Pulmonary Vein Transcatheter Plug Closure for Pulmonary Arteriovenous Malformation.

Pulmonary arteriovenous malformations (PAVMs) may manifest with bleeding or embolic events necessitating intervention. Transcatheter coil embolization through the pulmonary artery (PA) is an established approach. We present a case of recurrent PAVMs despite numerous PA coil embolizations. PAVM occlusion was achieved through plug placement by a transseptal and pulmonary venous approach. (Level of Difficulty: Advanced.).

Multifactorial Interventions to Reduce Duration and Variability in Delays to Identification of Serious Injury After Falls in Hospital Inpatients.

OBJECTIVES: Inpatient falls are the most commonly reported safety incidents and are associated with serious injuries. This study aimed to use multifactorial interventions to reduce the delays to the diagnosis of serious injury in a time series analysis after serious incidents relating to falls within a central London Trust. METHODS: A multiprofessional project team undertook process mapping to identify opportunities for improvement at different stages in the management of a fall. The interventions included an educational teaching session aimed at doctors, a lanyard card designed by doctors using the plan-do-study-act methodology, a falls-specific pager for radiographers, and a new system to refer to portering. Quantitative data were obtained using an serious incident database where serious injury occurred (SI data; n = 65) and routinely collected incident reporting database on falls regardless of injury (IR data; n = 178). Qualitative questionnaire data (n = 70) were also used to evaluate doctors' confidence in falls assessment before and after interventions. RESULTS: Results in the IR data demonstrated a significant reduction in the median (interquartile range) minutes delay in the time to review a patient after a fall from 81 (43-180) to 51 (26-112; P = 0.003) and the time to order imaging from 102 (45-370) to 50 (33-96; P = 0.04). Analysis of the SI database demonstrated a nonstatistically significant reduction in the overall time taken to detect serious injury after a fall from 348 (126-756) to 192 (108-384) minutes (P = 0.070). Furthermore, analysis using statistical process control charts showed evidence of special cause variation and a shift in the process in detecting serious harm after a fall. Junior doctors' confidence in investigations improved from 53% to 76% (P = 0.04) after the intervention. CONCLUSIONS: The cumulative application of multiple interventions with small individual effects resulted in a substantial positive effect on delays and variability in diagnosis of serious harm. Given a similar institutional context, the more effective interventions in our study could be adopted elsewhere.

Clinical Significance of Early Echocardiographic Changes after Resuscitated Out-of-Hospital Cardiac Arrest.

BACKGROUND: Left Ventricular Systolic Dysfunction (LVSD) is common after out-of-hospital cardiac arrest (OOHCA) and can manifest globally or regionally, although its clinical significance has not been robustly studied. This study evaluates the association between LVSD, extent of coronary artery disease (CAD) and outcome in those undergoing early echocardiography and coronary angiography after OOHCA. METHODS: Trans-thoracic echocardiography (TTE) was performed in OOHCA patients on arrival to our centre between May 2012 and December 2017. Rates of cardiogenic shock and extent of CAD, respectively classified by SCAI grade and the SYNTAX score, were measured. The primary end-point was 12-month mortality. RESULTS: From 398 patients in the King's Out of Hospital Cardiac Arrest Registry (KOCAR), 266 patients (median age 61 [53-71], 76% male) underwent both TTE and coronary angiography on arrival. 96 patients (36%) had significant LVSD (Left Ventricular Ejection Fraction [LVEF] <40%) and 139 (52.2%) patients had regional wall motion abnormalities (RWMAs). Patients with LVEF <40% had more SCAI grade C-E shock (65.3% vs. 34.5%, p <0.001) and higher 12-month mortality (55.2% vs 31.8%, p <0.001) which was more likely to be due to a cardiac aetiology (27.3% vs 5.3%, p <0.001). Patients with RWMAs had higher median SYNTAX scores (14.75 vs 7, p=0.001), culprit coronary lesions (83.5% vs. 45.3%, p <0.001) and lower 12-month mortality (29.5% vs 52%, p <0.001). CONCLUSIONS: Patients with LVEF <40% at presentation have an increased mortality, driven by cardiac aetiology death, while the presence of RWMAs is associated with a higher rate of culprit coronary lesions, representing a potentially reversible cause of the arrest, and improved survival at 1 year.

Human γ2-AMPK Mutations.

In humans, dominant mutations in the gene encoding the regulatory γ2-subunit of AMP-activated protein kinase (PRKAG2) result in a highly penetrant phenotype dominated by cardiac features: left ventricular hypertrophy, ventricular pre-excitation, atrial tachyarrhythmia, cardiac conduction disease, and myocardial glycogen storage. The discovery of a link between the cell's fundamental energy sensor, AMPK, and inherited cardiac disease catalyzed intense interest into the biological role of AMPK in the heart. In this chapter, we provide an introduction to the spectrum of human disease resulting from pathogenic variants in PRKAG2, outlining its discovery, clinical genetics, and current perspectives on its pathogenesis and highlighting mechanistic insights derived through the evaluation of disease models. We also present a clinical perspective on the major components of the cardiomyopathy associated with mutations in PRKAG2, together with less commonly described extracardiac features, its prognosis, and principles of management.

Preliminary Dual-Center Experience with the Bolton Treovance Endograft.

PURPOSE: To present the performance and safety of the Treovance stent graft for endovascular aortic aneurysm repair in a "real-world" patient cohort. METHODS: Patients from 2 centers, deemed unfit for open repair, were electively treated with the Treovance endograft. Clinical preoperative, operative, and up to 1-year postoperative follow-up data of patients were retrospectively analyzed. RESULTS: This study included 46 patients with abdominal aortic aneurysm (44 male), mean age of 78 years ± 8 standard deviation (SD; range: 58-93 years). All met the manufacturer's recommended anatomical requirements: average maximum sac diameter 63 mm ± 10 SD (range: 52-86 mm), proximal neck length 29 mm ± 12 SD (range: 11-60 mm), and neck angulation 30° ± 21 SD (range: 0°-70°). Fourteen had moderate to severe iliac tortuosity. A primary technical success rate of 80% was achieved (100% assisted primary technical success rate): 7 patients required adjunctive procedures intraoperatively and 2 successful treatments for type I endoleaks, which occurred within 24 hours postoperatively. There was 100% survival at 1-year follow-up; however, 4 (8.7%) patients required reintervention: 1 for a type I endoleak, 2 for limb stenosis, and 1 for a type II endoleak with an enlarging sac. No other device-related complications were identified. Reintervention and complication rates in hostile versus nonhostile anatomies were not statistically significant ( P = .28 and P = .42, respectively). CONCLUSION: The Treovance stent graft has a comparable safety profile to other next-generation stent grafts during the first year after endovascular aneurysm repair, which provides a rationale for further interrogation of its outcomes through clinical trials.

Chronic Activation of γ2 AMPK Induces Obesity and Reduces ß Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.