Cerebrovascular Involvement in Transthyretin Amyloid Cardiomyopathy.

Background: Intracardiac thrombosis is common in transthyretin amyloid cardiomyopathy (ATTR-CM), and patients are at risk for thromboembolic events. However, silent cerebral infarcts and the extent of cerebral small vessel disease in patients with cardiac amyloidosis are unknown. Methods: Thirty-two consecutively selected ATTR-CM patients were prospectively studied by cerebral magnetic resonance imaging (cMRI) and compared with 43 CHA2DS2-VASc-matched controls (Co). Structural clinical standard cMRI sequences and features of cerebral vessel involvement were included and quantified by two board certified neuroradiologists in consensus blinded to clinical status. Group differences were estimated using generalized (logistic) linear regression models adjusting for vascular risk factors based on the CHA2DS2-VASc score. Results: The median CHA2DS2-VASc score was 4 for ATTR-CM and Co (p = 0.905). There were no differences between groups in the frequency of current or former smokers (p = 0.755), body-mass-index > 30 (p = 0.106), and hyperlipidemia (p = 0.869). The number of territorial infarcts (4 vs. 0, p = 0.018) was higher in ATTR-CM compared to Co, as was the mean number of cerebral microbleeds (1.4 vs. 0.3, p ≤ 0.001) and the number of Virchow-Robin spaces (43.8 vs. 20.6, p ≤ 0.001). Lacunar lesion presence was higher in ATTR-CM (6 vs. 2, p = 0.054). CHA2DS2-VASc score, atrial fibrillation, anticoagulation, and the interaction term of CHA2DS2-VASc score and atrial fibrillation did not affect the probability of a territorial ischemic lesion or lacunar lesion in logistic regression modeling. Conclusions: In patients with ATTR-CM free from clinically apparent neurological symptoms, cMRI revealed unreported significant small cerebral vessel disease and territorial ischemia. Our findings may support low thresholds for anticoagulation and cMRI in patients with ATTR-CM.

Transthyretin amyloid cardiomyopathy among patients with heart failure and preserved ejection fraction: the AMY score.

AIMS: Transthyretin 'wild-type' amyloid cardiomyopathy (ATTRwt-CM) is a differential diagnosis of heart failure with preserved ejection fraction (HFpEF). The clinical work-up for ATTRwt-CM is challenging. Considering a combination of clinical variables specific for ATTRwt-CM might aid in identifying patients at risk. METHODS AND RESULTS: Sixty patients (78 ± 6 years, 8% female) were diagnosed with ATTRwt-CM by endomyocardial biopsy. Preserved ejection fraction (LVEF >45%) was present in 41 of the patients. Those were 1:1 propensity score age- and sex-matched to a cohort of patients with HFpEF. ATTRwt-CM patients had less obesity (P = 0.01) and higher septal thickness (IVSd, P < 0.01) as well as more diastolic dysfunction (E/e', P < 0.01). On multivariable regression IVSd > 14 mm, E/e' > 14 and absence of obesity (P > 0.01 for all) were identified as predictors for ATTRwt-CM. A weighted point-based score was derived with IVSd > 14 mm = 1 point; absence of obesity = 2 points; and E/e' > 14 = 3 points. Area under the curve (AUC) for the summation score was 0.91 (0.84-0.97, P < 0.01) and a score of more than 3 points predicted ATTRwt-CM with good sensitivity (78%) and specificity (90%). The score was validated in an external cohort of 142 patients with ATTRwt-CM and 419 HFpEF patients showing sufficient accuracy (AUC 0.91, 0.88-0.94, P < 0.01). A value greater than 3 points demonstrated a high sensitivity (93%) and a negative predictive value of 97%. CONCLUSIONS: A score based on basic clinical and echocardiographic features helps to distinguish ATTRwt-CM from typical HFpEF. This could facilitate the diagnostic work-up for these patients and enable earlier disease screening on a large scale.

Myocardial structural and functional changes in cardiac amyloidosis: insights from a prospective observational patient registry.

AIMS: The pathophysiological hallmark of cardiac amyloidosis (CA) is the deposition of amyloid within the myocardium. Consequently, extracellular volume (ECV) of affected patients increases. However, studies on ECV progression over time are lacking. We aimed to investigate the progression of ECV and its prognostic impact in CA patients. METHODS AND RESULTS: Serial cardiac magnetic resonance (CMR) examinations, including ECV quantification, were performed in consecutive CA patients. Between 2012 and 2021, 103 CA patients underwent baseline and follow-up CMR, including ECV quantification. Median ECVs at baseline of the total (n = 103), transthyretin [(ATTR) n = 80], and [light chain (AL) n = 23] CA cohorts were 48.0%, 49.0%, and 42.6%, respectively. During a median period of 12 months, ECV increased significantly in all cohorts [change (Δ) +3.5% interquartile range (IQR): -1.9 to +6.9, P < 0.001; Δ +3.5%, IQR: -2.0 to +6.7, P < 0.001; and Δ +3.5%, IQR: -1.6 to +9.1, P = 0.026]. Separate analyses for treatment-naïve (n = 21) and treated (n = 59) ATTR patients revealed that the median change of ECV from baseline to follow-up was significantly higher among untreated patients (+5.7% vs. +2.3%, P = 0.004). Survival analyses demonstrated that median change of ECV was a predictor of outcome [total: hazard ratio (HR): 1.095, 95% confidence interval (CI): 1.047-1.0145, P < 0.001; ATTR: HR: 1.073, 95% CI: 1.015-1.134, P = 0.013; and AL: HR: 1.131, 95% CI: 1.041-1.228, P = 0.003]. CONCLUSION: The present study supports the use of serial ECV quantification in CA patients, as change of ECV was a predictor of outcome and could provide information in the evaluation of amyloid-specific treatments.

Monitoring tafamidis treatment with quantitative SPECT/CT in transthyretin amyloid cardiomyopathy.

AIMS: Tafamidis treatment positively affects left ventricular (LV) structure and function and improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). We aimed to investigate the relationship between treatment response and cardiac amyloid burden identified by serial quantitative 99mTc-DPD SPECT/CT. We furthermore aimed to identify nuclear imaging biomarkers that could be used to quantify and monitor response to tafamidis therapy. METHODS AND RESULTS: Forty wild-type ATTR-CM patients who underwent 99mTc-DPD scintigraphy and SPECT/CT imaging at baseline and after treatment with tafamidis 61 mg once daily [median, 9.0 months (interquartile range 7.0-10.0)] were divided into two cohorts based on the median (-32.3%) of the longitudinal percent change in standardized uptake value (SUV) retention index. ATTR-CM patients with a reduction greater than or equal to the median (n = 20) had a significant decrease in SUV retention index (P < 0.001) at follow-up, which translated into significant benefits in serum N-terminal prohormone of brain natriuretic peptide levels (P = 0.006), left atrial volume index (P = 0.038), as well as LV [LV global longitudinal strain: P = 0.028, LV ejection fraction (EF): P = 0.027, LV cardiac index (CI): P = 0.034] and right ventricular (RV) [RVEF: P = 0.025, RVCI: P = 0.048] functions compared with patients with a decrease less than the median (n = 20). CONCLUSION: Treatment with tafamidis in ATTR-CM patients results in a significant reduction in SUV retention index, associated with significant benefits for LV and RV function and cardiac biomarkers. Serial quantitative 99mTc-DPD SPECT/CT imaging with SUV may be a valid tool to quantify and monitor response to tafamidis treatment in affected patients. TRANSLATIONAL PERSPECTIVE: 99mTc-DPD SPECT/CT imaging with determination of SUV retention index as part of a routine annual examination can provide evidence of treatment response in ATTR-CM patients receiving disease-modifying therapy. Further long-term studies with 99mTc-DPD SPECT/CT imaging may help to evaluate the relationship between tafamidis-induced reduction in SUV retention index and outcome in patients with ATTR-CM and will demonstrate whether highly disease-specific 99mTc-DPD SPECT/CT imaging is more sensitive than routine diagnostic monitoring.

Cardiac amyloidosis: a significant blind spot of the H2FPEF score.

BACKGROUND: Cardiac amyloidosis (CA) often mimics heart failure with preserved ejection fraction (HFpEF). Due to very different treatment strategies, an exact diagnosis and differentiation between pure HFpEF and CA-related heart failure (HF) is important. In the present study, we assessed the recently published H2FPEF score in patients with pure HFpEF, transthyretin (ATTR), as well as light chain (AL) amyloidosis-related HFpEF and tested whether it differentiates between these entities. METHODS: The H2FPEF scores consists of easy-to-assess clinical (Body Mass Index, number of hypertensive drugs, presence of atrial fibrillation, age) and echocardiographic (systolic pulmonary arterial pressure, E/E´) parameters. It can be computed in a categorical way resulting in scores between 0 and 9 points (0-1: HFpEF rule out, 2-5: further testing required, 6-9: HFpEF rule in), or in a continual way providing an exact percentage of a patient's HFpEF probability. Continuous and categorical variables were compared using the Kruskal-Wallis, Mann-Whitney-U, and χ2-tests. Diagnostic accuracy was computed from 2x2 tables. Survival analysis was performed with Kaplan-Meier curves. A P value of <0.05 was set as the level of significance. RESULTS: A total of 100 patients with pure HFpEF, 53 patients with ATTR, and 34 patients with AL CA were included in the present study. Median age (HFpEF: 71.5 years; ATTR CA: 77.0 years; AL CA: 60.0 years; P<0.001), gender distribution (HFpEF [female]: 73.0%, ATTR (female): 18.9%, AL [female]: 38.2%; P<0.001), and N-terminal prohormone of brain natriuretic peptide (HFpEF: 1045pg/mL; ATTR CA: 1927pg/mL; AL CA: 4308pg/mL; P<0.001) differed significantly between study cohorts. Median H2FPEF scores were highest among HFpEF (categorical: 5.0 points; continual: 95.1%), followed by ATTR (categorical: 4.0 points; continual: 89.0%), and AL CA (categorical: 3.0 points; continual: 31.2%). Respective P values were <0.001. Low H2FPEF scores (0-1 points) were found among patients in the AL CA cohort (29.4%), but not among HFpEF or ATTR CA patients (P<0.001). The majority of patients, irrespective of disease entity were in the intermediate score range (2-5 points, HFpEF: 80.0% ATTR CA: 94.3%, AL CA: 67.9%; P=0.006). High scores (6-9 points) were most often found among HFpEF patients (20.0%), followed by ATTR CA (5.7%) and AL CA (2.9%), (P=0.007). CONCLUSIONS: The H2FPEF score should be used with caution, as there is a significant overlap between HFpEF and CA-related HF.

Impact of tafamidis on myocardial strain in transthyretin amyloid cardiomyopathy.

AIMS: The impact of tafamidis on myocardial strain in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) have been barely investigated. We aimed to determine tafamidis-induced changes using serial speckle tracking echocardiography and to identify imaging parameters for specific therapy monitoring. METHODS AND RESULTS: ATTR-CM patients underwent serial TTE with two-dimensional (2 D) speckle tracking imaging. Patients receiving tafamidis free acid 61 mg (n = 62) or tafamidis meglumine 20 mg (n = 21) once daily (QD) showed stable measurements at follow-up (61 mg: 8.5 months, 20 mg: 7.0 months) in LV global longitudinal strain (GLS) (61 mg: -11.75% vs. -11.58%, p = 0.534; 20 mg: -10.61% vs. -10.12%, p = 0.309), right ventricular (RV) GLS (61 mg: -14.18% vs. -13.72%, p = 0.377; 20 mg: -14.53% vs. -13.99%, p = 0.452) and left atrial (LA) reservoir strain (LASr; 61 mg: 8.80% vs. 9.42%, p = 0.283; 20 mg: 8.23% vs. 8.67%, p = 0.589), whereas treatment-naïve ATTR-CM patients (n = 54) had clear signs of disease progression at the end of the observation period (10.5 months; LV-GLS: -11.71% vs. -10.59%, p = 0.001; RV-GLS: -14.36% vs. -12.99%, p = 0.038; LASr: 10.67% vs. 8.41%, p = 0.005). Between-group comparison at follow-up revealed beneficial effects of tafamidis free acid 61 mg on LASr (p = 0.003) and the LV (LV-GLS: p = 0.030, interventricular septum (IVS): p = 0.006), resulting in clinical benefits (six-minute walk distance (6-MWD): p = 0.006, NT-proBNP: p= <0.001), while patients treated with tafamidis meglumine 20 mg QD showed positive effects on LASr (p = 0.039), but no differences with respect to the LV (LV-GLS: p = 0.274, IVS: p = 0.068) and clinical status (6-MWD: p = 0.124, NT-proBNP: p = 0.053) compared to the natural course. CONCLUSIONS: Treatment with tafamidis free acid 61 mg in ATTR-CM patients delays the deterioration of LA and LV longitudinal function, resulting in significant clinical benefits compared with natural history. Serial TTE with 2 D speckle tracking imaging may be appropriate for disease-specific therapy monitoring.

Impact of Tafamidis and Optimal Background Treatment on Physical Performance in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: In patients with transthyretin amyloid cardiomyopathy, tafamidis was shown to slow the decline in 6-minute walking distance as compared with placebo. We aimed to define the impact of tafamidis and optimal background treatment on functional capacity as determined by cardiopulmonary exercise testing (CPET). METHODS: Seventy-eight consecutive patients were enrolled in the study. They underwent CPET at baseline, and outcome defined as death or heart failure hospitalization was obtained for a time period of up to 30 months. Fifty-four patients completed a follow-up CPET at 9±3 months (range, 4-16 months). Improvement in peak VO2 at follow-up was defined as ∆peak VO2≥1.0 mL/(kg·min), stable peak VO2 was defined as 0≤∆peak VO2<1.0 mL/(kg·min), and decline in peak VO2 was defined by ∆peak VO2<0 mL/(kg·min). RESULTS: Baseline peak VO2>14 mL/(kg·min) as well as minute ventilation/carbon dioxide production slope≤34 were associated with a lower risk of death or heart failure hospitalization (P=0.002, P=0.007, respectively). In 54 patients, who received tafamidis and underwent repeat CPET testing, an improvement in physical performance (P=0.002) was observed at follow-up. When comparing pre and post-treatment parameters, 29 patients (54%) showed an increase in percent predicted peak VO2 (P<0.0001), an improvement of peak VO2 (P<0.0001), and better physical performance at follow-up (P<0.0001). Patients with stable or improved peak VO2 had less advanced heart disease at baseline (P=0.046). CONCLUSIONS: Our findings demonstrate that baseline peak VO2 and baseline minute ventilation/carbon dioxide production slope predict outcomes and an improvement in physical performance as measured by CPET was observed in patients receiving tafamidis, who had less advanced disease at baseline, emphasizing the importance of early diagnosis.

Machine learning-derived electrocardiographic algorithm for the detection of cardiac amyloidosis.

BACKGROUND: Diagnosis of cardiac amyloidosis (CA) requires advanced imaging techniques. Typical surface ECG patterns have been described, but their diagnostic abilities are limited. OBJECTIVE: The aim was to perform a thorough electrophysiological characterisation of patients with CA and derive an easy-to-use tool for diagnosis. METHODS: We applied electrocardiographic imaging (ECGI) to acquire electroanatomical maps in patients with CA and controls. A machine learning approach was then used to decipher the complex data sets obtained and generate a surface ECG-based diagnostic tool. FINDINGS: Areas of low voltage were localised in the basal inferior regions of both ventricles and the remaining right ventricular segments in CA. The earliest epicardial breakthrough of myocardial activation was visualised on the right ventricle. Potential maps revealed an accelerated and diffuse propagation pattern. We correlated the results from ECGI with 12-lead ECG recordings. Ventricular activation correlated best with R-peak timing in leads V1-V3. Epicardial voltage showed a strong positive correlation with R-peak amplitude in the inferior leads II, III and aVF. Respective surface ECG leads showed two characteristic patterns. Ten blinded cardiologists were asked to identify patients with CA by analysing 12-lead ECGs before and after training on the defined ECG patterns. Training led to significant improvements in the detection rate of CA, with an area under the curve of 0.69 before and 0.97 after training. INTERPRETATION: Using a machine learning approach, an ECG-based tool was developed from detailed electroanatomical mapping of patients with CA. The ECG algorithm is simple and has proven helpful to suspect CA without the aid of advanced imaging modalities.

Tafamidis treatment delays structural and functional changes of the left ventricle in patients with transthyretin amyloid cardiomyopathy.

AIMS: Tafamidis improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, it is not yet known whether tafamidis affects cardiac amyloid deposition and structural changes in the myocardium. We aimed to determine disease-modifying effects on myocardial amyloid progression and to identify imaging parameters that could be applied for specific therapy monitoring. METHODS AND RESULTS: ATTR-CM patients underwent serial cardiac magnetic resonance (CMR) imaging using T1 mapping techniques to derive extracellular volume (ECV). Patients receiving tafamidis 61 mg (n = 35) or 20 mg (n = 15) once daily showed stable measurements at follow-up (FU) {61 mg: 9.0 [interquartile range (IQR) 7.0-11.0] months, 20 mg: 11.0 (IQR 8.0-18.0) months} in left ventricular (LV) ejection fraction (LVEF; 61 mg: 47.6% vs. 47.5%, P = 0.935; 20 mg: 52.4% vs. 52.1%, P = 0.930), LV mass index (LVMI; 61 mg: 110.2 vs. 106.2 g/m2, P = 0.304; 20 mg: 114.5 vs. 115.4 g/m2, P = 0.900), and ECV (61 mg: 47.5% vs. 47.7%, P = 0.861; 20 mg: 56.7% vs. 57.5%, P = 0.759), whereas treatment-naïve ATTR-CM patients (n = 19) had clear signs of disease progression at the end of the observation period [12.0 (IQR 10.0-21.0) months; LVEF: 53.3% vs. 45.7%, P = 0.031; LVMI: 98.9 vs. 106.9 g/m2, P = 0.027; ECV: 49.3% vs. 54.6%, P = 0.023]. Between-group comparison at FU revealed positive effects in tafamidis 61 mg-treated compared to treatment-naïve patients (LVEF: P = 0.035, LVMI: P = 0.036, ECV: P = 0.030), while those treated with 20 mg showed no difference in the above LV measurements when compared with treatment-naïve (P = 0.120, P = 0.287, P = 0.158). However, both treatment groups showed clinically beneficial effects compared to the natural course [61 mg, 6-min walk distance (6-MWD): P = 0.005, N-terminal prohormone of brain natriuretic peptide (NT-proBNP): P = 0.002; 20 mg, 6-MWD: P = 0.023, NT-proBNP: P = 0.003]. CONCLUSION: Tafamidis delays myocardial amyloid progression in ATTR-CM patients, resulting in structural, functional, and clinical benefits compared to the natural course. Serial CMR including measurement of ECV may be appropriate for disease-specific therapy monitoring.

Early implementation of renal replacement therapy after lung transplantation does not impair long-term kidney function in patients with idiopathic pulmonary arterial hypertension.

OBJECTIVES: In patients with idiopathic pulmonary arterial hypertension, cardiac function can be impaired in the early postoperative phase after lung transplantation because the chronically untrained left ventricle is prone to fail. Thus, restrictive fluid management is pivotal to unload the left heart. In our institution, continuous renal replacement therapy is implemented liberally whenever a patient cannot be balanced negatively. It remains unclear whether such strategy impairs long-term kidney function. METHODS: We retrospectively reviewed our institutional database for patients with idiopathic pulmonary arterial hypertension who underwent transplantation between 2000 and 2018. The impact of postoperative continuous renal replacement therapy on long-term outcomes was investigated using a linear mixed model and multivariable Cox regression. RESULTS: A total of 87 idiopathic pulmonary arterial hypertension lung transplant recipients were included in this analysis. In 38 patients (43%), continuous renal replacement therapy was started in the early postoperative period for a median of 16 days (10-22). In this group, urine production significantly decreased and patients began to acquire a positive fluid balance; however, homeostatic functions of the kidney were still preserved at the time of continuous renal replacement therapy initiation. All patients were successfully weaned from continuous renal replacement therapy and fully recovered their kidney function at the time of hospital discharge. No difference in kidney function was found between continuous renal replacement therapy and noncontinuous renal replacement therapy in patients within 5 years. CONCLUSIONS: Early implementation of continuous renal replacement therapy for perioperative volume management does not impair long-term kidney function in idiopathic pulmonary arterial hypertension lung transplant recipients. Our data suggest that such a strategy leads to excellent long-term outcomes.

Convolutional Neural Networks for Fully Automated Diagnosis of Cardiac Amyloidosis by Cardiac Magnetic Resonance Imaging.

AIMS: We tested the hypothesis that artificial intelligence (AI)-powered algorithms applied to cardiac magnetic resonance (CMR) images could be able to detect the potential patterns of cardiac amyloidosis (CA). Readers in CMR centers with a low volume of referrals for the detection of myocardial storage diseases or a low volume of CMRs, in general, may overlook CA. In light of the growing prevalence of the disease and emerging therapeutic options, there is an urgent need to avoid misdiagnoses. METHODS AND RESULTS: Using CMR data from 502 patients (CA: n = 82), we trained convolutional neural networks (CNNs) to automatically diagnose patients with CA. We compared the diagnostic accuracy of different state-of-the-art deep learning techniques on common CMR imaging protocols in detecting imaging patterns associated with CA. As a result of a 10-fold cross-validated evaluation, the best-performing fine-tuned CNN achieved an average ROC AUC score of 0.96, resulting in a diagnostic accuracy of 94% sensitivity and 90% specificity. CONCLUSIONS: Applying AI to CMR to diagnose CA may set a remarkable milestone in an attempt to establish a fully computational diagnostic path for the diagnosis of CA, in order to support the complex diagnostic work-up requiring a profound knowledge of experts from different disciplines.

Machine Learning Enables Prediction of Cardiac Amyloidosis by Routine Laboratory Parameters: A Proof-of-Concept Study.

(1) Background: Cardiac amyloidosis (CA) is a rare and complex condition with poor prognosis. While novel therapies improve outcomes, many affected individuals remain undiagnosed due to a lack of awareness among clinicians. This study was undertaken to develop an expert-independent machine learning (ML) prediction model for CA relying on routinely determined laboratory parameters. (2) Methods: In a first step, we developed baseline linear models based on logistic regression. In a second step, we used an ML algorithm based on gradient tree boosting to improve our linear prediction model, and to perform non-linear prediction. Then, we compared the performance of all diagnostic algorithms. All prediction models were developed on a training cohort, consisting of patients with proven CA (positive cases, n = 121) and amyloidosis-unrelated heart failure (HF) patients (negative cases, n = 415). Performances of all prediction models were evaluated on a separate prognostic validation cohort with 37 CA-positive and 124 CA-negative patients. (3) Results: Our best model, based on gradient-boosted ensembles of decision trees, achieved an area under the receiver operating characteristic curve (ROC AUC) score of 0.86, with sensitivity and specificity of 89.2% and 78.2%, respectively. The best linear model had an ROC AUC score of 0.75, with sensitivity and specificity of 84.6 and 71.7, respectively. (4) Conclusions: Our work demonstrates that ML makes it possible to utilize basic laboratory parameters to generate a distinct CA-related HF profile compared with CA-unrelated HF patients. This proof-of-concept study opens a potential new avenue in the diagnostic workup of CA and may assist physicians in clinical reasoning.

Discriminatory power of scoring systems for outcome prediction in patients with extracorporeal membrane oxygenation following cardiovascular surgery†.

OBJECTIVES: Although extracorporeal membrane oxygenation (ECMO) represents a rapidly evolving treatment option in patients with refractory heart or lung failure, survival remains poor and appropriate risk stratification challenging because established risk prediction models have not been validated for this specific population. METHODS: This observational single-centre registry included a total of 240 patients treated with venoarterial ECMO therapy following cardiovascular surgery and analysed the discriminatory power of the European System of Cardiac Operative Risk Evaluation (EuroSCORE) additive, the EuroSCORE II, the Sequential Organ Failure Assessment (SOFA) score, the Simplified Acute Physiology Score (SAPS) II, the SAPS III, the Acute Physiology and Chronic Health Evaluation (APACHE) II, the Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage renal failure (RIFLE) classification, the survival after venoarterial ECMO (SAVE) score, the prEdictioN of Cardiogenic shock OUtcome foR AMI patients salvaGed by VA-ECMO (ENCOURAGE) score and the Society of Thoracic Surgeons (STS) risk model for outcome prediction. RESULTS: During a median follow-up time of 37 months (interquartile range 19-67), 65% of the patients died. Only the SAVE score and the SAPS II were significantly associated with the 30-day mortality rate with a hazard ratio (HR) of 1.06 [95% confidence interval (CI) 1.02-1.11; P = 0.002] for the SAVE score and an HR of 1.02 (95% CI 1.01-1.03; P = 0.004) for the SAPS II with a modest discriminatory power displayed by a C-index of 0.61 and 0.57, respectively. Seven out of 10 scoring systems revealed significant association with long-term mortality, with the SAVE score and the SAPS II remaining the strongest predictors of long-term mortality with an HR of 1.06 (95% CI 1.03-1.09; P < 0.001, C-index 0.61) for the SAVE score and an HR of 1.02 (95% CI 1.01-1.03; P < 0.001, C-index 0.58) for the SAPS II. CONCLUSIONS: Risk assessment based on established risk models in patients with ECMO remains difficult. Only the SAPS II and the SAVE score were exclusively found to be suitable for short- and long-term outcome prediction in this specific vulnerable patient population.

Impact of Right Ventricular Performance in Patients Undergoing Extracorporeal Membrane Oxygenation Following Cardiac Surgery.

BACKGROUND: Extracorporeal membrane oxygenation following cardiac surgery safeguards end-organ oxygenation but unfavorably alters cardiac hemodynamics. Along with the detrimental effects of cardiac surgery to the right heart, this might impact outcome, particularly in patients with preexisting right ventricular (RV) dysfunction. We sought to determine the prognostic impact of RV function and to improve established risk-prediction models in this vulnerable patient cohort. METHODS AND RESULTS: Of 240 patients undergoing extracorporeal membrane oxygenation support following cardiac surgery, 111 had echocardiographic examinations at our institution before implantation of extracorporeal membrane oxygenation and were thus included. Median age was 67 years (interquartile range 60-74), and 74 patients were male. During a median follow-up of 27 months (interquartile range 16-63), 75 patients died. Fifty-one patients died within 30 days, 75 during long-term follow-up (median follow-up 27 months, minimum 5 months, maximum 125 months). Metrics of RV function were the strongest predictors of outcome, even stronger than left ventricular function (P<0.001 for receiver operating characteristics comparisons). Specifically, RV free-wall strain was a powerful predictor univariately and after adjustment for clinical variables, Simplified Acute Physiology Score-3, tricuspid regurgitation, surgery type and duration with adjusted hazard ratios of 0.41 (95%CI 0.24-0.68; P=0.001) for 30-day mortality and 0.48 (95%CI 0.33-0.71; P<0.001) for long-term mortality for a 1-SD (SD=-6%) change in RV free-wall strain. Combined assessment of the additive EuroSCORE and RV free-wall strain improved risk classification by a net reclassification improvement of 57% for 30-day mortality (P=0.01) and 56% for long-term mortality (P=0.02) compared with the additive EuroSCORE alone. CONCLUSIONS: RV function is strongly linked to mortality, even after adjustment for baseline variables and clinical risk scores. RV performance improves established risk prediction models for short- and long-term mortality.

Cardiac arrest does not affect survival in post-operative cardiovascular surgery patients undergoing extracorporeal membrane oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (ECMO) is rapidly evolving as bailout option in patients with refractory cardiogenic shock after cardiovascular surgery (CV). Cardiac arrest represents a common and severe complication in the immediate post-operative phase. We therefore evaluated the impact of cardiac arrest at time of ECMO implantation on short- and long-term mortality in patients following CV surgery. METHODS AND RESULTS: We included 385 patients undergoing veno-arterial extracorporeal membrane oxygenation therapy following CV surgery at a university-affiliated tertiary-care center into our single-center registry. Thirty patients underwent cardiopulmonary resuscitation (CPR) followed by immediate initiation of ECMO support. During a median follow-up time of 44 months (IQR 21-76 months), 68% of patients (n=262) died. We did not detect a significant impact of CPR during ECMO initiation on 30-day mortality (HR 1.04, 95%CI 0.89-1.83, P=0.86) as well as for long-term mortality (HR 1.01, 95%CI 0.63-1.61, P=0.97). Results were virtually unchanged for 30-day (HR 0.88, 95%CI 0.44-1.73, P=0.70) and long-term mortality (HR 0.93, 95%CI 0.54-1.60, P=0.79) after adjustment for age, sex, left ventricular ejection fraction, SAPS2 score, type of CV surgery, and year of study inclusion in order to unveil a potential negative confounding. CONCLUSION: Cardiac arrest did not affect short-tem and long-term mortality in a large cohort of patients with therapy refractory cardiogenic shock undergoing ECMO support following CV surgery. Our results suggest that the decision to initiate ECMO support in this specific patient population should not be influenced by the occurrence of cardiac arrest.

Liver function predicts survival in patients undergoing extracorporeal membrane oxygenation following cardiovascular surgery.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) represents a valuable and rapidly evolving therapeutic option in patients with severe heart or lung failure following cardiovascular surgery. However, despite significant advances in ECMO techniques and management, prognosis remains poor and accurate risk stratification challenging. We therefore evaluated the predictive value of liver function variables on all-cause mortality in patients undergoing venoarterial ECMO support after cardiovascular surgery. METHODS: We included into our single-center registry a total of 240 patients undergoing venoarterial ECMO therapy following cardiovascular surgery at a university-affiliated tertiary care center. RESULTS: The median follow-up was 37 months (interquartile range 19-67 months), and a total of 156 patients (65%) died. Alkaline phosphatase and total bilirubin were the strongest predictors for 30-day mortality, with adjusted hazard ratios (HRs) per 1-standard deviation increase of 1.36 (95% confidence interval [CI] 1.10-1.68; P = 0.004) and 1.22 (95% CI 1.07-1.40; P = 0.004), respectively. The observed associations persisted for long-term mortality, with adjusted HRs of 1.27 (95% CI 1.03-1.56; P = 0.023) for alkaline phosphatase and 1.22 (95% CI 1.07-1.39; P = 0.003) for total bilirubin. CONCLUSIONS: The present study demonstrates that elevated values of alkaline phosphatase and total bilirubin are sensitive parameters for predicting the short-term and long-term outcomes of ECMO patients.

Urinary Output Predicts Survival in Patients Undergoing Extracorporeal Membrane Oxygenation Following Cardiovascular Surgery.

OBJECTIVES: Extracorporeal membrane oxygenation represents a valuable and rapidly evolving therapeutic option in patients with severe heart or lung failure following cardiovascular surgery. However, survival remains poor and accurate risk stratification challenging. Therefore, we evaluated the predictive value of urinary output within 24 hours after extracorporeal membrane oxygenation initiation on mortality in patients undergoing venoarterial extracorporeal membrane oxygenation support following cardiovascular surgery and aimed to improve established risk prediction models. DESIGN: Single-center, observational registry. SETTING: University-affiliated tertiary care center. PATIENTS: We included 205 patients undergoing veno-arterial extracorporeal membrane oxygenation therapy following cardiovascular surgery at a university-affiliated tertiary-care center into our single-centre registry. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During a median follow-up time of 35 months (interquartile range, 19-69), 64% of patients died. Twenty-four-hour urinary output was the strongest predictor of outcome among renal function variables with an adjusted hazard ratio per 1 SD of 0.55 (95% CI, 0.40-0.76; p < 0.001) for 30-day mortality and of 0.65 (95% CI, 0.53-0.86; p = 0.002) for 2-year long-term mortality. Most remarkably, 24-hour urinary output showed additional prognostic value beyond that achievable with the simplified acute physiology score-3 and sequential organ failure assessment score indicated by improvements in the category-free net reclassification index for 30-day mortality (simplified acute physiology score-3: 36%, p = 0.015; sequential organ failure assessment score: 36%, p = 0.02), as well as for 2-year mortality (simplified acute physiology score-3: 33%, p = 0.02; sequential organ failure assessment score: 43%, p = 0.005). CONCLUSIONS: We identified 24-hour urinary output as a strong and easily available predictor of mortality in patients undergoing extracorporeal membrane oxygenation therapy following cardiovascular surgery. Implementation of 24-hour urinary output leads to a substantial improvement of established risk prediction models in this vulnerable patient population. These results are particularly compelling because measurement of urinary output is inexpensive and routinely performed in all critical care units.