Incidence and risk factors of late right heart failure in chronic mechanical circulatory support.

BACKGROUND: Late right heart failure (LRHF) is a common complication during long-term left ventricular assist device (LVAD) support. We aimed to identify risk factors for LRHF after LVAD implantation. METHODS: Patients undergoing primary LVAD implantation between 2006 and 2019 and surviving the perioperative period were included for this study (n = 261). Univariate Cox proportional hazards analysis was used to assess the association of clinical covariates and LRHF, stratified for device type. Variables with p < 0.10 entered the multivariable model. In a subset of patients with complete echocardiography or right catheterization data, this multivariable model was extended. Postoperative cardiopulmonary exercise test data were compared in patients with and without LRHF. RESULTS: Nineteen percentage of patients suffered from LRHF after a median of 12 months, of which 67% required hospitalization. A history of atrial fibrillation (AF) (HR: 2.06 [1.08-3.93], p = 0.029), a higher preoperative body mass index (BMI) (HR: 1.07 [1.01-1.13], p = 0.023), and intensive care unit (ICU) duration (HR: 1.03 [1.00-1.06], p = 0.025) were independent predictors of LHRF in the multivariable model. A significant relation between the severity of tricuspid regurgitation (TR) and LRHF (HR: 1.91 [1.13-3.21], p = 0.016) was found in patients with echocardiographic data. Patients with LRHF demonstrated a lower maximal workload and peak VO2 at 6 months postoperatively. CONCLUSION: A history of AF, BMI, and longer ICU stay may help identify patients at high risk for LRHF. Severity of TR was significantly related to LRHF in a subset of patients.

Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury.

BACKGROUND: Cardiac ischemic injury induces a pathological remodeling response, which can ultimately lead to heart failure. Detailed mechanistic insights into molecular signaling pathways relevant for different aspects of cardiac remodeling will support the identification of novel therapeutic targets. METHODS: Although genome-wide transcriptome analysis on diseased tissues has greatly advanced our understanding of the regulatory networks that drive pathological changes in the heart, this approach has been disadvantaged by the fact that the signals are derived from tissue homogenates. Here we used tomo-seq to obtain a genome-wide gene expression signature with high spatial resolution spanning from the infarcted area to the remote to identify new regulators of cardiac remodeling. Cardiac tissue samples from patients suffering from ischemic heart disease were used to validate our findings. RESULTS: Tracing transcriptional differences with a high spatial resolution across the infarcted heart enabled us to identify gene clusters that share a comparable expression profile. The spatial distribution patterns indicated a separation of expressional changes for genes involved in specific aspects of cardiac remodeling, such as fibrosis, cardiomyocyte hypertrophy, and calcium handling (Col1a2, Nppa, and Serca2). Subsequent correlation analysis allowed for the identification of novel factors that share a comparable transcriptional regulation pattern across the infarcted tissue. The strong correlation between the expression levels of these known marker genes and the expression of the coregulated genes could be confirmed in human ischemic cardiac tissue samples. Follow-up analysis identified SOX9 as common transcriptional regulator of a large portion of the fibrosis-related genes that become activated under conditions of ischemic injury. Lineage-tracing experiments indicated that the majority of COL1-positive fibroblasts stem from a pool of SOX9-expressing cells, and in vivo loss of Sox9 blunted the cardiac fibrotic response on ischemic injury. The colocalization between SOX9 and COL1 could also be confirmed in patients suffering from ischemic heart disease. CONCLUSIONS: Based on the exact local expression cues, tomo-seq can serve to reveal novel genes and key transcription factors involved in specific aspects of cardiac remodeling. Using tomo-seq, we were able to unveil the unknown relevance of SOX9 as a key regulator of cardiac fibrosis, pointing to SOX9 as a potential therapeutic target for cardiac fibrosis.

Soluble ST2 in end-stage heart failure, before and after support with a left ventricular assist device.

BACKGROUND: The interleukin-33 (IL-33)/suppressor of tumorigenicity 2 (ST2) pathway is suggested to play an important role in fibrosis, remodelling and the progression of heart failure (HF). Increased soluble (sST2) levels are associated with adverse outcome in the average HF population. Less is known about sST2 levels in end-stage HF. Therefore, we studied sST2 levels in end-stage HF and the effect of unloading by left ventricular assist device (LVAD) support on sST2 levels. METHOD AND RESULTS: Serial plasma measurements of sST2 were performed pre-implantation and 1, 3 and 6 months after (LVAD) implantation in 38 patients. sST2 levels were elevated in end-stage HF just prior to LVAD implantation (74.2 ng/mL [IQR 54.7-116.9]; normal <35 ng/mL) and decreased substantially during LVAD support, to 29.5 ng/mL [IQR 24.7-46.6](P < .001). Patients with INTERMACS profile I had significantly higher sST2 levels compared to patients in profile II and profile III. A moderate correlation was found between sST2 and C-reactive protein (r = .580, P < .010). CONCLUSION: Levels of sST2 are elevated in end-stage HF patients with variability that suggests multiple inputs to a pro-inflammatory and pro-fibrotic pathway. Cardiogenic shock and increased C-reactive protein levels are associated with higher sST2 levels. LVAD support results in a significant drop in sST2 levels with normalization within 3 months postimplantation. This suggests that LVAD support leads to lessening of fibrosis and inflammation, which might eventually be used to target medical policy: explantation of the LVAD versus permanent use or cardiac transplantation.

Soluble Suppression of Tumorigenicity-2 Predicts Mortality and Right Heart Failure in Patients With a Left Ventricular Assist Device.

BACKGROUND: Soluble suppression of tumorigenicity-2 (sST2) predicts mortality in patients with heart failure. The predictive value of sST2 in patients with a left ventricular assist device remains unknown. Therefore, we studied the relationship between sST2 and outcome after left ventricular assist device implantation. METHODS AND RESULTS: sST2 levels of patients with a left ventricular assist device implanted between January 2015 and December 2022 were included in this observational study. The median follow-up was 25 months, during which 1573 postoperative sST2 levels were measured in 199 patients, with a median of 29 ng/mL. Survival of patients with normal and elevated preoperative levels was compared using Kaplan-Meier analysis, which did not differ significantly (P=0.22) between both groups. The relationship between postoperative sST2, survival, and right heart failure was evaluated using a joint model, which showed a significant relationship between the absolute sST2 level and mortality, with a hazard ratio (HR) of 1.20 (95% CI, 1.10-1.130; P<0.01) and an HR of 1.22 (95% CI, 1.07-1.39; P=0.01) for right heart failure, both per 10-unit sST2 increase. The sST2 instantaneous change was not predictive for survival or right heart failure (P=0.99 and P=0.94, respectively). Multivariate joint model analysis showed a significant relationship between sST2 with mortality adjusted for NT-proBNP (N-terminal pro-B-type natriuretic peptide), with an HR of 1.19 (95% CI, 1.00-1.42; P=0.05), whereas the HR of right heart failure was not significant (1.22 [95% CI, 0.94-1.59]; P=0.14), both per 10-unit sST2 increase. CONCLUSIONS: Time-dependent postoperative sST2 predicts all-cause mortality after left ventricular assist device implantation after adjustment for NT-proBNP. Future research is warranted into possible target interventions and the optimal monitoring frequency.

Simulation of changes in myocardial tissue properties during left ventricular assistance with a rotary blood pump.

We considered a mathematical model to investigate changes in geometric and hemodynamic indices of left ventricular function in response to changes in myofiber contractility and myocardial tissue stiffness during rotary blood pump support. Left ventricular assistance with a rotary blood pump was simulated based on a previously published biventricular model of the assisted heart and circulation. The ventricles in this model were based on the one-fiber model that relates ventricular function to myofiber contractility and myocardial tissue stiffness. The simulations showed that indices of ventricular geometry, left ventricular shortening fraction, and ejection fraction had the same response to variations in myofiber contractility and myocardial tissue stiffness. Hemodynamic measures showed an inverse relation compared with geometric measures. Particularly, pulse pressure and arterial dP/dtmax increased when myofiber contractility increased, whereas increasing myocardial tissue stiffness decreased these measures. Similarly, the lowest pump speed at which the aortic valve remained closed increased when myofiber contractility increased and decreased when myocardial tissue stiffness increased. Therefore, simultaneous monitoring of hemodynamic parameters and ventricular geometry indirectly reflects the status of the myocardial tissue. The appropriateness of this strategy will be evaluated in the future, based on in vivo studies.

Exercise hemodynamics during extended continuous flow left ventricular assist device support: the response of systemic cardiovascular parameters and pump performance.

Patients on continuous flow left ventricular assist devices (cf-LVADs) are able to return to an active lifestyle and perform all sorts of physical activities. This study aims to evaluate exercise hemodynamics in patients with a HeartMate II cf-LVAD (HM II). Thirty (30) patients underwent a bicycle exercise test. Along with exercise capacity, systemic cardiovascular responses and pump performance were evaluated at 6 and 12 months after HM II implantation. From rest to maximum exercise, heart rate increased from 87 ± 14 to 140 ± 32 beats/minute (bpm) (P<0.01), while systolic arterial blood pressure increased from 93 ± 12 to 116 ± 21 mm Hg (P<0.01). Total cardiac output (TCO) increased from 4.1 ± 1.1 to 8.5 ± 2.8 L/min (P<0.01) while pump flow increased less, from 5.1 ± 0.7 to 6.4 ± 0.6 L/min (P<0.01). Systemic vascular resistance (SVR) decreased from 1776 ± 750 to 1013 ± 83 dynes.s/cm(5) (P<0.001) and showed the strongest correlation with TCO (r= -0.72; P<0.01). Exercise capacity was affected by older age, while blood pressure increased significantly in men compared with women. Exercise capacity remained consistent at 6 and 12 months after HM II implantation, 51% ± 13% and 52% ± 13% of predicted VO2 max for normal subjects corrected for age and gender. In conclusion, pump flow of the HM II may contribute partially to TCO during exercise, while SVR was the strongest determinant of TCO.

Cost-effectiveness of continuous-flow left ventricular assist devices.

OBJECTIVES: Mechanical circulatory support through left ventricular assist devices (LVADs) improves survival and quality of life for patients with end-stage heart failure who are ineligible for cardiac transplantation. Our aim was to calculate the cost-effectiveness of continuous-flow LVADs. METHODS: A cost-utility analysis from a societal perspective was performed. A lifetime Markov model was set up in which continuous-flow LVAD was compared with optimal medical therapy (OMT). The treatment effect was modeled indirectly combining the results of the REMATCH trial comparing OMT with a pulsatile-flow LVAD and the HeartMate II Destination Therapy Trial comparing a pulsatile-flow LVAD with a continuous-flow LVAD. Cost data were based on real-world financial data of sixty-nine patients with a HeartMate II implantation from the University Medical Centre Utrecht (the Netherlands). One-way and probabilistic sensitivity analyses were performed. RESULTS: Comparing the continuous-flow HeartMate II with OMT, 3.23 (95 percent confidence interval [CI], 2.18-4.49) life-years were gained (LYG) or 2.83 (95 percent CI, 1.91-3.90) quality-adjusted life-years (QALYs). The cost of an LVAD implant was approximately €126,000, of which the device itself represented the largest cost, being €70,000. Total incremental costs amounted to €299,100 (95 percent CI, 190,500-521,000). This resulted in an incremental cost-effectiveness ratio of €94,100 (95 percent CI, 59,100-160,100) per LYG or €107,600 (95 percent CI, 66,700-181,100) per QALY. Sensitivity analyses showed these results were robust. CONCLUSIONS: Although LVAD destination therapy improves survival and quality of life, it remains a relatively expensive intervention which renders the reimbursement of this therapy questionable.

Spatial transcriptomics unveils ZBTB11 as a regulator of cardiomyocyte degeneration in arrhythmogenic cardiomyopathy.

AIMS: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that is characterized by progressive loss of myocardium that is replaced by fibro-fatty cells, arrhythmias, and sudden cardiac death. While myocardial degeneration and fibro-fatty replacement occur in specific locations, the underlying molecular changes remain poorly characterized. Here, we aim to delineate local changes in gene expression to identify new genes and pathways that are relevant for specific remodelling processes occurring during ACM. METHODS AND RESULTS: Using Tomo-Seq, genome-wide transcriptional profiling with high spatial resolution, we created transmural epicardial-to-endocardial gene expression atlases of explanted ACM hearts to gain molecular insights into disease-driving processes. This enabled us to link gene expression profiles to the different regional remodelling responses and allowed us to identify genes that are potentially relevant for disease progression. In doing so, we identified distinct gene expression profiles marking regions of cardiomyocyte degeneration and fibro-fatty remodelling and revealed Zinc finger and BTB domain-containing protein 11 (ZBTB11) to be specifically enriched at sites of active fibro-fatty replacement of myocardium. Immunohistochemistry indicated ZBTB11 to be induced in cardiomyocytes flanking fibro-fatty areas, which could be confirmed in multiple cardiomyopathy patients. Forced overexpression of ZBTB11 induced autophagy and cell death-related gene programmes in human cardiomyocytes, leading to increased apoptosis. CONCLUSION: Our study shows the power of Tomo-Seq to unveil new molecular mechanisms in human cardiomyopathy and uncovers ZBTB11 as a novel driver of cardiomyocyte loss.

Insights in the Prothrombotic Changes After Implantation of a Left Ventricular Assist Device in Patients With End-Stage Heart Failure: A Longitudinal Observational Study.

Thrombus formation is a common complication during left ventricular assist device (LVAD) therapy, despite anticoagulation with vitamin K antagonists (VKA) and a platelet inhibitor. Plasma levels of markers for primary and secondary hemostasis and contact activation were determined before LVAD implantation and 6 and 12 months thereafter in 37 adults with end-stage heart failure. Twelve patients received a HeartMate 3, 7 patients received a HeartWare, and 18 patients received a HeartMate II. At baseline, patients had elevated plasma levels of the platelet protein upon activation, ß-thromboglobulin, and active von Willebrand factor in thrombogenic state (VWFa), which remained high after LVAD implantation. Von Willebrand factor levels and VWF activity were elevated at baseline but normalized 12 months after LVAD implantation. High D -dimer plasma levels, at baseline, remained elevated after 12 months. This was associated with an increase in plasma thrombin-antithrombin-complex levels and plasma levels of contact activation marker-cleaved H-kininogen after LVAD implantation. Considering these results it could be concluded that LVAD patients show significant coagulation activation despite antithrombotic therapy, which could explain why patients are at high risk for LVAD-induced thrombosis. Continuous low-grade systemic platelet activation and contact activation may contribute to prothrombotic effects of LVAD.

Inotropic therapy in patients with advanced heart failure. A clinical consensus statement from the Heart Failure Association of the European Society of Cardiology.

This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline-directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end-of-life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support).

Reorganized PKA-AKAP associations in the failing human heart.

Here we reveal that the characterization of large-scale re-arrangements of signaling scaffolds induced by heart failure can serve as a novel concept to identify more specific therapeutic targets. In the mammalian heart, the cAMP pathway, with the cAMP-dependent protein kinase (PKA) in a central role, acts directly downstream of adrenergic receptors to mediate cardiac contractility and rhythm. Heart failure, characterized by severe alterations in adrenergic stimulation is, amongst other interventions, often treated with ß-blockers. Contrasting results, however, have shown both beneficial and detrimental effects of decreased cAMP levels in failing hearts. We hypothesize that the origin of this behavior lies in the complex spatiotemporal organization of the regulatory subunit of PKA (PKA-R), which associates tightly with various A-kinase anchoring proteins (AKAPs) to specifically localize PKA's activity. Using chemical proteomics directly applied to human patient and control heart tissue we demonstrate that the association profile of PKA-R with several AKAPs is severely altered in the failing heart, for instance effecting the interaction between PKA and the novel AKAP SPHKAP was 6-fold upregulated upon failing heart conditions. Also a significant increase in captured cGMP-dependent protein kinase (PKG) and phosphodiesterase 2 (PDE2) was observed. The observed altered profiles can already explain many aspects of the aberrant cAMP-response in the failing human heart, validating that this dataset may provide a resource for several novel, more specific, treatment options. This article is part of a Special Issue entitled "Local Signaling in Myocytes".

Automatic Identification of Patients With Unexplained Left Ventricular Hypertrophy in Electronic Health Record Data to Improve Targeted Treatment and Family Screening.

Background: Unexplained Left Ventricular Hypertrophy (ULVH) may be caused by genetic and non-genetic etiologies (e.g., sarcomere variants, cardiac amyloid, or Anderson-Fabry's disease). Identification of ULVH patients allows for early targeted treatment and family screening. Aim: To automatically identify patients with ULVH in electronic health record (EHR) data using two computer methods: text-mining and machine learning (ML). Methods: Adults with echocardiographic measurement of interventricular septum thickness (IVSt) were included. A text-mining algorithm was developed to identify patients with ULVH. An ML algorithm including a variety of clinical, ECG and echocardiographic data was trained and tested in an 80/20% split. Clinical diagnosis of ULVH was considered the gold standard. Misclassifications were reviewed by an experienced cardiologist. Sensitivity, specificity, positive, and negative likelihood ratios (LHR+ and LHR-) of both text-mining and ML were reported. Results: In total, 26,954 subjects (median age 61 years, 55% male) were included. ULVH was diagnosed in 204/26,954 (0.8%) patients, of which 56 had amyloidosis and two Anderson-Fabry Disease. Text-mining flagged 8,192 patients with possible ULVH, of whom 159 were true positives (sensitivity, specificity, LHR+, and LHR- of 0.78, 0.67, 2.36, and 0.33). Machine learning resulted in a sensitivity, specificity, LHR+, and LHR- of 0.32, 0.99, 32, and 0.68, respectively. Pivotal variables included IVSt, systolic blood pressure, and age. Conclusions: Automatic identification of patients with ULVH is possible with both Text-mining and ML. Text-mining may be a comprehensive scaffold but can be less specific than machine learning. Deployment of either method depends on existing infrastructures and clinical applications.

Elevated Plasma Immunoglobulin Levels Prior to Heart Transplantation Are Associated with Poor Post-Transplantation Survival.

Cardiac allograft vasculopathy (CAV) and antibody-mediated rejection are immune-mediated, long-term complications that jeopardize graft survival after heart transplantation (HTx). Interestingly, increased plasma levels of immunoglobulins have been found in end-stage heart failure (HF) patients prior to HTx. In this study, we aimed to determine whether increased circulating immunoglobulin levels prior to transplantation are associated with poor post-HTx survival. Pre-and post-HTx plasma samples of 36 cardiac transplant recipient patients were used to determine circulating immunoglobulin levels. In addition, epicardial tissue was collected to determine immunoglobulin deposition in cardiac tissue and assess signs and severity of graft rejection. High levels of IgG1 and IgG2 prior to HTx were associated with a shorter survival post-HTx. Immunoglobulin deposition in cardiac tissue was significantly elevated in patients with a survival of less than 3 years. Patients with high plasma IgG levels pre-HTx also had significantly higher plasma levels after HTx. Furthermore, high pre-HTX levels of IgG1 and IgG2 levels were also significantly increased in patients with inflammatory infiltrate in CAV lesions. Altogether the results of this proof-of-concept study suggest that an activated immune response prior to transplantation negatively affects graft survival.

Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.

RATIONALE: Idiopathic dilated cardiomyopathy (DCM) is inherited in approximately one third of cases, usually as an autosomal dominant trait. More than 30 loci have been identified, several of which encode sarcomeric proteins which can also be mutated to cause hypertrophic cardiomyopathy. One contractile protein gene well known as a hypertrophic cardiomyopathy disease gene, but with no reported mutation in autosomal dominant DCM, is TNNI3 which encodes cardiac troponin I. OBJECTIVE: To test TNNI3 as a candidate gene, a panel of 96 probands with DCM was analyzed. METHODS AND RESULTS: Genomic DNA was isolated and TNNI3 exons screened by heteroduplex analysis. Exons with aberrant profiles were sequenced and variants evaluated by segregation analysis and study of normal controls. We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each associated with severe and early onset familial DCM. Of the 5 mutation carriers, cardiac transplantation was required in 3, at ages 6, 15, and 24 years. Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin revealed that troponin reconstituted with either mutant troponin I gave lower maximum ATPase rates and lower Ca(2+) sensitivity than wild type. Furthermore, mutant thin filaments had reduced Ca(2+) affinity compared with normal. CONCLUSIONS: The functional alterations mirror closely a consistent phenotype found in proven DCM mutations in other thin filament proteins, thus supporting the interpretation that these mutations are disease-causing. These are the first reported autosomal dominant DCM-causing mutations in TNNI3, and so the findings expand the spectrum of disease-causing genes that lead to either hypertrophic cardiomyopathy or DCM depending on the specific mutation.

Endomyocardial biopsy with co-localization of a lymphoplasmacytic lymphoma and AL amyloidosis.

In about 4% of cases, amyloid light chain (AL) amyloidosis is due to an underlying lymphoplasmacytic lymphoma (LPL) or other monoclonal protein forming low-grade B-cell lymphoma, instead of a plasma cell neoplasm. We report an unusual case of a 55-year-old male with co-localization of an IgG positive LPL and AL amyloidosis in his endomyocardial biopsy (EMB). The patient was diagnosed 4 years earlier with a low grade B-cell non Hodgkin lymphoma stage IV, at the time classified as marginal zone lymphoma. He received several lines of treatment for his lymphoma, which had shown progressive disease. Four years after initial diagnosis, he developed increasing dyspnea on exertion. Echocardiography demonstrated left and right ventricular hypertrophy with classical apical sparing, suspicious for cardiac amyloidosis. Bone marrow biopsy revealed massive infiltration by his low grade B-cell lymphoma, which was now reclassified as LPL based on the demonstration of a MYD88 L265P mutation. An EMB confirmed the presence of amyloid, which was typed as AL amyloidosis by the use of immunoelectron microscopy. In addition, mild B-cell infiltrates were present in the EMB, which were shown to be part of his LPL by the demonstration of the MYD88 L265P mutation using the highly sensitive droplet digital polymerase chain reaction technique. This is a rare case of cardiac AL amyloidosis based on an IgG kappa positive LPL, in which not only the amyloid but also the lymphoma itself were present in the EMB. In addition, this case nicely illustrates the use of 2 highly sensitive techniques (immunoelectron microscopy and droplet digital polymerase chain reaction), which both can be performed on small, formalin-fixed paraffin-embedded biopsies.

A data mining-based cross-industry process for predicting major bleeding in mechanical circulatory support.

Aims: Over a third of patients, treated with mechanical circulatory support (MCS) for end-stage heart failure, experience major bleeding. Currently, the prediction of a major bleeding in the near future is difficult because of many contributing factors. Predictive analytics using data mining could help calculating the risk of bleeding; however, its application is generally reserved for experienced researchers on this subject. We propose an easily applicable data mining tool to predict major bleeding in MCS patients. Methods and results: All data of electronic health records of MCS patients in the University Medical Centre Utrecht were included. Based on the cross-industry standard process for data mining (CRISP-DM) methodology, an application named Auto-Crisp was developed. Auto-Crisp was used to evaluate the predictive models for a major bleeding in the next 3, 7, and 30 days after the first 30 days post-operatively following MCS implantation. The performance of the predictive models is investigated by the area under the curve (AUC) evaluation measure. In 25.6% of 273 patients, a total of 142 major bleedings occurred during a median follow-up period of 542 [interquartile range (IQR) 205-1044] days. The best predictive models assessed by Auto-Crisp had AUC values of 0.792, 0.788, and 0.776 for bleedings in the next 3, 7, and 30 days, respectively. Conclusion: The Auto-Crisp-based predictive model created in this study had an acceptable performance to predict major bleeding in MCS patients in the near future. However, further validation of the application is needed to evaluate Auto-Crisp in other research projects.

One year improvement of exercise capacity in patients with mechanical circulatory support as bridge to transplantation.

AIMS: Mechanical circulatory support (MCS) results in substantial improvement of prognosis and functional capacity. Currently, duration of MCS as a bridge to transplantation (BTT) is often prolonged due to shortage of donor hearts. Because long-term results of exercise capacity after MCS are largely unknown, we studied serial cardiopulmonary exercise tests (CPETs) during the first year after MCS implantation. METHODS AND RESULTS: Cardiopulmonary exercise tests at 6 and 12 months after MCS implantation in BTT patients were retrospectively analysed, including clinical factors related to exercise capacity. A total of 105 MCS patients (67% male, 50 ± 12 years) underwent serial CPET at 6 and 12 months after implantation. Power (105 ± 35 to 114 ± 40 W; P ≤ 0.001) and peak VO2 per kilogram (pVO2/kg) improved significantly (16.5 ± 5.0 to 17.2 ± 5.5 mL/kg/min (P = 0.008)). Improvement in pVO2 between 6 and 12 months after LVAD implantation was not related to heart failure aetiology or haemodynamic severity prior to MCS. We identified maximal heart rate at exercise as an important factor for pVO2. Younger age and lower BMI were related to further improvement. At 12 months, 25 (24%) patients had a normal exercise capacity (Weber classification A, pVO2 > 20 mL/kg/min). CONCLUSIONS: Exercise capacity (power and pVO2) increased significantly between 6 and 12 months after MCS independent of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile or heart failure aetiology. Heart rate at exercise importantly relates to exercise capacity. This long-term improvement in exercise capacity is important information for the growing group of long-term MCS patients as this is critical for the quality of life of patients.

Prognostic Value of Peak Oxygen Uptake in Patients Supported With Left Ventricular Assist Devices (PRO-VAD).

OBJECTIVES: The purpose of this study was to examine whether peak oxygen uptake (pVO2) and other cardiopulmonary exercise test (CPET)-derived variables could predict intermediate-term mortality in stable continuous flow LVAD recipients. BACKGROUND: pVO2 is a cornerstone in the selection of patients for heart transplantation, but the prognostic power of pVO2 obtained in patients treated with a left ventricular assist device (LVAD) is unknown. METHODS: We collected data for pVO2 and outcomes in adult LVAD recipients in a retrospective, multicenter study and evaluated cutoff values for pVO2 including: 1) values above or below medians; 2) grouping patients in tertiles; and 3) pVO2 ≤14 ml/kg/min if the patient was not treated with beta-blockers (BB) or pVO2 ≤12 ml/kg/min if the patient was taking BB therapy. RESULTS: Nine centers contributed data from 450 patients. Patients were 53 ± 13 years of age; 78% were male; body mass index was 25 ± 5 kg/m2 with few comorbidities (stroke: 11%; diabetes: 18%; and peripheral artery disease: 4%). The cause of heart failure (HF) was most often nonischemic (66%). Devices included were the HeartMate II and 3 (Abbott); and Heartware ventricular assist devices Jarvik and Duraheart (Medtronic). The index CPET was performed at a median of 189 days (154-225 days) after LVAD implantation, and mean pVO2 was 14.1 ± 5 ml/kg/min (47% ± 14% of predicted value). Lower pVO2 values were strongly associated with poorer survival regardless of whether patients were analyzed for absolute pVO2 in ml/kg/min, pVO2 ≤12 BB/14 ml/kg/min, or as a percentage of predicted pVO2 values (P ≤ 0.001 for all). For patients with pVO2 >12 BB/14 and ventilation/carbon dioxide relationship (VE/VCO2) slope <35, the 1-year survival was 100%. CONCLUSIONS: Even after LVAD implantation, pVO2 has prognostic value, similar to HF patients not supported by mechanical circulatory support devices. (PROgnostic Value of Exercise Capacity Measured as Peak Oxygen Uptake [pVO2] in Recipients of Left Ventricular Assist Devices [PRO-VAD]; NCT04423562).

Propensity score-based analysis of long-term outcome of patients on HeartWare and HeartMate 3 left ventricular assist device support.

AIMS: Left ventricular assist device therapy has become the cornerstone in the treatment of end-stage heart failure and is increasingly used as destination therapy next to bridge to transplant or recovery. HeartMate 3 (HM3) and HeartWare (HVAD) are centrifugal continuous flow devices implanted intrapericardially and most commonly used worldwide. No randomized controlled trials have been performed yet. Analysis based on large registries may be considered as the best alternative but has the disadvantage of different standard of care between centres and missing data. Bias is introduced, because the decision which device to use was not random, even more so because many centres use only one type of left ventricular assist device. Therefore, we performed a propensity score (PS)-based analysis of long-term clinical outcome of patients that received HM3 or HVAD in a single centre. METHODS AND RESULTS: Between December 2010 and December 2019, 100 patients received HVAD and 81 patients HM3 as primary implantation at the University Medical Centre Utrecht. We performed PS matching with an extensive set of covariates, resulting in 112 matched patients with a median follow-up of 28 months. After PS matching, survival was not significantly different (P = 0.21) but was better for HM3. The cumulative incidences for haemorrhagic stroke (P = 0.01) and pump thrombosis (P = 0.02) were significantly higher for HVAD patients. The cumulative incidences for major bleeding, ischaemic stroke, right heart failure, and driveline infection were not different between the groups. We found no interaction between the surgeon who performed the implantation and survival (P = 0.59, P = 0.78, and P = 0.89). Sensitivity analysis was performed, by PS matching without patients on preoperative temporary support resulting in 74 matched patients. This also resulted in a non-significant difference in survival (P = 0.07). The PS-adjusted Cox regression showed a worse but non-significant (P = 0.10) survival for HVAD patients with hazard ratio 1.71 (95% confidence interval 0.91-3.24). CONCLUSIONS: Survival was not significantly different between both groups after PS matching, but was better for HM3, with a significantly lower incidence of haemorrhagic stroke and pump thrombosis for HM3. These results need to be interpreted carefully, because matching may have introduced greater imbalance on unmeasured covariates. A multicentre approach of carefully selected centres is recommended to enlarge the number of matched patients.