Association of Glutamate Infusion With Risk of Acute Kidney Injury After Coronary Artery Bypass Surgery: A Pooled Analysis of 2 Randomized Clinical Trials.

Importance: Acute kidney injury (AKI) after cardiac surgery is associated with increased morbidity and mortality, and measures to prevent AKI have had limited success. Glutamate has been reported to enhance natural postischemic recovery of the heart, but not among animals and humans with diabetes. Objective: To summarize pooled results from the GLUTAMICS (Glutamate for Metabolic Intervention in Coronary Surgery) trials regarding the effect of glutamate on postoperative AKI among patients without diabetes undergoing coronary artery bypass graft (CABG) surgery. Design, Setting, and Participants: Data on a total of 791 patients without diabetes from 2 prospective, randomized, double-blind multicenter trials performed at 5 cardiac surgery centers in Sweden between October 4, 2005, and November 12, 2009, and between November 15, 2015, and September 30, 2020, were pooled. Patients had acute coronary syndrome, left ventricular ejection fraction of 0.30 or less, or a European System for Cardiac Risk Evaluation II score of 3.0 or more and underwent CABG with or without additional valve procedure. Statistical analysis was performed from May to November 2023. Interventions: Intravenous infusion of 0.125-M l-glutamic acid or saline at 1.65 mL/kg/h for 2 hours during reperfusion, after which the infusion rate was halved and an additional 50 mL was given. Main Outcomes and Measures: The primary end point was AKI, defined as postoperative increase of plasma creatinine of 50% or more, corresponding to the Risk stage or higher in the Risk, Injury, Failure, Loss, and End-Stage kidney disease (RIFLE) criteria. Results: A total of 791 patients without diabetes (391 who received glutamate [mean (SD) age, 69.3 (9.1) years; 62 women (15.9%)] and 400 controls [mean (SD) age, 69.6 (9.5) years; 73 women (18.3%)]) were randomized. Baseline data did not differ between groups. Glutamate was associated with a significantly lower risk of AKI (relative risk, 0.49 [95% CI, 0.29-0.83]). Dialysis was required for 2 patients in the glutamate group and 5 patients in the control group. In multivariable analysis, glutamate remained significantly associated with a protective effect against AKI (odds ratio, 0.47 [95% CI, 0.26-0.86]). In the glutamate and control groups, the rate of postoperative mortality at 30 days or less was 0.5% (2 of 391) vs 1.0% (4 of 400), and the rate of stroke at 24 hours or less was 0.8% (3 of 391) vs 1.8% (7 of 400). Conclusions and Relevance: In this pooled analysis of 2 randomized clinical trials, infusion of glutamate was associated with a markedly lower risk of AKI after CABG among patients without diabetes. The findings are exploratory and need to be confirmed in prospective trials. Trial Registration: ClinicalTrials.gov Identifiers: NCT00489827 and NCT02592824.

Glutamate Infusion Reduces Myocardial Dysfunction after Coronary Artery Bypass Grafting According to NT-proBNP: Summary of 2 Randomized Controlled Trials (GLUTAmate for Metabolic Intervention in Coronary Surgery [GLUTAMICS I-II]).

BACKGROUND: Glutamate is reported to enhance the recovery of oxidative metabolism and contractile function of the heart after ischemia. The effect appears to be blunted in diabetic hearts. Elevated plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) reflects myocardial dysfunction. In the GLUTAmate for Metabolic Intervention in Coronary Surgery (GLUTAMICS) II trial, the proportion of patients with diabetes had nearly doubled to 47% compared with the cohort used for sample size estimation, and a significant effect on the postoperative rise in NT-proBNP was only observed in patients without diabetes. OBJECTIVE: We aimed to summarize the pooled NT-proBNP results from both GLUTAMICS trials and address the impact of diabetes. METHODS: Data from 2 prospective, randomized, double-blind multicenter trials with similar inclusion criteria and endpoints were pooled. Patients underwent a coronary artery bypass grafting (CABG) ± valve procedure and had a left-ventricular ejection fraction of ≤0.30 or a European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) of ≥3.0 with at least 1 cardiac risk factor. Intravenous infusion of 0.125 M L-glutamic acid or saline at 1.65 mL/kg/h was started 10-20 min before reperfusion and continued for 150 min. The primary endpoint was the difference between preoperative and day 3 postoperative NT-proBNP levels. RESULTS: A total of 451 patients, 224 receiving glutamate and 227 controls, fulfilled the inclusion criteria. Glutamate was associated with a reduced primary endpoint (5344 ± 5104 ng/L and 6662 ± 5606 ng/L in glutamate and control groups, respectively; P = 0.01). Postoperative mortality at ≤30 d was 0.9% and 3.5% (P = 0.11), whereas stroke at ≤24 h was 0.4% and 2.6% in glutamate and control groups, respectively (P = 0.12). No adverse events related to glutamate were observed. A significant interaction regarding the primary endpoint was only detected between glutamate and insulin-treated diabetes groups (P = 0.04). Among patients without insulin-treated diabetes, the primary endpoint was 5047 ± 4705 ng/L and 7001 ± 5830 ng/L in the glutamate and control groups, respectively (P = 0.001). CONCLUSIONS: Infusion of glutamate reduced the postoperative rise in NT-proBNP after CABG in medium- to high-risk patients. A significantly blunted effect was observed only in insulin-treated patients with diabetes. CLINICAL TRIAL DETAILS: This trial was registered at www. CLINICALTRIALS: gov as NCT02592824.

Effect of cryothermic and radiofrequency Cox-Maze IV ablation on atrial size and function assessed by 2D and 3D echocardiography, a randomized trial. To freeze or to burn.

BACKGROUND: Atrial linear scars in Cox-Maze IV procedures are achieved using Cryothermy (Cryo) or radiofrequency (RF) techniques. The subsequent postoperative left atrial (LA) reverse remodelling is unclear. We used 2- and 3-dimensional echocardiography (2-3DE) to compare the impact of Cryo and RF procedures on LA size and function 1 year after Cox-maze IV ablation concomitant with Mitral valve (MV) surgery. METHODS: Seventy-two patients with MV disease and AF were randomized to Cryo (n = 35) or RF (n = 37) ablation. Another 33 patients were enroled without ablation (NoMaze). All patients underwent an echocardiogram the day before and 1 year after surgery. The LA function was assessed on 2D strain by speckle tracking and 3DE. RESULTS: Forty-two ablated patients recovered sinus rhythm (SR) 1 year after surgery. They had comparable left and right systolic ventricular function, LA volume index (LAVI), and 2D reservoir strain before surgery. At follow-up, the 3DE extracted reservoir and booster function were higher after RF (37 ± 10% vs. 26 ± 6%; p < 0.001) than Cryo ablation (18 ± 9 vs. 7 ± 4%; p < 0.001), while passive conduit function was comparable between groups (24 ± 11 vs. 20 ± 8%; p = 0.17). The extent of LAVI reduction depended on the duration of AF preoperatively. CONCLUSIONS: SR restoration after MV surgery and maze results in LA size reduction irrespective of the energy source used. Compared to RF, the extension of ablation area produced by Cryo implies a structural LA remodelling affecting LA systolic function.

Glutamate infusion associated with reduced rises of p-Copeptin after coronary surgery: Substudy of GLUTAMICS II.

BACKGROUND: Glutamate plays a key role for post-ischaemic recovery of myocardial metabolism. According to post hoc analyses of the two GLUTAMICS trials, patients without diabetes benefit from glutamate with less myocardial dysfunction after coronary artery bypass surgery (CABG). Copeptin reflects activation of the Arginine Vasopressin system and is a reliable marker of heart failure but available studies in cardiac surgery are limited. We investigated whether glutamate infusion is associated with reduced postoperative rises of plasma Copeptin (p-Copeptin) after CABG. METHODS: A prespecified randomised double-blind substudy of GLUTAMICS II. Patients had left ventricular ejection fraction ≤0.30 or EuroSCORE II ≥3.0 and underwent CABG ± valve procedure. Intravenous infusion of 0.125 M L-glutamic acid or saline at 1.65 mL/kg/h was commenced 10-20 min before the release of the aortic cross-clamp and then continued for another 150 min P-Copeptin was measured preoperatively and postoperatively on day one (POD1) and day three. The primary endpoint was an increase in p-Copeptin from the preoperative level to POD1. Postoperative stroke ≤24 h and mortality ≤30 days were safety outcomes. RESULTS: We included 181 patients of whom 48% had diabetes. The incidence of postoperative mortality ≤30 days (0% vs. 2.1%; p = .50) and stroke ≤24 h (0% vs. 3.2%; p = .25) did not differ between the glutamate group and controls. P-Copeptin increased postoperatively with the highest values recorded on POD1 without significant inter-group differences. Among patients without diabetes, p-Copeptin did not differ preoperatively but postoperative rise from preoperative level to POD1 was significantly reduced in the glutamate group (73 ± 66 vs. 115 ± 102 pmol/L; p = .02). P-Copeptin was significantly lower in the Glutamate group on POD1 (p = .02) and POD 3 (p = .02). CONCLUSIONS: Glutamate did not reduce rises of p-Copeptin significantly after moderate to high-risk CABG. However, glutamate was associated with reduced rises of p-Copeptin among patients without diabetes. These results agree with previous observations suggesting that glutamate mitigates myocardial dysfunction after CABG in patients without diabetes. Given the exploratory nature of these findings, they need to be confirmed in future studies.

Risk and protective factors for atrial fibrillation after cardiac surgery and valvular interventions: an umbrella review of meta-analyses.

OBJECTIVE: Postoperative atrial fibrillation (POAF) is a common complication affecting approximately one-third of patients after cardiac surgery and valvular interventions. This umbrella review systematically appraises the epidemiological credibility of published meta-analyses of both observational and randomised controlled trials (RCT) to assess the risk and protective factors of POAF. METHODS: Three databases were searched up to June 2021. According to established criteria, evidence of association was rated as convincing, highly suggestive, suggestive, weak or not significant concerning observational studies and as high, moderate, low or very low regarding RCTs. RESULTS: We identified 47 studies (reporting 61 associations), 13 referring to observational studies and 34 to RCTs. Only the transfemoral transcatheter aortic valve replacement (TAVR) approach was associated with the prevention of POAF and was supported by convincing evidence from meta-analyses of observational data. Two other associations provided highly suggestive evidence, including preoperative hypertension and neutrophil/lymphocyte ratio. Three associations between protective factors and POAF presented a high level of evidence in meta-analyses, including RCTs. These associations included atrial and biatrial pacing and performing a posterior pericardiotomy. Nineteen associations were supported by moderate evidence, including use of drugs such as amiodarone, b-blockers, glucocorticoids and statins and the performance of TAVR compared with surgical aortic valve replacement. CONCLUSIONS: Our study provides evidence confirming the protective role of amiodarone, b-blockers, atrial pacing and posterior pericardiotomy against POAF as well as highlights the risk of untreated hypertension. Further research is needed to assess the potential role of statins, glucocorticoids and colchicine in the prevention of POAF. PROSPERO REGISTRATION NUMBER: CRD42021268268.

Effect of glutamate infusion on NT-proBNP after coronary artery bypass grafting in high-risk patients (GLUTAMICS II): A randomized controlled trial.

BACKGROUND: Animal and human data suggest that glutamate can enhance recovery of myocardial metabolism and function after ischemia. N-terminal pro-brain natriuretic peptide (NT-proBNP) reflects myocardial dysfunction after coronary artery bypass surgery (CABG). We investigated whether glutamate infusion can reduce rises of NT-proBNP in moderate- to high-risk patients after CABG. METHODS AND FINDINGS: A prospective, randomized, double-blind study enrolled patients from November 15, 2015 to September 30, 2020, with a 30-day follow-up at 4 academic cardiac surgery centers in Sweden. Patients underwent CABG ± valve procedure and had left ventricular ejection fraction ≤0.30 or EuroSCORE II ≥3.0. Intravenous infusion of 0.125 M L-glutamic acid or saline at 1.65 mL/kg/h started 10 to 20 minutes before releasing the aortic cross-clamp, then continued for another 150 minutes. Patients, staff, and investigators were blinded to the treatment. The primary endpoint was the difference between preoperative and day-3 postoperative NT-proBNP levels. Analysis was intention to treat. We studied 303 patients (age 74 ± 7 years; females 26%, diabetes 47%), 148 receiving glutamate group and 155 controls. There was no significant difference in the primary endpoint associated with glutamate administration (5,390 ± 5,396 ng/L versus 6,452 ± 5,215 ng/L; p = 0.086). One patient died ≤30 days in the glutamate group compared to 6 controls (0.7% versus 3.9%; p = 0.12). No adverse events linked to glutamate were observed. A significant interaction between glutamate and diabetes was found (p = 0.03). Among patients without diabetes the primary endpoint (mean 4,503 ± 4,846 ng/L versus 6,824 ± 5,671 ng/L; p = 0.007), and the incidence of acute kidney injury (11% versus 29%; p = 0.005) was reduced in the glutamate group. These associations remained significant after adjusting for differences in baseline data. The main limitations of the study are: (i) it relies on a surrogate marker for heart failure; and (ii) the proportion of patients with diabetes had almost doubled compared to the cohort used for the sample size estimation. CONCLUSIONS: Infusion of glutamate did not significantly reduce postoperative rises of NT-proBNP. Diverging results in patients with and without diabetes agree with previous observations and suggest that the concept of enhancing postischemic myocardial recovery with glutamate merits further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02592824. European Union Drug Regulating Authorities Clinical Trials Database (Eudra CT number 2011-006241-15).

Evaluation of left ventricular diastolic function in patients operated for aortic stenosis.

BACKGROUND: Left ventricular diastolic dysfunction is common in patients with aortic valve stenosis (AS) and reportedly affects prognosis after surgical aortic valve replacement (SAVR). Here we investigated whether and how diastolic function (assessed following the most recent guidelines) was affected by SAVR, and whether preoperative diastolic function affected postoperative outcome. We also examined whether long-term mortality was associated with preoperative NT-proBNP and postoperative heart failure (PHF). METHODS: We performed a prospective observational study of 273 patients with AS who underwent AVR with or without concomitant coronary artery bypass surgery. Of these patients, 247 were eligible for assessment of left ventricular (LV) filling pressure. Preoperatively and at the 6-month postoperative follow-up, we measured N-terminal pro-B type natriuretic peptide (NT-proBNP) in serum and assessed diastolic function with Doppler echocardiography. PHF was diagnosed using prespecified criteria. Multivariable logistic regression was performed to explore variables associated with high LV filling pressure. Cox regression was performed to explore variables associated with mortality, accounting for timeto-event. RESULTS: At the time of surgery, 22% (n = 54) of patients had diastolic dysfunction expressed as high LV filling pressure. Of these 54 patients, 27 (50%) showed postoperative diastolic function improvement. Among the 193 patients with preoperative low LV filling pressure, 24 (12%) showed postoperative diastolic function deterioration. Increased long-term mortality was associated with PHF and high preoperative NT-proBNP, but not with preoperative or postoperative diastolic dysfunction. Cox regression revealed the following independent risk factors for long-term mortality: diabetes, renal dysfunction, preoperative NT-proBNP>960 ng/L, age, and male gender. CONCLUSIONS: Surgery for aortic stenosis improved diastolic function in patients with high LV filling pressure in 50% of the patients. Our results could not confirm the previously suggested role of diastolic dysfunction as a marker for poor long-term survival after SAVR. Our findings showed that both PHF and high preoperative NT-proBNP were associated with long-term mortality.

Survival after aortic root replacement with a stentless xenograft is determined by patient characteristics.

OBJECTIVES: Our objective was to examine intermediate-term survival and reinterventions in unselected patients, stratified according to indication, who received a Freestyle (Medtronic Inc, Minneapolis, Minn) bioprosthesis as a full aortic root replacement. METHODS: Data from medical records were retrospectively collected for patients who had aortic root replacement using Freestyle bioprostheses between 1999 and 2018 at 6 North-Atlantic centers. Survival status was extracted from national registries and results stratified according to indication for surgery. RESULTS: We included 1030 implantations in 1008 patients with elective indications for surgery: aneurysm (39.8%), small root (8.3%), and other (13.8%), and urgent/emergent indications: endocarditis (26.7%) and Stanford type A aortic dissection (11.4%). Across indications, 46.3% were nonelective cases and 34.0% were reoperations. Median age was 66.0 (interquartile range, 58.0-71.8) years and median follow-up was 5.0 (interquartile range, 2.6-7.9) years. Thirty-day mortality varied from 2.9% to 27.4% depending on indication. Intermediate survival for 90-day survivors with elective indications were not different from the general population standardized for age and sex (P = .95, .83, and .16 for aneurysms, small roots, and other, respectively). In contrast, patients with endocarditis and type A dissection had excess mortality (P < .001). Freedom from valve reinterventions was 95.0% and 94.4% at 5 and 8 years, respectively. In all, 52 patients (5.2%) underwent reinterventions, most because of endocarditis. CONCLUSIONS: At intermediate term follow-up this retrospective study provides further support for the use of the Freestyle bioprosthesis in the real-world setting of diverse, complex, and often high-risk aortic root replacement and suggests that outcome is determined by patient and disease, rather than by prosthesis, characteristics.

Utility of NT-proBNP as an objective marker of postoperative heart failure after coronary artery bypass surgery: a prospective observational study.

BACKGROUND: Postoperative heart failure (PHF) is the main cause for mortality after cardiac surgery but unbiased evaluation of PHF is difficult. We investigated the utility of postoperative NT-proBNP as an objective marker of PHF after coronary artery bypass surgery (CABG). METHODS: Prospective study on 382 patients undergoing isolated CABG for acute coronary syndrome. NT-proBNP was measured preoperatively, the first (POD1) and third postoperative morning (POD3). A blinded Endpoints Committee used prespecified criteria for PHF. Use of circulatory support was scrutinized. RESULTS: After adjusting for confounders PHF was associated with 1.46 times higher NT-proBNP on POD1 (p = 0.002), 1.54 times higher on POD3 (p < 0.0001). In severe PHF, NT-proBNP was 2.18 times higher on POD1 (p = 0.001) and 1.81 times higher on POD3 (p = 0.019). Postoperative change of NT-proBNP was independently associated with PHF (OR 5.12, 95% CI 1.86-14.10, p = 0.002). The use of inotropes and ICU resources increased with incremental quartiles of postoperative NT-proBNP. CONCLUSIONS: Postoperative NT-proBNP can serve as an objective marker of the severity of postoperative myocardial dysfunction. Due to overlap in individuals, NT-proBNP is useful mainly for comparisons at cohort level. As such, it provides a tool for study purposes when an unbiased assessment of prevention or treatment of PHF is desirable. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00489827 https://clinicaltrials.gov/ct2/show/NCT00489827?term=glutamics&draw=2&rank=1 .

A Well-Defined Endobronchial Tumor in a 26-Year-Old Man.

CASE PRESENTATION: A 26-year-old man presented with a 2-week history of productive cough and a 1-year history of effort-related dyspnea. His medical history was significant for hay fever and exertion-triggered asthma. He was not taking medicines regularly but was using inhaled salbutamol as needed. He was an ex-smoker, with a previous history of 2-pack years.

Cerebrovascular Reserve Capacity as a Predictor of Postoperative Delirium: A Pilot Study.

Introduction: Postoperative delirium is a common complication after cardiac surgery with cardiopulmonary bypass (CPB). Compromised regulation of the cerebral circulation may be a predisposing factor for delirium. However, the potential relationship between cerebrovascular reserve capacity and delirium is unknown. The aim of this study was to investigate if impaired cerebrovascular reserve capacity was associated with postoperative delirium. Methods: Forty-two patients scheduled for cardiac surgery with CPB were recruited consecutively. All patients underwent preoperative transcranial Doppler (TCD) ultrasound with calculation of breath-hold index (BHI). BHI < 0.69 indicated impaired cerebrovascular reserve capacity. In addition, patients were examined with preoperative neuropsychological tests such as MMSE (Mini Mental State Examination) and AQT (A Quick Test of cognitive speed). Postoperative delirium was assessed using Nursing Delirium Screening Scale (Nu-DESC) in which a score of ≥2 was considered as delirium. Results: Six patients (14%) scored high for postoperative delirium and all demonstrated impaired preoperative cerebrovascular reserve capacity. Median (25th-75th percentile) BHI in patients with postoperative delirium was significantly lower compared to the non-delirium group [0.26 (-0.08-0.44) vs. 0.83 (0.57-1.08), p = 0.002]. Preoperative MMSE score was lower in patients who developed postoperative delirium (median, 25th-75th percentile; 26.5, 24-28 vs. 28.5, 27-29, p = 0.024). Similarly, patients with postoperative delirium also displayed a slower performance during the preoperative cognitive speed test AQT color and form (mean ± SD; 85.8 s ± 19.3 vs. 69.6 s ± 15.8, p = 0.043). Conclusion: The present findings suggest that an extended preoperative ultrasound protocol with TCD evaluation of cerebrovascular reserve capacity and neuropsychological tests may be valuable in identifying patients with increased risk of developing delirium after cardiac surgery.

The impact of glutamate infusion on postoperative NT-proBNP in patients undergoing coronary artery bypass surgery: a randomized study.

BACKGROUND: Glutamate, a key intermediate in myocardial metabolism, may enhance myocardial recovery after ischemia and possibly reduce the incidence and severity of postoperative heart failure in coronary artery bypass surgery (CABG). N-terminal pro-B-type natriuretic peptide (NT-proBNP) can be used to assess postoperative heart failure (PHF) after CABG. Our hypothesis was that glutamate enhances myocardial recovery in post-ischemic heart failure and, therefore, will be accompanied by a mitigated postoperative increase of NT-proBNP. METHODS: Substudy of the GLUTAmate for Metabolic Intervention in Coronary Surgery (GLUTAMICS) trial (ClinicalTrials.gov Identifier: NCT00489827) a prospective triple-center double-blind randomized clinical trial on 399 patients undergoing CABG with or without concomitant procedure for acute coronary syndrome at three Swedish Cardiac Surgery centres (Linköping, Örebro, and Karlskrona) from May 30, 2007 to November 12, 2009. Patients were randomly assigned to intravenous infusion of 0.125 M L-glutamic acid or saline (1.65 mL/kg of body weight per hour) intraoperatively and postoperatively. Plasma NT-proBNP was measured preoperatively, the first (POD1) and third postoperative morning (POD3). A Clinical Endpoints Committee, blinded to both intervention and NT-proBNP used prespecified criteria to diagnose PHF. The primary endpoints were the absolute levels of postoperative NT-proBNP and the difference between preoperative and postoperative levels of NT-proBNP. RESULTS: Overall no significant difference was detected in postoperative NT-proBNP levels between groups. However, in high-risk patients (upper quartile of EuroSCORE II ≥ 4.15; glutamate group n = 56; control group n = 45) glutamate was associated with significantly lower postoperative increase of NT-proBNP (POD3-Pre: 3900 [2995-6260] vs. 6745 [3455-12,687] ng•L-1, p = 0.012) and lower NT-proBNP POD3 (POD3: 4845 [3426-7423] vs. 8430 [5370-14,100] ng•L-1, p = 0.001). After adjusting for significant differences in preoperative demographics, NT-proBNP POD3 in the glutamate group was 0.62 times of that in the control group (p = 0.002). Patients in the glutamate group also had shorter ICU stay (21 [19-26] vs. 25 [22-46] h, p = 0.025) and less signs of myocardial injury (Troponin T POD3 (300 [170-500] vs. 560 [210-910] ng•L-1, p = 0.025). CONCLUSIONS: Post hoc analysis of postoperative NT-proBNP suggests that intravenous infusion of glutamate may prevent or mitigate myocardial dysfunction in high-risk patients undergoing CABG. Further studies are necessary to confirm these findings. Trial registration Swedish Medical Products Agency 151:2003/70403 (prospectively registered with amendment about this substudy filed March 17, 2007). ClinicalTrials.gov Identifier: NCT00489827 (retrospectively registered) https://clinicaltrials.gov/ct2/show/NCT00489827?term=glutamics&draw=1&rank=1.

Novel SMAD3 p.Arg386Thr genetic variant co-segregating with thoracic aortic aneurysm and dissection.

BACKGROUND: Pathogenic variants in the SMAD3 gene affecting the TGF-ß/SMAD3 signaling pathway with aortic vessel involvement cause Loeys-Dietz syndrome 3, also known as aneurysms-osteoarthritis syndrome. METHODS: Description of clinical history of a family in Sweden using clinical data, DNA sequencing, bioinformatics, and pedigree analysis. RESULTS: We report a novel SMAD3 variant, initially classified as a genetic variant of uncertain clinical significance (VUS), and later found to be co-segregating with aortic dissection in the family. The index patient presented with a dissecting aneurysm of the aorta including the ascending, descending, and abdominal parts. Genotype analysis revealed a heterozygous missense SMAD3 variant: NM_005902.3(SMAD3): c.11576G > C (p.Arg386Thr). The same variant was also identified in a 30 years old formalin-fixed paraffin-embedded block of tissue from a second cousin, who died at 26 years of age from a dissecting aneurysm of the aorta. CONCLUSION: A "variant of uncertain significance" according to the ACMG guidelines has always a scope for reappraisal. Genetic counselling to relatives, and the offering of surveillance service is important to families with aortic aneurysm disease. The report also highlight the potential use of FFPE analysis from deceased relatives to help in the interpretation of variants.

NT-proBNP and postoperative heart failure in surgery for aortic stenosis.

Objective: Postoperative heart failure (PHF) after aortic valve replacement (AVR) for aortic stenosis (AS) may initially appear mild and transient but has serious long-term consequences. Methods to assess PHF are not well documented. We studied the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and PHF after AVR for AS. Methods: This is a prospective, observational, longitudinal study of 203 patients undergoing elective first-time AVR for AS. Plasma NT-proBNP was assessed at preoperative evaluation, the day before surgery, and the first (POD1) and third postoperative morning. A clinical endpoints committee, blinded to NT-proBNP results, used prespecified haemodynamic criteria to diagnose PHF. The mean follow-up was 8.6±1.1 years. Results: No patient with PHF (n=18) died within 30 days after surgery, but PHF was associated with poor long-term survival (HR 3.01, 95% CI 1.45 to 6.21, p=0.003). NT-proBNP was significantly higher in patients with PHF only on POD1 (6415 (3145-11 220) vs 2445 (1540-3855) ng/L, p<0.0001). NT-proBNP POD1 provided good discrimination of PHF (area under the curve=0.82, 95% CI 0.72 to 0.91, p<0.0001; best cut-off 5290 ng/L: sensitivity 63%, specificity 85%). NT-proBNP POD1 ≥5290 ng/L identified which patients with PHF carried a risk of poor long-term survival, and PHF with NT-proBNP POD1 ≥ 5290 ng/L emerged as a risk factor for long-term mortality in the multivariable Cox regression (HR 6.20, 95% CI 2.72 to 14.1, p<0.0001). Conclusions: The serious long-term consequences associated with PHF after AVR for AS were confirmed. NT-proBNP level on POD1 aids in the assessment of PHF and identifies patients at particular risk of poor long-term survival.

Rise and fall of NT-proBNP in aortic valve intervention.

Objectives: To describe the dynamics of N-terminal pro-B-type natriuretic peptide (NT-proBNP) from preoperative evaluation to 6-month follow-up in patients undergoing aortic valve intervention, and to evaluate NT-proBNP with regard to 1-year mortality. Methods: At preoperative evaluation, we prospectively included 462 patients accepted for aortic valve intervention. The median time to surgical aortic valve replacement (SAVR; n=336) or transcatheter aortic valve implantation (TAVI; n=126) was 4 months. NT-proBNP was measured at enrolment for preoperative evaluation, on the day of surgery, postoperatively on day 1, day 3 and at the 6-month follow-up. Subgroups of patients undergoing SAVR with aortic regurgitation and aortic stenosis with and without coronary artery bypass were also analysed. Results: NT-proBNP remained stable in all subgroups during the preoperative waiting period, but displayed a substantial transient early postoperative increase with a peak on day 3 except in the TAVI group, which peaked on day 1. At the 6-month follow-up, NT-proBNP had decreased to or below the preoperative level in all groups. In the SAVR group, NT-proBNP preoperatively and on postoperative days 1 and 3 revealed significant discriminatory power with regard to 1-year mortality (area under the curve (AUC)=0.79, P=0.0001; AUC=0.71, P=0.03; and AUC=0.79, P=0.002, respectively). This was not found in the TAVI group, which had higher levels of NT-proBNP both preoperatively and at the 6-month follow-up compared with the SAVR group. Conclusions: The dynamic profile of NT-proBNP differed between patients undergoing TAVI and SAVR. NT-proBNP in the perioperative course was associated with increased risk of 1-year mortality in SAVR but not in TAVI.

Impact of underlying heart disease per se on the utility of preoperative NT-proBNP in adult cardiac surgery.

OBJECTIVE: The primary aim was to investigate the role of underlying heart disease on preoperative NT-proBNP levels in patients admitted for adult cardiac surgery, after adjusting for the known confounders age, gender, obesity and renal function. The second aim was to investigate the predictive value of preoperative NT-proBNP with regard to severe postoperative heart failure (SPHF) and postoperative mortality. METHODS: A retrospective cohort study based on preoperative NT-proBNP measurements in an unselected cohort including all patients undergoing first time surgery for coronary artery disease (CAD; n = 2226), aortic stenosis (AS; n = 406) or mitral regurgitation (MR; n = 346) from April 2010 to August 2016 in the southeast region of Sweden (n = 2978). Concomitant procedures were not included, with the exception of Maze or tricuspid valve procedures. RESULTS: Preoperative NT-proBNP was 1.67 times (p<0.0001) and 1.41 times (p<0.0001) higher in patients with AS or MR respectively, than in patients with CAD after adjusting for confounders. NT-proBNP demonstrated significant discrimination with regard to SPHF in CAD (AUC = 0.79, 95%CI 0.73-0.85, p<0.0001), MR (AUC = 0.80, 95%CI 0.72-0.87, p<0.0001) and AS (AUC = 0.66, 95%CI 0.51-0.81, p = 0.047). In CAD patients NT-proBNP demonstrated significant discrimination with regard to postoperative 30-day or in-hospital mortality (AUC = 0.78; 95%CI 0.71-0.85, p<0.0001). The number of deaths was too few in the AS and MR group to permit analysis. Elevated NT-proBNP emerged as an independent risk factor for SPHF, and postoperative mortality in CAD. CONCLUSIONS: Patients with AS or MR have higher preoperative NT-proBNP than CAD patients even after adjusting for confounders. The predictive value of NT-proBNP with regard to SPHF was confirmed in CAD and MR patients but was less convincing in AS patients.

Cox-maze IV cryoablation and postoperative heart failure in mitral valve surgery patients.

OBJECTIVE: The indications for and the risk and benefit of concomitant surgical ablation for atrial fibrillation (AF) have not been fully delineated. Our aim was to survey whether the Cox-maze IV procedure is associated with postoperative heart failure (PHF) or other adverse short-term outcomes after mitral valve surgery (MVS). DESIGN: Consecutive patients with AF undergoing MVS with (n = 50) or without (n = 66) concomitant Cox-maze IV cryoablation were analysed regarding perioperative data and one-year mortality. RESULTS: The patients in the Maze group were younger, were in lower NYHA classes, had better right ventricular function and had lower pulmonary artery pressure. The Maze group had 30 min longer median cross-clamp time (CCT) and 50% had PHF compared with 33% in the No-maze group, p = 0.09. Two patients in the No-maze group died within one year of surgery. Congestive heart failure (OR 4.3 [CI 95%: 1.8-10], p < 0.0001) and CCT (OR 1.03 [CI 95%: 1.01-1.04], p = 0.001) were associated with PHF. CONCLUSION: The current data cannot exclude that concomitant cryoablation increases the risk for PHF, possibly by increasing the cross clamp time.

Post hoc analysis of the glutamics-trial: intravenous glutamate infusion and use of inotropic drugs after cabg.

BACKGROUND: Intravenous glutamate reduced the risk of developing severe circulatory failure after isolated coronary artery bypass graft surgery (CABG) for acute coronary syndrome (ACS) in a double-blind randomised clinical trial (GLUTAMICS-ClinicalTrials.gov Identifier: NCT00489827 ). Here our aim was to study if glutamate was associated with reduced the use of inotropes. METHODS: Post-hoc analysis of 824 patients undergoing isolated CABG for ACS in the GLUTAMICS-trial. ICU-records were retrospectively scrutinised including hourly registration of inotropic drug infusion, dosage and total duration during the operation and postoperatively. RESULTS: ICU-records were found for 171 out of 177 patients who received inotropes perioperatively. Only one fourth of the patients treated with inotropes fulfilled study criteria for postoperative heart failure at weaning from cardiopulmonary bypass (CPB) or later in the ICU. Inotropes were mainly given preemptively to facilitate weaning from CPB or to treat postoperative circulatory instability (bleeding, hypovolaemia). Except for a significantly lower use of epinephrine there were only trends towards lower need of other inotropes overall in the glutamate group. In patients treated with inotropes (glutamate n = 17; placebo n = 13) who fulfilled study criteria for left ventricular failure at weaning from CPB the average duration of inotropic treatment (34 ± 20 v 80 ± 77 h; p = 0.014) and the number of inotropes used (1.35 ± 0.6 v 1.85 ± 0.7; p = 0.047) were lower in the glutamate group. CONCLUSIONS: Intravenous glutamate was associated with a minor influence on inotrope use overall in patients undergoing CABG for ACS whereas a considerable and significant reduction was observed in patients with heart failure at weaning from CPB.

Evaluation of the Valve Academic Research Consortium-2 Criteria for Myocardial Infarction in Transcatheter Aortic Valve Implantation: A Prospective Observational Study.

OBJECTIVE: To evaluate the relevance of the individual components of the Valve Academic Research Consortium (VARC)-2 criteria for periprocedural myocardial infarction (MI) in transcatheter aortic valve implantation (TAVI). The association between biomarkers and adverse procedural outcome has been established. However, the additive prognostic importance of signs and symptoms are more uncertain. METHODS: A total of 125 consecutive TAVI patients were prospectively included in this study. Biomarkers for MI were analyzed and signs and symptoms according to VARC-2 criteria were collected from clinical records. RESULTS: The criteria of elevated biomarkers and of signs or symptoms were found in 27 (22%) and 32 (26%) of the patients, respectively. According to VARC-2 definition, 12 (10%) had MI. VARC-2 definition of MI, Troponin T (TnT) > 600 ng/L, and presence of signs or symptoms correlated with 6 months mortality, prolonged ICU stay, elevation of N-terminal prohormone brain natriuretic peptide, and renal impairment. No signs or symptoms were found in 7 (44%) of the patients who fulfilled the criterion of elevated TnT > 600 ng/L. In the group with positive TnT criterion, there were no significant differences between those with and without signs or symptoms in respect to levels of TnT (1014 [585-1720] ng/L versus 704 [515-905] ng/L, p = 0.17) or creatine kinase-MB (36 [25-52] µg/L versus 29 [25-39] µg/L, p = 0.32). In the multivariate Cox regression analysis, TnT > 600 ng/L was the only significant independent variable associated with 6-months postprocedural mortality. CONCLUSIONS: Myocardial injury in TAVI, measured with biomarkers, correlates well with adverse procedural outcome. In this study it is also the strongest predictor for early postprocedural mortality. The additional requirement of signs or symptoms for the diagnosis of MI results in omission of a considerable number of clinically significant MI.

Differences in recovery of left and right ventricular function following aortic valve interventions: a longitudinal echocardiographic study in patients undergoing surgical, transapical or transfemoral aortic valve implantation.

OBJECTIVES: To evaluate longitudinal left and right ventricular function (LVF and RVF) after transcatheter aortic valve implantation (TAVI) as compared to surgical aortic valve replacement (SAVR) and LVF and RVF after TAVI by the transfemoral (TF) or transapical (TA) approach. BACKGROUND: Knowledge about differences in recovery of LVF and RVF after TAVI and SAVR is scarce. METHODS: Sixty patients (age 81 ± 7 years, logistic EuroSCORE 16 ± 10%), undergoing TAVI (TF: n = 35 and TA: n = 25), were examined by echocardiography including atrioventricular plane displacement (AVPD) and peak systolic velocities (PSV) by tissue Doppler at basal RV free wall, LV lateral wall and septum preprocedurally, 7 weeks and 6 months postprocedurally. Twenty-seven SAVR patients were matched to 27 TAVI patients by age, gender and LVF. RESULTS: Early postintervention, TAVI patients had improved longitudinal LVF. However, when analyzed separately, only TF, but not TA patients, had improved LV lateral and septal AVPD and PSV (all P ≤ 0.01). All TAVI patients, as well as the TF and TA group had unchanged longitudinal LVF between the early and late follow-ups (all P > 0.05). The SAVR group had higher septal LVF than the matched TAVI group preprocedurally, while postoperatively this difference was diminished. Longitudinal RVF was better in the TF group than in the TA group pre- and postprocedurally. Although the SAVR group had superior longitudinal RVF preoperatively, this was inferior to TAVI postoperatively. CONCLUSIONS: Postprocedural longitudinal LVF and RVF in patients undergoing TF-TAVI, TA-TAVI, or SAVR differ considerably. Preservation of longitudinal RVF after TAVI might influence the selection of aortic valve intervention in the future.