Methadone in combination with magnesium, ketamine, lidocaine, and dexmedetomidine improves postoperative outcomes after coronary artery bypass grafting: an observational multicentre study.

BACKGROUND: An optimal pharmacological strategy for fast-track cardiac anesthesia (FTCA) is unclear. This study evaluated the effectiveness and safety of an FTCA program using methadone and non-opioid adjuvant infusions (magnesium, ketamine, lidocaine, and dexmedetomidine) in patients undergoing coronary artery bypass grafting. METHODS: This retrospective, multicenter observational study was conducted across private and public teaching sectors. We studied patients managed by a fast-track protocol or via usual care according to clinician preference. The primary outcome was the total mechanical ventilation time in hours adjusted for hospital, body mass index, category of surgical urgency, cardiopulmonary bypass time and EuroSCORE II. Secondary outcomes included successful extubation within four postoperative hours, postoperative pain scores, postoperative opioid requirements, and the development of postoperative complications. RESULTS: We included 87 patients in the fast-track group and 88 patients in the usual care group. Fast-track patients had a 35% reduction in total ventilation hours compared with usual care patients (p = 0.007). Thirty-five (40.2%) fast-track patients were extubated within four hours compared to 10 (11.4%) usual-care patients (odds ratio: 5.2 [95% CI: 2.39-11.08; p < 0.001]). Over 24 h, fast-track patients had less severe pain (p < 0.001) and required less intravenous morphine equivalent (22.00 mg [15.75:32.50] vs. 38.75 mg [20.50:81.75]; p < 0.001). There were no significant differences observed in postoperative complications or length of hospital stay between the groups. CONCLUSION: Implementing an FTCA protocol using methadone, dexmedetomidine, magnesium, ketamine, lignocaine, and remifentanil together with protocolized weaning from a mechanical ventilation protocol is associated with significantly reduced time to tracheal extubation, improved postoperative analgesia, and reduced opioid use without any adverse safety events. A prospective randomized trial is warranted to further investigate the combined effects of these medications in reducing complications and length of stay in FTCA. TRIALS REGISTRATION: The study protocol was registered in the Australian New Zealand Clinical Trials Registry ( https://www.anzctr.org.au/ACTRN12623000060640.aspx , retrospectively registered on 17/01/2023).

Open arch-my way! Branch first continuous perfusion arch repair (BF-CPAR).

We herein describe our technique of "branch first continuous perfusion arch repair (BF-CPAR)" which does away with both cerebral circulatory arrest and the need for deep hypothermia. We use this technique for all aortic surgeries including for type A acute aortic dissections. Supplementary Information: The online version contains supplementary material available at 10.1007/s12055-023-01535-2.

The cervical branch-first technique in complex resternotomy.

Background: Branch-first total aortic arch repair is a paradigm shift in the technical approach for uninterrupted neuroprotection during open aortic surgery. This technique is further modified to instigate hazardous sternal reentry in patients with hostile mediastinal anatomy at risk of aortic injury. Methods: Intraoperative preparation and the illustrated operative technique of the cervical branch-first technique are described. The accompanying case series narrates the experiences and outcomes of 4 patients who underwent successful complex reoperative aortic surgery utilizing this technique. Results: The indications for resternotomy included a sixth reoperation for recurrent mycotic aortic pseudoaneurysm, a third reoperation for extensive infective endocarditis, a reoperation for complete Bentall graft dehiscence with contained aortic rupture, and a third reoperation for residual type A dissection. All patients survived their proposed surgery. Two patients were operated on in an emergency setting. Two patients separated from cardiopulmonary bypass with extracorporeal support. None experienced permanent neurological sequelae, gut ischemia, peripheral arterial complications, or in-hospital mortality. One mortality due to decompensated heart failure was reported at 6 months postoperatively. Conclusions: The cervical branch-first technique offers unparalleled advantage in neuroprotection from an early stage of complex reoperative aortic surgery. It provides an independent circuit for complete antegrade cerebral perfusion, irrespective of suspension to circulatory flows to the rest of the body during complex reentry into hostile chests. Our experience to date has demonstrated promising outcomes and further refinements will guide patient selection best suited for this technique.

Valve-sparing aortic root replacement: Long-term variables significantly associated with mortality and morbidity.

OBJECTIVES: In aortic root surgery, valve-sparing aortic root replacement is an attractive alternative by mitigating the risks inherent to prosthetic valves; however, little is known about the variables that impact its durability. We review our mid- to long-term outcomes after valve-sparing aortic root replacement and describe factors that impact survival and valve reintervention and insufficiency. METHODS: A retrospective review of 284 consecutive patients undergoing valve-sparing aortic root replacement between November 1999 and January 2022 at Austin Health, Melbourne, Australia, was undertaken, with a median follow-up of 6.43 ± 4.83 years, but up to 22.0 years. Freedom from mortality, aortic reintervention, and insufficiency was analyzed using Kaplan-Meier methods, Cox proportional hazard models, and Fine-Gray analysis. RESULTS: The median age of patients at intervention was 60.0 years (interquartile range, 48.0-67.0), of whom 68 (23.9%) had bicuspid aortic valve disease, 27 (9.5%) had Marfan syndrome, 119 (41.9%) had severe aortic root dilation (>50 mm), and 155 had (54.6%) severe aortic insufficiency at the time of intervention. The 30-day mortality was 1.8%, with freedom from mortality of 96.0% (95% CI, 92.6-97.8) at 5 years and 88.2% (95% CI, 81.4-92.6) at 10 years. Freedom from aortic reintervention was 92.2% (95% CI, 87.7-95.2) at 5 years and 79.8% (95% CI, 71.8-85.8) at 10 years. Factors associated with reintervention were concomitant leaflet repair (hazard ratio, 8.13, 95% CI, 1.07-61.7) and bicuspid valvulopathy (hazard ratio, 2.23, 95% CI, 1.07-4.68), with reintervention in the bicuspid aortic valve being more likely due to aortic stenosis and in the tricuspid aortic valve due to aortic insufficiency (chi-square P = .05). The freedom from aortic insufficiency was 89.1% (95% CI, 83.5-92.9), 84.9% (95% CI, 77.8-89.9) at 5 and 10 years, respectively, and 80.7% (95% CI, 71.0-87.4). CONCLUSIONS: Valve-sparing aortic root replacement has excellent long-term outcomes, with low mortality and reintervention rates. Concomitant leaflet repair and bicuspid valve disease are the only long-term factors associated with reintervention.

Branch-first Continuous Perfusion Aortic Arch Replacement: Midterm Results.

BACKGROUND: Aortic arch surgery necessitates interruption of perfusion, thus conferring higher morbidity and mortality compared with other aortic surgery. This report describes a branch-first continuous perfusion aortic arch replacement (BF-CPAR) technique that overcomes these shortcomings and describes midterm results with this technique. METHODS: This report represents the corresponding author's 15-year experience with BF-CPAR, which involves preliminary mobilization and branch reconstruction before circulatory arrest by using a modified trifurcation graft. Demographic, procedural, and outcome (mortality, reintervention, morbidity, and stroke) were analyzed with Kaplan-Meier and Cox regression. RESULTS: Over 15 years (July 2005-February 2021), 155 patients underwent BF-CPAR, at a median age of 66.8 years, 106 (68.3%) on an elective basis and 49 (31.6%) on an emergency basis. There were no aortic deaths after the first postoperative year, thereby resulting in a 1- and 10-year freedom from aortic death constant at 95.6% in patients undergoing elective BF-CPAR and 93.3% in patients undergoing emergency BF-CPAR patients, respectively. Freedom from reintervention on the operated segment at 5 and 9 years was 93.2% and 93.2% in patients undergoing elective cases and 97.1% and 91.4% in emergency cases, respectively. The 10-year freedom from any aortic reintervention was 72.8% in elective patients and 29.2% in emergency patients; there were 38 reinterventions, 76.3% (n = 29/38) done for progression of aneurysmal or dissection disease, of which 79.3% (n = 23/29) were completed endovascularly. Freedom from cerebrovascular-related events at 5 and 10 years was 90.3% and 82.6% in patients undergoing elective BF-CPAR and 75.4% for both time points in patients undergoing emergency BF-CPAR, respectively. CONCLUSIONS: BF-CPAR has excellent 10-year results for elective and emergency cases of arch replacement.

Modern Cardiac Surgical Outcomes in Nonagenarians: A Multicentre Retrospective Observational Study.

Background: There have been multiple recent advancements in the selection, optimisation and management of patients undergoing cardiac surgery. However, there is limited data regarding the outcomes in nonagenarians, despite this cohort being increasingly referred for these interventions. The objective of this study was to describe the patient characteristics, management and outcomes of a cohort of nonagenarians undergoing cardiac surgery receiving contemporary peri-operative care. Methods: After receiving ethics approval, we conducted a retrospective observational study of nonagenarians who had undergone cardiac surgery requiring a classic median sternotomy. All operative indications were included. We excluded patients who underwent transcatheter aortic valve implantation (TAVI), and surgery on the thoracic aorta via an endovascular approach (TEVAR). Patients undergoing TEVAR often have the procedure done under sedation and regional blocks with local anesthetic solution. There is no open incision and these patients do not require cardiopulmonary bypass. We also excluded patients undergoing minimally invasive mitral valve surgery via a videoscope assisted approach. These patients do not have a median sternotomy, have the procedure done via erector spinae block, and often are extubated on table. Data were collected from four hospitals in Victoria, Australia, over an 8-year period (January 2012-December 2019). The primary objective was to assess 6-month mortality in nonagenarian patients undergoing cardiac surgery and to provide a detailed overview of postoperative complications. We hypothesized that cardiac surgery in nonagenarian patients would be associated with a 6-month postoperative mortality <10%. As a secondary outcome, we hypothesized that significant postoperative complications (i.e., Clavien Dindo Grade IIIb or greater) would occur in > 30% of patients. Results: A total of 12,358 adult cardiac surgery patients underwent surgery during the study period, of whom 18 nonagenarians (0.15%) fulfilled inclusion criteria. The median (IQR) [min-max] age was 91.0 years (90.0:91.8) [90-94] and the median body mass index was 25.0 (kg/m2) (22.3:27.0). Comorbidities, polypharmacy, and frailty were common. The median predicted mortality as per EuroSCORE-II was 6.1% (4.1:14.5). There were no cases of intra-operative, in-hospital, or 6-month mortality. One (5.6%) patient experienced two Grade IIIa complications. Three (16.7%) patients experienced Grade IIIb complications. Three (16.7%) patients had an unplanned hospital readmission within 30 days of discharge. The median value for postoperative length of stay was 11.6 days (9.8:17.6). One patient was discharged home and all others were discharged to an inpatient rehabilitation facility. Conclusion: In this selected, contemporary cohort of nonagenarian patients undergoing cardiac surgery, postoperative 6-month mortality was zero. These findings support carefully selected nonagenarian patients being offered cardiac surgery (Trials Registry: https://www.anzctr.org.au/ACTRN12622000058774.aspx).

Immediate Higher-Dose Prothrombin Complex Concentrate Without Fresh Frozen Plasma or Fibrinogen Concentrate for Significant Coagulopathic Cardiac Surgical Field Bleeding.

BACKGROUND: Treatment of significant coagulopathic cardiac surgical field bleeding with immediate higher-dose prothrombin complex concentrate (PCC) without fresh frozen plasma (FFP) or fibrinogen concentrate is unexplored. AIMS: To study characteristics, chest drainage, and clinical outcomes of patients with significant coagulopathic surgical field bleeding treated with immediate higher-dose (defined at >15 IU/kg based on factor IX) PCC without FFP or fibrinogen concentrate. METHODS: We screened sequential cardiac surgery patients. We reviewed electronic blood bank data, Australian Society of Cardiothoracic Surgery database information and anaesthetic, intensive care unit (ICU), ward and radiological charts and electronic data. We identified patients deemed by the operating surgeon to require treatment for significant coagulopathic surgical field bleeding who underwent immediate higher-dose PCC without FFP or fibrinogen concentrate. RESULTS: Among 168 patients, we identified 30 who underwent immediate higher-dose PCC without FFP or fibrinogen concentrate. Median age was 68 years, 23 were male, 17 underwent coronary artery bypass surgery and three underwent complex surgery (David procedure, redo mitral valve surgery, and redo thoraco-abdominal aneurysm repair). Median dose of PCC was 2,500 IU. In addition, 27% underwent platelets and one underwent cryoprecipitate. Chest drainage at 24 hours was 505 ml. Survival to hospital discharge was 100%. There were no cases of pulmonary embolism, stroke, or other thrombotic events. Stage 1 AKI occurred in one patient. CONCLUSION: In a pilot cohort of patients with significant coagulopathic surgical field bleeding, immediate higher-dose PCC without FFP or fibrinogen concentrate was feasible and had an acceptable efficacy and safety profile, which justifies future controlled studies.

"Branch-First total arch replacement": a valuable alternative to frozen elephant trunk in acute type A aortic dissection?

The "Branch-First total arch replacement" technique has been used extensively in both elective and acute situations, including in type A aortic dissection. The focus of the Branch-First technique is to reduce the risk of neurological and end-organ dysfunction associated with arch replacement by optimising neuroprotection, distal organ perfusion and myocardial protection. The Branch-First technique is a valuable alternative to the frozen elephant trunk (FET) technique in type A aortic dissection, providing a stable landing zone for subsequent interventions on the distal aorta should they be required. Combining the Branch-First technique with FET in appropriate cases can further improve outcomes. We discuss the merits of the Branch-First technique, and contrast them to those of FET techniques for repair of type A aortic dissection.

Branch-first continuous perfusion aortic arch replacement: insight into our results.

BACKGROUND: Aortic-arch surgery often necessitates interruption of perfusion conferring higher morbidity and mortality compared to other aortic segments. We describe our Branch-first continuous-perfusion aortic-arch replacement (BF-CPAR) technique which overcomes these shortcomings, describing technique, results and improved outcomes. METHODS: This represents the senior author's 15-year experience with BF-CPAR. Description of demographics, procedures and outcomes have been stratified by dissection and aneurysm etiology, with prediction of mortality, cerebrovascular events, renal failure, and end-organ ischemia undertaken using multivariable logistic regression analysis. RESULTS: From July 2005 to February 2021, 155 patients underwent BF-CPAR, 93 for aneurysms and 62 for dissections. Median age at intervention was 66.8 years, 96 (61.9%) male, 18 (11.6%) with history of previous dissection repair, and 49 (31.6%) on an emergent basis. We observed an overall mortality of 4.5% (N.=7) and stroke of 3.2% (N.=5). Comparing elective to urgent cases, the mortality and stroke rates were significantly lower at 0.0% and 1.9% versus 14.2% and 6.1% (risk differences: 14.3% and 2.3%, P<0.01) respectively. Predictors of mortality were age (1.11 per year, 95% CI: 1.00-1.23, P=0.05); of stroke were hypercholesterolemia (14.4, 1.84-111.9, P=0.01) and hypertension (0.07, 0.01-0.84, P<0.01); and of dialysis were dissection (6.60, 1.76-24.7, P<0.01). CONCLUSIONS: BF-CPAR is safe and adds to the armamentarium of aortic arch repair. In elective and uncomplicated acute-dissection cases, it has no mortality and low stroke (1.9%), and vital organ dysfunction risk. Its results which are comparable to many of the best currently reported series, is driven by avoidance of cerebral circulatory arrest and reduction of cardiac and visceral ischemic time.

STABILISE; treatment of aortic dissection, a single Centre experience.

PURPOSE: To outline the process of the STABILISE technique and its use; reporting patient outcomes and midterm follow up for complicated aortic dissection. MATERIALS AND METHODS: Single centre retrospective analysis from January 2011 to January 2021 using the STABILISE technique which utilises balloon assistance to facilitate intimal disruption and promote aortic relamination. RESULTS: Sixteen patients underwent endovascular aortic repair with the STABILISE technique for aortic dissection over the study period. Fourteen patients (14/16; 88%) had acute dissection. Two of 16 (12%) were chronic. The median age of the patient cohort was 61 years (range 32-80 years) and consisted of a male majority (n = 11; 69%). The median time from diagnosis to intervention was 5 days (1-115 days; IQR 1-17.3). More than half (56%) had surgical repair of a acute type A aortic dissection prior to radiological intervention. The procedure was technically successful with no procedural mortality. Two patients were lost to follow up and two died in the post-operative period. Twelve patients had ongoing follow up with an average number of 2.9 ± 1.6 scans performed. Follow up was available in thirteen patients (81%) with a median follow up period of 1097 days (IQR 707-1657). The rate of re-intervention (n = 2/16; 13%) requiring additional stenting was in line with published re-intervention data (15%). Follow up showed a reduction in false lumen size following treatment with total luminal dimensions remaining stable over the follow-up period. CONCLUSION: The STABILISE technique as a procedure for complicated aortic dissection, either acute or chronic, appears safe with stable mid-term aortic remodelling and patient outcomes. LEVEL OF EVIDENCE: Level 3, Retrospective cohort study.

Paving the way for E-vita open NEO hybrid prosthesis implantation for complex aortic arch disease in Asia-Pacific.

We report first in man implantations of the newly designed Evita-open-NEO hybrid prosthesis for complex aortic arch disease from three different countries in Asia-Pacific including instructions on how to proceed with perioperative coagulation management.

Fast-track recovery program after cardiac surgery in a teaching hospital: a quality improvement initiative.

OBJECTIVE: Fast-track cardiac anesthesia (FTCA) is a technique that may improve patient access to surgery and maximize workforce utilization. However, feasibility and factors impacting FTCA implementation remain poorly explored both locally and internationally. We describe the specific intraoperative and postoperative protocols for our FTCA program, assess protocol compliance and identify reasons for FTCA failure. RESULTS: We tested the program in 16 patients undergoing elective cardiac surgery requiring cardiopulmonary bypass. There was 100% compliance with the FTCA protocols. Four (25%) patients successfully completed the FTCA protocol (extubated < 4 h postoperatively and discharged from the intensive care unit on the same operative day).

Trends and controversies in type A aortic surgery in the 21st century: Branch first aortic arch replacement.

BACKGROUND: Acute type A dissection (ATAAD) remains a morbid condition with reported surgical mortality as high as 26%. AIMS: We describe our surgical approach to ATAAD using a "branch first" total arch replacement technique which avoids a traditional approach of ascending aorta and "hemi-arch" replacement utilising deep hypothermic circulatory arrest (DHCA) and an open distal anastomosis. We also discuss the indications for adjunct techniques such as the frozen elephant trunk or complete aortic repair with endovascular methods. MATERIALS & METHODS: Thirty-nine patients underwent a "branch first" total aortic arch replacement for ATAAD. RESULTS: We had an overall 5(12.8%) hospital mortalities and 2 (5.1%) strokes. There were no deaths or strokes in patients without pre-operative organ malperfusion or shock. DISCUSSION: Arch replacement using the "branch-first technique" allows for complete proximal aortic replacement and sets up for straightforward future distal aortic intervention. CONCLUSION: The use of a branch first aortic arch replacement technique in ATAAD results in improved outcomes and is an approach applicable to all cardiac surgeons not only the aortic sub specialist.

COVID-19: An Australian center's perspective.

SARS CoV-2 (COVID 19) is having a deep and lasting impact around the world. We review the effect it has had on our cardiothoracic surgery practice in Australia and give insights into our contingency planning, restructuring, practice changes, and the effect on our patients in this evolving pandemic.

Long-Term Results of the RAPCO Trials.

BACKGROUND: An internal thoracic artery graft to the left anterior descending artery is standard in coronary bypass surgery, but controversy exists on the best second conduit. The RAPCO trials (Radial Artery Patency and Clinical Outcomes) were designed to compare the long-term patency of the radial artery (RA) with that of the right internal thoracic artery (RITA) and the saphenous vein (SV). METHODS: In RAPCO-RITA (the RITA versus RA arm of the RAPCO trial), 394 patients <70 years of age (or <60 years of age if they had diabetes mellitus) were randomized to receive RA or free RITA graft on the second most important coronary target. In RAPCO-SV (the SV versus RA arm of the RAPCO trial), 225 patients ≥70 years of age (or ≥60 years of age if they had diabetes mellitus) were randomized to receive RA or SV graft. The primary outcome was 10-year graft failure. Long-term mortality was a nonpowered coprimary end point. The main analysis was by intention to treat. RESULTS: In the RA versus RITA comparison, the estimated 10-year patency was 89% for RA versus 80% for free RITA (hazard ratio for graft failure, 0.45 [95% CI, 0.23-0.88]). Ten-year patient survival estimate was 90.9% in the RA arm versus 83.7% in the RITA arm (hazard ratio for mortality, 0.53 [95% CI, 0.30-0.95]). In the RA versus SV comparison, the estimated 10-year patency was 85% for the RA versus 71% for the SV (hazard ratio for graft failure, 0.40 [95% CI, 0.15-1.00]), and 10-year patient survival estimate was 72.6% for the RA group versus 65.2% for the SV group (hazard ratio for mortality, 0.76 [95% CI, 0.47-1.22]). CONCLUSIONS: The 10-year patency rate of the RA is significantly higher than that of the free RITA and better than that of the SV. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00475488.

Continuous Magnesium Infusion to Prevent Atrial Fibrillation After Cardiac Surgery: A Sequential Matched Case-Controlled Pilot Study.

OBJECTIVE: The authors aimed to test whether a bolus of magnesium followed by continuous intravenous infusion might prevent the development of atrial fibrillation (AF) after cardiac surgery. DESIGN: Sequential, matched, case-controlled pilot study. SETTING: Tertiary university hospital. PARTICIPANTS: Matched cohort of 99 patients before and intervention cohort of 99 consecutive patients after the introduction of a continuous magnesium infusion protocol. INTERVENTIONS: The magnesium infusion protocol consisted of a 10 mmol loading dose of magnesium sulphate followed by a continuous infusion of 3 mmol/h over a maximum duration of 96 hours or until intensive care unit discharge. MEASUREMENTS AND MAIN RESULTS: The study groups were balanced except for a lower cardiac index in the intervention cohort. The mean duration of magnesium infusion was 27.93 hours (95% confidence interval [CI]: 24.10-31.76 hours). The intervention group had greater serum peak magnesium levels: 1.72 mmol/L ± 0.34 on day 1, 1.32 ± 0.36 on day 2 versus 1.01 ± 1.14 and 0.97 ± 0.13, respectively, in the control group (p < 0.01). Atrial fibrillation occurred in 25 patients (25.3%) in the intervention group and 40 patients (40.4%) in the control group (odds ratio 0.49, 95% CI, 0.27-0.92; p = 0.023). On a multivariate Cox proportional hazards model, the hazard ratio for the development of AF was significantly less in the intervention group (hazard ratio 0.45, 95% CI, 0.26-0.77; p = 0.004). CONCLUSION: The magnesium delivery strategy was associated with a decreased incidence of postoperative AF in cardiac surgery patients. These findings provide a rationale and preliminary data for the design of future randomized controlled trials.

Current status in decision making to treat acute type A dissection: limited versus extended repair.

Acute type A aortic dissection remains one of the most challenging conditions in aortic surgery. Despite the advancements in the field, the mortality rate still remains high. Though there is a general consensus that the ascending aorta should be replaced, the distal extension of the surgery still remains a controversy. Few surgeons argue for a conservative approach to reduce operative and postoperative morbidity while others considering the problems associated with "downstream problems" support an aggressive approach including a frozen elephant trunk. The cohort in the Indian subcontinent and APAC is far different from the western world. Many factors determine the decision for surgery apart from the pathology of the disease. Economy, availability of the suitable prosthesis, the experience of the surgeon, ease of access to the medical facility all contribute to the decision making to treat acute type A dissection.

Plasma ACE2 Activity Predicts Mortality in Aortic Stenosis and Is Associated With Severe Myocardial Fibrosis.

OBJECTIVES: This study investigated the relationship between plasma angiotensin-converting enzyme 2 (ACE2) activity levels and the severity of stenosis and myocardial remodeling in patients with aortic stenosis (AS) and determined if plasma ACE2 levels offered incremental prognostic usefulness to predict all-cause mortality. BACKGROUND: ACE2 is an integral membrane protein that degrades angiotensin II and has an emerging role as a circulating biomarker of cardiovascular disease. METHODS: Plasma ACE2 activity was measured in 127 patients with AS; a subgroup had myocardial tissue collected at the time of aortic valve replacement. RESULTS: The median plasma ACE2 activity was 34.0 pmol/ml/min, and levels correlated with increased valvular calcification (p = 0.023) and the left ventricular (LV) mass index (r = 0.34; p < 0.001). Patients with above-median plasma ACE2 had higher LV end-diastolic volume (57 ml/m2 vs. 48 ml/m2; p = 0.021). Over a median follow-up of 5 years, elevated plasma ACE2 activity was an independent predictor of all-cause mortality after adjustment for relevant clinical, imaging, and biochemical parameters (HR: 2.28; 95% CI: 1.03 to 5.06; p = 0.042), including brain natriuretic peptide activation (integrated discrimination improvement: 0.08; p < 0.001). In 22 patients with plasma and tissue, increased circulating ACE2 was associated with reduced myocardial ACE2 gene expression (0.7-fold; p = 0.033) and severe myocardial fibrosis (p = 0.027). CONCLUSIONS: In patients with AS, elevated plasma ACE2 was a marker of myocardial structural abnormalities and an independent predictor of mortality with incremental value over traditional prognostic markers. Loss of ACE2 from the myocardium was associated with increased fibrosis and higher circulating ACE2 levels.