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Background Since 1998, there has been a national programme for paediatric heart transplantations (HT) in the Netherlands. In this study, we investigated waiting list mortality, survival post-HT, the incidence of common complications, and the patients’ functional status during follow-up. Methods All children listed for HT from 1998 until October 2020 were included. Follow-up lasted until 1 January 2021. Data were collected from the patient charts. Survival, post-operative complications as well as the functional status (Karnofsky/Lansky scale) at the end of follow-up were measured. Results In total, 87 patients were listed for HT, of whom 19 (22%) died while on the waiting list. Four patients were removed from the waiting list and 64 (74%) underwent transplantation. Median recipient age at HT was 12.0 (IQR 7.2–14.4) years old; 55% were female. One-, 5‑, and 10-year survival post-HT was 97%, 95%, and 88%, respectively. Common transplant-related complications were rejections (50%), Epstein-Barr virus infections (31%), cytomegalovirus infections (25%), post-transplant lymphoproliferative disease (13%), and cardiac allograft vasculopathy (13%). The median functional score (Karnofsky/Lansky scale) was 100 (IQR 90–100). Conclusion Children who undergo HT have an excellent survival rate up to 10 years post-HT. Even though complications post-HT are common, the functional status of most patients is excellent. Waiting list mortality is high, demonstrating that donor availability for this vulnerable patient group remains a major limitation for further improvement of outcome.

Mechanical device malfunction remains a known issue in left ventricular assist devices (LVADs). We investigated the incidence of mechanical device malfunction in the HeartMate II and HeartMate 3 LVADs. We conducted a retrospective study of all HeartMate II and HeartMate 3 LVADs implanted in our center. We evaluated major malfunction, potential major malfunction, minor malfunction, and need of device exchange. In total, 163 patients received an LVAD; in 63 (39%) a HeartMate II, and in 100 (61%) a HeartMate 3, median support time of respectively 24.6 months (interquartile range [IQR]: 32.4) and 21.1 months [IQR: 27.2]. Mechanical device malfunction, consisting of both major and potential major malfunction, occurred significantly less in the HeartMate 3 patients with a hazard ratio (HR) of 0.37 (95% confidence interval [CI]: 0.15-0.87, p = 0.022). Major malfunction alone occurred significantly less in HeartMate 3 patients with a HR of 0.18 (95% CI: 0.05-0.66, p = 0.009). HeartMate 3 patients had a significantly decreased hazard of a pump or outflow graft exchange (HR 0.13, 95% CI: 0.08-0.81, p = 0.008). System controller defects occurred significantly less in HM 3 patients (p = 0.007), but battery-clips defects occurred significantly more in HM 3 patients (p = 0.039). Major device malfunction including pump or outflow graft exchange occurred significantly less in HeartMate 3 compared to HeartMate II, while minor malfunctions were similar. Periodical assessment of the technical integrity of the device remains necessary during long-term LVAD support.

Background: This study aimed to identify heart failure (HF) subphenotypes using 92 repeatedly measured circulating proteins in 250 patients with heart failure with reduced ejection fraction, and to investigate their clinical characteristics and prognosis. Methods: Clinical data and blood samples were collected tri-monthly until the primary endpoint (PEP) or censoring occurred, with a maximum of 11 visits. The Olink Cardiovascular III panel was measured in baseline samples and the last two samples before the PEP (in 66 PEP cases), or the last sample before censoring (in 184 PEP-free patients). The PEP comprised cardiovascular death, heart transplantation, Left Ventricular Assist Device implantation, and hospitalization for HF. Cluster analysis was performed on individual biomarker trajectories to identify subphenotypes. Then biomarker profiles and clinical characteristics were investigated, and survival analysis was conducted. Results: Clustering revealed three clinically diverse subphenotypes. Cluster 3 was older, with a longer duration of, and more advanced HF, and most comorbidities. Cluster 2 showed increasing levels over time of most biomarkers. In cluster 3, there were elevated baseline levels and increasing levels over time of 16 remaining biomarkers. Median follow-up was 2.2 (1.4–2.5) years. Cluster 3 had a significantly poorer prognosis compared to cluster 1 (adjusted event-free survival time ratio 0.25 (95%CI:0.12–0.50), p < 0.001). Repeated measurements clusters showed incremental prognostic value compared to clusters using single measurements, or clinical characteristics only. Conclusions: Clustering based on repeated biomarker measurements revealed three clinically diverse subphenotypes, of which one has a significantly worse prognosis, therefore contributing to improved (individualized) prognostication.

Iron deficiency (ID) is a common comorbidity in heart failure (HF). In these patients, intravenous iron administration can improve clinical outcomes and quality of life (QoL). However, data on ID are lacking in patients who have transitioned toward left ventricular assist device (LVAD) or heart transplantation (HTx). All patients who underwent LVAD (n = 84) surgery or HTx (n = 67) at our center between 2012 and 2019, aged ≥18 years with a follow-up of ≥3 months, were included. Retrospectively, the prevalence of ID up to 1 year preoperatively, and up to February 2020 postoperatively, as well as all iron administrations were assessed during this period. Iron status was assessed in 61% and 51% of the LVAD and HTx patients preoperatively, and 81% and 84%, respectively, postoperatively. Of these patients, 53% and 71% of the LVAD and HTx patients preoperatively were diagnosed with ID preoperatively, and 71% and 77%, respectively, postoperatively. ID was more frequently diagnosed >3 months postoperatively. Sixty-three percent of the LVAD (mostly intravenous) and 63% of the HTx patients (mostly oral) received iron administration. ID is highly prevalent pre- and post-LVAD and HTx. It is plausible that substitution can have similar QoL gains as in regular HF patients.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are frequently used for primary and secondary prevention in patients with cardiomyopathies due to different etiologies. However, long-term outcome studies in patients with noncompaction cardiomyopathy (NCCM) are scarce.OBJECTIVES: This study summarizes the long-term outcome of ICD therapy in patients with NCCM compared with those with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM).METHODS: Prospective data from our single-center ICD registry were used to analyze the ICD interventions and survival in patients with NCCM (n = 68) compared with patients with DCM (n = 458) and patients with HCM (n = 158) from January 2005 to January 2018.RESULTS: This NCCM population with an ICD for primary prevention comprised 56 (82%) patients with a median age of 43 years and 52% males, compared with 85% in patients with DCM and 79% in patients with HCM (P = 0.20). During a median follow-up of 5 years (IQR: 2.0-6.9 years), appropriate and inappropriate ICD interventions were not significantly different. Nonsustained ventricular tachycardia during Holter monitoring in patients with NCCM was the only significant risk factor for appropriate ICD therapy in patients with NCCM, with a HR of 5.29 (95% CI: 1.12-24.96). The long-term survival was significantly better in the univariable analysis in the NCCM group. However, there was no difference in multivariable Cox regression analyses between the cardiomyopathy groups.CONCLUSIONS: At 5 years of follow-up, the rate of appropriate and inappropriate ICD interventions in NCCM was comparable to that in DCM or HCM. In multivariable analysis, no differences in survival were found between the cardiomyopathy groups.

Introduction The aim of the present study was to assess the safety and efficacy of renal sympathetic denervation (RDN) in patients with heart failure with reduced ejection fraction (HFrEF). Methods We randomly assigned 50 patients with a left ventricular ejection fraction (LVEF) ≤ 35% and NYHA class ≥ II, in a 1:1 ratio, to either RDN and optimal medical therapy (OMT) or OMT alone. The primary safety endpoint was the occurrence of a combined endpoint of cardiovascular death, rehospitalisation for heart failure, and acute kidney injury at 6 months. The primary efficacy endpoint was the change in iodine-123 meta-iodobenzylguanidine (123I‑MIBG) heart-to-mediastinum ratio (HMR) at 6 months. Results Mean age was 60 ± 9 years, 86% was male and mean LVEF was 33 ± 8%. At 6 months, the primary safety endpoint occurred in 8.3% vs 8.0% in the RDN and OMT groups, respectively (p = 0.97). At 6 months, the mean change in late HMR was −0.02 (95% CI: −0.08 to 0.12) in the RDN group, versus −0.02 (95% CI: −0.09 to 0.12) in the OMT group (p = 0.95) whereas the mean change in washout rate was 2.34 (95% CI: −6.35 to 1.67) in the RDN group versus −2.59 (95% CI: −1.61 to 6.79) in the OMT group (p-value 0.09). Conclusion RDN with the Vessix system in patients with HFrEF was safe, but did not result in significant changes in cardiac sympathetic nerve activity at 6 months as measured using 123I‑MIBG.

Summary Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects long‐term outcomes in heart transplant (HTx) patients. We prospectively evaluated the feasibility of coronary computed tomography angiography (CCTA) for the detection of CAV during clinical implementation at our center. All consecutive HTx patients >4 years post‐transplant were actively converted from myocardial perfusion imaging to CCTA for the annual assessment of CAV. Between February 2018 and May 2019, 129/172 (75%) HTx patients underwent a CCTA. Renal impairment (n = 21/43) was the most frequent reason for patients could not undergo CCTA. CCTA image quality was good–excellent in 118/129 (92%) patients, and the radiation dose was 2.1 (1.6–2.8) mSv. CCTA showed obstructive CAV in 19/129 (15%) patients. Thirteen (10%) patients underwent additional tests, of which 8 patients underwent coronary revascularization within 90 days of CCTA. After 1 year, 3 additional coronary angiograms were performed, resulting in one revascularization in a patient with known severe CAV who developed ventricular tachycardia. One myocardial infarction after coronary stenting and 2 non‐cardiac deaths were observed. CCTA can be successfully implemented for routine detection of CAV with good image quality and low radiation dose. CCTA allows CAV evaluation with the limited need for additional invasive testing., CCTA can be safely and successfully implemented as a noninvasive alternative for routine detection of CAV in HTx patients with good image quality and low radiation dose.

Aims: This study aimed to investigate the left ventricular (LV) remodelling and long-term prognosis of patients with new-onset acute heart failure (HF) with reduced ejection fraction who were pharmacologically managed and survived until hospital discharge. We compared patients with ischaemic and non-ischaemic aetiology. Methods and results: This cohort study consisted of 111 patients admitted with new-onset acute HF in the period 2008–2016 [62% non-ischaemic aetiology, 48% supported by inotropes, vasopressors, or short-term mechanical circulatory devices, and left ventricular ejection fraction (LVEF) at discharge 28% (interquartile range 22–34)]. LV dimensions, LVEF, and mitral valve regurgitation were used as markers for LV remodelling during up to 3 years of follow-up. Both patients with non-ischaemic and ischaemic HF had significant improvement in LVEF (P

OBJECTIVES This retrospective study investigated the correlation between the angular position of the left ventricular assist device (LVAD) inflow cannula and relapsing low-flow alarms. METHODS Medical charts were reviewed of all patients with HeartMate 3 LVAD support for relapsing low-flow alarms. A standardized protocol was created to measure the angular position with a contrast-enhanced computed tomography scan. Statistics were done using a gamma frailty model with a constant rate function. RESULTS For this analysis, 48 LVAD-supported patients were included. The majority of the patients were male (79%) with a median age of 57 years and a median follow-up of 30 months (interquartile range: 19–41). Low-flow alarm(s) were experienced in 30 (63%) patients. Angulation towards the septal–lateral plane showed a significant increase in low-flow alarms over time with a constant rate function of 0.031 increase in low-flow alarms per month of follow-up per increasing degree of angulation (P = 0.048). When dividing this group using an optimal cut-off point, a significant increase in low-flow alarms was observed when the septal–lateral angulation was 28° or more (P = 0.001). Anterior–posterior and maximal inflow cannula angulation did not show a significant difference. CONCLUSIONS This study showed an increasing number of low-flow alarms when the degrees of LVAD inflow cannula expand towards the septal–lateral plane. This emphasizes the importance of the LVAD inflow cannula angular position to prevent relapsing low-flow alarms with the risk of diminished quality of life and morbidity.

Post-transplant diabetes mellitus (PTDM) is a frequent complication post-heart transplantation (HT), however long-term prevalence studies are missing. The aim of this study was to determine the prevalence and determinants of PTDM as well as prediabetes long-term post-HT using oral glucose tolerance tests (OGTT). Also, the additional value of OGTT compared to fasting glucose and glycated hemoglobin (HbA1c) was investigated. All patients > 1 year post-HT seen at the outpatient clinic between August 2018 and April 2021 were screened with an OGTT. Patients with known diabetes, an active infection/rejection/malignancy or patients unwilling or unable to undergo OGTT were excluded. In total, 263 patients were screened, 108 were excluded. The included 155 patients had a median age of 54.3 [42.2–64.3] years, and 63 (41%) were female. Median time since HT was 8.5 [4.8–14.5] years. Overall, 51 (33%) had a normal range, 85 (55%) had a prediabetes range and 19 (12%) had a PTDM range test. OGTT identified prediabetes and PTDM in more patients (18% and 50%, respectively), than fasting glucose levels and HbA1c. Age at HT (OR 1.03 (1.00–1.06), p = 0.044) was a significant determinant of an abnormal OGTT. Prediabetes as well as PTDM are frequently seen long-term post-HT. OGTT is the preferred screening method.

Aims The aim of this study was to compare early- and late-term survival and causes of death between patients with and without a concomitant aortic valve (AoV) procedure during continuous-flow left ventricular assist device (LVAD) surgery. Methods and results All adult primary continuous-flow LVAD patients on the International Society of Heart and Lung Transplantation (ISHLT) Mechanically Assisted Circulatory Support (IMACS) Registry (n = 15 267) were included in this analysis and stratified into patients submitted to a concomitant AoV procedure (AoV replacement or AoV repair) and patients without an AoV procedure. The primary outcome was early (≤90 days) survival post-LVAD surgery. Secondary outcomes were late survival (survival during the entire follow-up period) and conditional survival (in patients who survived the first 90 days post-LVAD surgery), and determinants. Patients who underwent concomitant AoV replacement (n = 457) had significantly reduced late survival compared with patients with AoV repair (n = 328) or without an AoV procedure (n = 14 482) (56% vs. 61% and 62%, respectively; P = 0.001). After adjustment for other significant predictors, concomitant AoV replacement remained an independent predictor for early [hazard ratio (HR) 1.226, 95% confidence interval (CI) 1.037–1.449] and late (HR 1.477, 95% CI 1.154–1.890) mortality. However, patients undergoing AoV replacement or repair, in whom the presence of moderate-to-severe AoV regurgitation was diagnosed prior to LVAD implantation, had survival similar to patients not undergoing AoV interventions. Conclusions Concomitant AoV surgery in patients undergoing LVAD implantation is an independent predictor of mortality. Additional research is needed to determine the best AoV surgical strategy at the time of LVAD surgery.

Background It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes.Hypothesis Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants.Methods During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-beta-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation.Results Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m(2) eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m(2) eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0]).Conclusion Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive.

Aims: Evidence on the association of macrophage- and neutrophil-related blood biomarkers with clinical outcome in heart failure patients is limited, and, with the exception of C-reactive protein, no data exist on their temporal evolution. We aimed to investigate whether temporal patterns of these biomarkers are related to clinical outcome in patients with stable chronic heart failure (CHF). Methods and Results: In 263 patients with CHF, we performed serial plasma measurements of scavenger receptor cysteine-rich type 1 protein M130 (CD163), tartrate-resistant acid phosphatase type 5 (TRAP), granulins (GRN), spondin-1 (SPON1), peptidoglycan recognition protein 1 (PGLYRP1), and tissue factor pathway inhibitor (TFPI). The Cardiovascular Panel III (Olink Proteomics AB, Uppsala, Sweden) was used. During 2.2 years of follow-up, we collected 1984 samples before the occurrence of the composite primary endpoint (PE) or censoring. For efficiency, we selected 567 samples for the measurements (all baseline samples, the last two samples preceding the PE, and the last sample before censoring in event-free patients). The relationship between repeatedly measured biomarker levels and the PE was evaluated by joint models. Mean (±standard deviation) age was 67 ± 13 years; 189 (72%) were men; left ventricular ejection fraction (%) was 32 ± 11. During follow-up, 70 (27%) patients experienced the PE. Serially measured biomarkers predicted the PE in a multivariable model adjusted for baseline clinical characteristics [hazard ratio (95% confidence interval) per 1-standard deviation change in biomarker]: CD163 [2.07(1.47–2.98), P < 0.001], TRAP [0.62 (0.43–0.90), P = 0.009], GRN [2.46 (1.64–3.84), P < 0.001], SPON1 [3.94 (2.50–6.50), P < 0.001], and PGLYRP1 [1.62 (1.14–2.31), P = 0.006]. Conclusions: Changes in plasma levels of CD163, TRAP, GRN, SPON1, and PGLYRP1 precede adverse cardiovascular events in patients with CHF.

Background: Many patients undergoing durable left ventricular assist device (LVAD) implantation suffer from chronic kidney disease (CKD). Therefore, we investigated the effect of LVAD support on CKD. Methods: A retrospective multicenter cohort study, including all patients undergoing LVAD (HeartMate II (n = 330), HeartMate 3 (n = 22) and HeartWare (n = 48) implantation. In total, 227 (56.8%) patients were implanted as bridge-to-transplantation; 154 (38.5%) as destination therapy; and 19 (4.7%) as bridge-to-decision. Serum creatinine measurements were collected over a 2-year follow-up period. Patients were stratified based on CKD stage. Results: Overall, 400 patients (mean age 53 ± 14 years, 75% male) were included: 186 (46.5%) patients had CKD stage 1 or 2; 93 (23.3%) had CKD stage 3a; 82 (20.5%) had CKD stage 3b; and 39 (9.8%) had CKD stage 4 or 5 prior to LVAD implantation. During a median follow-up of 179 days (IQR 28–627), 32,629 creatinine measurements were available. Improvement of kidney function was noticed in every preoperative CKD-stage group. Following this improvement, estimated glomerular filtration rates regressed to baseline values for all CKD stages. Patients showing early renal function improvement were younger and in worse preoperative condition. Moreover, survival rates were higher in patients showing early improvement (69% vs 56%, log-rank P = 0. 013). Conclusions: Renal function following LVAD implantation is characterized by improvement, steady state and subsequent deterioration. Patients who showed early renal function improvement were in worse preoperative condition, however, and had higher survival rates at 2 years of follow-up.

Aims: Many heart transplant recipients will develop end-stage renal disease in the post-operative course. The aim of this study was to identify the long-term incidence of end-stage renal disease, determine its risk factors, and investigate what subsequent therapy was associated with the best survival. Methods and results: A retrospective, single-centre study was performed in all adult heart transplant patients from 1984 to 2016. Risk factors for end-stage renal disease were analysed by means of multivariable regression analysis and survival by means of Kaplan–Meier. Of 685 heart transplant recipients, 71 were excluded: 64 were under 18 years of age and seven were re-transplantations. During a median follow-up of 8.6 years, 121 (19.7%) patients developed end-stage renal disease: 22 received conservative therapy, 80 were treated with dialysis (46 haemodialysis and 34 peritoneal dialysis), and 19 received a kidney transplant. Development of end-stage renal disease (examined as a time-dependent variable) inferred a hazard ratio of 6.45 (95% confidence interval 4.87–8.54, P < 0.001) for mortality. Tacrolimus-based therapy decreased, and acute kidney injury requiring renal replacement therapy increased the risk for end-stage renal disease development (hazard ratio 0.40, 95% confidence interval 0.26–0.62, P < 0.001, and hazard ratio 4.18, 95% confidence interval 2.30–7.59, P < 0.001, respectively). Kidney transplantation was associated with the best median survival compared with dialysis or conservative therapy: 6.4 vs. 2.2 vs. 0.3 years (P < 0.0001), respectively, after end-stage renal disease development. Conclusions: End-stage renal disease is a frequent complication after heart transplant and is associated with poor survival. Kidney transplantation resulted in the longest survival of patients with end-stage renal disease.

Purpose of ReviewWe aim to summarize recent insights and provide an up-to-date overview on the role of intra-aortic balloon pump (IABP) counterpulsation in cardiogenic shock (CS).Recent FindingsIn the largest randomized controlled trial (RCT) of patients with CS after acute myocardial infarction (AMICS), IABP did not lower mortality. However, recent data suggest a role for IABP in patients who have persistent ischemia after revascularization. Moreover, in the growing population of CS not caused by acute coronary syndrome (ACS), multiple retrospective studies and one small RCT report on significant hemodynamic improvement following (early) initiation of IABP support, which allowed bridging of most patients to recovery or definitive therapies like heart transplant or a left ventricular assist device (LVAD).SummaryRoutine use of IABP in patients with AMICS is not recommended, but many patients with CS either from ischemic or non-ischemic cause may benefit from IABP at least for hemodynamic improvement in the short term. There is a need for a larger RCT regarding the role of IABP in selected patients with ACS, as well as in patients with non-ACS CS.

Supplemental Digital Content is available in the text., Background. Previous studies on the association between cytomegalovirus (CMV) infection and cardiac allograft vasculopathy (CAV) were conducted on patients transplanted in the prevalganciclovir prophylaxis era. The aim of our study is to evaluate this relation in heart transplantation (HTx) recipients treated according to current prophylactic and immunosuppressive regimens. Methods. This single-center retrospective study included all consecutive adult patients that underwent HTx between January 1, 2000, and May 31, 2018. Clinically relevant CMV infection was defined as either plasma CMV DNAemia ≥ 1000 IU/mL with/without clinical symptoms or

Objectives Invasively measured fractional flow reserve (FFR) is associated with outcome in heart transplant (HTx) patients. Coronary computed tomography angiography (CCTA)–derived FFR (FFRct) provides additional functional information from anatomical CT images. We describe the first use of FFRct in HTx patients. Methods HTx patients underwent CCTA with FFRct to screen for cardiac allograft vasculopathy. FFRct was measured distal to each coronary stenosis > 30% and FFRct ≤ 0.8 indicated hemodynamically significant stenosis. FFRct was also measured at the most distal location of each vessel. Overall distal FFRct was calculated as the mean of the distal values in the left, right, and circumflex coronary artery in each patient. Results Seventy-three patients (age 56 (42–65) years, 63% males) at 11 (8–16) years after HTx were included. Eighteen (25%) patients had a focal hemodynamically significant stenosis (stenosis > 30% with FFRct ≤ 0.8). In the 55 patients without a hemodynamically significant focal FFRct stenosis (FFRct > 0.80), the distal left anterior descending artery FFRct was p = 0.93). Conclusions FFRct performed on CCTA scans of HTx patients demonstrated that 25% of patients had a focal coronary stenosis with FFRct ≤ 0.8. Even without a focal stenosis, FFRct values are often abnormal in HTx patients. Key Points • This is the first report describing the use of FFRct in in heart transplant patients. • FFRct identifies patients after heart transplantation with hemodynamically significant coronary stenosis. • Even without a focal stenosis, FFRct values are often abnormal in heart transplant patients.

PurposeBecause of the current lack of evidence-based antimicrobial treatment guidelines, Left Ventricular Assist Device (LVAD) infections are often treated according to local insights. Here, we propose a flowchart for protocolized treatment, in order to improve outcome.MethodsThe flowchart was composed based on literature, consensus and expert opinion statements. It includes choice, dosage and duration of antibiotics, and indications for suppressive therapy, with particular focus on Staphylococcus aureus (SA) (Figure 1). The preliminary treatment results of 28 patients (2 from start cephalexin suppressive therapy) after implementation in July 2018 are described.ResultsCumulative incidence for first episode of infection in a 3-year time period was 27% (26 of 96 patients with an LVAD). Twenty-one of 23 (91%) first episodes of driveline infection (10 superficial and 13 deep; nine of 13 caused by SA) were successfully treated with antibiotics according to flowchart with complete resolution of clinical signs and symptoms. For two patients with deep driveline infections, surgery was needed in addition. There were no relapses of deep driveline infections, and only 2 SA deep driveline re-infections after 6 months. Nine patients received cephalexin of whom four patients (44%) developed a breakthrough infection with cephalexin-resistant gram-negative bacteria.ConclusionsThe first results of this protocolized treatment approach of LVAD infections are promising. Yet, initiation of cephalexin suppressive therapy should be carefully considered given the occurrence of infections with resistant micro-organisms. The long-term outcome of this approach needs to be established in a larger number of patients, preferably in a multi-center setting.

Purpose Poor left ventricular (LV) function may affect the physiological intraventricular blood flow and physiological vortex formation. The aim of this study was to investigate the pattern of intraventricular blood flow dynamics in patients with LV assist devices (LVADs) using echocardiographic particle image velocimetry. Materials and methods This prospective study included 17 patients (mean age 57 ± 11 years, 82% male) who had received an LVAD (HeartMate 3, Abbott Laboratories, Chicago, Illinois, USA) because of end-stage heart failure and poor LV function. Eleven (64%) patients had ischemic cardiomyopathy, and six patients (36%) had nonischemic cardiomyopathy. All patients underwent echocardiography, including intravenous administration of an ultrasound-enhancing agent (SonoVue, Bracco, Milan, Italy). Echocardiographic particle image velocimetry was used to quantify LV blood flow dynamics, including vortex formation (Hyperflow software, Tomtec imaging systems Gmbh, Unterschleissheim, Germany). Results Contrast-enhanced ultrasound was well tolerated in all patients and was performed without adverse reactions or side effects. The LVAD function parameters did not change during or after the ultrasound examination. The LVAD flow was on average 4.3 ± 0.3 L/min, and the speed was 5247 ± 109 rotations/min. The quantification of LV intraventricular flow demonstrated substantial impairment of vortex parameters. The energy dissipation, vorticity, and kinetic energy fluctuation indices were severely impaired. Conclusions Echo particle velocimetry is safe and feasible for the quantitative assessment of intraventricular flow in patients with an LVAD. The intraventricular LV flow and vortex parameters are severely impaired in these patients.

We describe the first patient with a left ventricular assist device (LVAD) driveline infection caused by Mycobacterium chelonae presenting with persistent infection despite conventional antibiotics. Treatment was successful with surgical debridement, driveline exit relocation, and a 4-month period of antibiotics. In the case of a culture-negative LVAD driveline infection, non-tuberculous mycobacteria should be considered. This case illustrates that multidisciplinary collaboration is essential in providing optimal care for LVAD patients.

AimsWe aim to study the feasibility and clinical value of pulmonary artery pressure monitoring with the CardioMEMS™device in order to optimize and guide treatment in patients with a HeartMate3left ventricular assist device (LVAD).Methods and resultsIn this single-centre, prospective pilot study, we will include10consecutive patients with New YorkHeart Association Class IIIb or IV with Interagency Registry for Mechanically Assisted Circulatory Support Classes2–5scheduledfor implantation of a HeartMate3LVAD. Prior to LVAD implantation, patients will receive a CardioMEMS sensor, for dailypulmonary pressure readings. The haemodynamic information provided by the CardioMEMS will be used to improvehaemodynamic status prior to LVAD surgery and optimize the timing of LVAD implantation. Post-LVAD implantation, thehaemodynamic changes will be assessed for additive value in detecting potential complications in an earlier stage (bleedingand tamponade). During the outpatient clinic phase, we will assess whether the haemodynamic feedback can optimize pumpsettings, detect potential complications, and further tailor the clinical management of these patients.ConclusionsThe HEMO-VAD study is thefirst prospective pilot study to explore the safety and feasibility of usingCardioMEMS for optimization of LVAD therapy with additional (remote) haemodynamic information.

Objective This article investigates whether longitudinally measured fibrinolysis factors are associated with cardiac events in patients with chronic heart failure (CHF). Methods A median of 9 (interquartile range [IQR] 5–10) serial, tri-monthly blood samples per patient were prospectively collected in 263 CHF patients during a median follow-up of 2.2 (IQR 1.4–2.5) years. Seventy patients (cases) reached the composite endpoint of cardiac death, heart failure hospitalization, left ventricular assist device, or heart transplantation. From all longitudinal samples, we selected baseline samples in all patients and the last two samples before the event in cases or the last sample available in event-free patients. Herein, we measured plasminogen activator inhibitor 1 (PAI-1), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), and soluble urokinase plasminogen activator surface receptor (suPAR). Associations between temporal biomarker patterns during follow-up and the cardiac event were investigated using a joint model. Results Cases were on average older and showed higher New York Heart Association class than those who remained event-free. They also had lower blood pressures, and were more likely to have diabetes, renal failure, and atrial fibrillation. Longitudinally measured PAI-1, uPA, and suPAR were independently associated with adverse cardiac events after correction for clinical characteristics (hazard ratio [95% confidence interval]) per standard deviation increase of 2.09 (1.28–3.45) for PAI-1, 1.91 (1.18–3.24) for uPA, and 3.96 (2.48–6.63) for suPAR. Serial measurements of tPA were not significantly associated with the event after correction for multiple testing. Conclusion Longitudinally measured PAI-1, uPA, and suPAR are strongly associated with adverse cardiac events during the course of CHF. If future research confirms our results, these fibrinolytic factors may carry potential for improved, and personalized, heart failure surveillance and treatment monitoring.

Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) is useful in the evaluation of cardiac allograft vasculopathy (CAV) in heart transplant (HTx) recipients. The current study evaluated the long-term prognostic value of stress SPECT MPI for predicting all-cause mortality and cardiac events in HTx recipients. The study population consisted of 166 HTx recipients (mean age 54 ± 10 years, 84% male) who underwent exercise or dobutamine stress 99mTc-tetrofosmin SPECT MPI for the assessment of CAV. An abnormal SPECT MPI was defined as the presence of a fixed or a reversible perfusion defect. Endpoints were all-cause mortality, cardiac mortality, and non-fatal myocardial infarction (MI). MPI abnormalities were detected in 55 patients (33%), including fixed defects in 28 patients (17%), partially reversible in 17 patients (10%), and completely reversible defects in 10 patients (6%). During a median follow-up of 12.8 years (range 0-15, mean follow-up 9.5 years), 109 (66%) patients died (all-cause mortality), of which 67 (40%) were due to cardiac causes. A total of 5 (3%) patients experienced a non-fatal MI. HTx recipients with a normal stress 99mTc-tetrofosmin SPECT MPI had a significantly better prognosis as compared with those with an abnormal study, up to 5 years after the initial test. The presence of a reversible perfusion defect was a significant predictor of all-cause mortality, cardiac mortality, and major cardiac events, during the entire follow-up period. Stress 99mTc-tetrofosmin SPECT MPI provides valuable prognostic information for the prediction of long-term outcome in HTx recipients. Patients with a normal stress 99mTc-tetrofosmin SPECT MPI have a significantly better prognosis as compared with those with an abnormal study, up to 5 years after initial testing.

This report describes the first heart transplantation recipient with acute biventricular heart failure symptoms caused by a post-myocarditis state, late after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. No other viral pathogens could be detected. Computed tomography angiography did not show cardiac allograft vasculopathy, and myocardial biopsy demonstrated no clinically relevant rejection. Subsequent cardiovascular magnetic resonance imaging revealed extensive epicardial delayed enhancement without myocardial edema. Heart failure medication was initiated and an implantable cardioverter defibrillator was implanted (due to non-sustained ventricular tachycardias), leading to a partial recovery of the ejection fraction. Further studies are needed to investigate the number of heart transplant recipients with myocardial damage after a SARS-CoV-2 infection.

Background: We aimed to assess differences in clinical characteristics, prognosis, and the temporal evolution of circulating biomarkers in male and female patients with HFrEF. Methods: We included 250 patients (66 women) with chronic heart failure (CHF) between 2011 and 2013 and performed trimonthly blood sampling during a median follow-up of 2.2 years [median (IQR) of 8 (5–10) urine and 9 (5–10) plasma samples per patient]. After completion of follow-up we measured 8 biomarkers. The primary endpoint (PE) was the composite of cardiac death, cardiac transplantation, left ventricular assist device implantation, and hospitalization due to acute or worsened CHF. Joint models were used to determine whether there were differences in the temporal patterns of the biomarkers between men and women as the PE approached. Results: A total of 66 patients reached the PE of which 52 (78.8%) were male and 14 (21.2%) were female. The temporal patterns of all studied biomarkers were associated with the PE, and overall showed disadvantageous changes as the PE approached. For NT-proBNP, HsTnT, and CRP, women showed higher levels over the entire follow-up duration and concomitant numerically higher hazard ratios [NT-proBNP: women: HR(95%CI) 7.57 (3.17–21.93), men: HR(95%CI) 3.14 (2.09–4.79), p for interaction = 0.104, HsTnT: women: HR(95%CI) 6.38 (2.18–22.46), men: HR(95%CI) 4.91 (2.58–9.39), p for interaction = 0.704, CRP: women: HR(95%CI) 7.48 (3.43–19.53), men: HR(95%CI) 3.29 [2.27–5.44], p for interaction = 0.106). In contrast, temporal patterns of glomerular and tubular renal markers showed similar associations with the PE in men and women. Conclusion: Although interaction terms are not statistically significant, the associations of temporal patterns of NT-proBNP, HsTnT, and CRP appear more outspoken in women than in men with HFrEF, whereas associations seem similar for temporal patterns of creatinine, eGFR, Cystatin C, KIM-1 and NAG. Larger studies are needed to confirm these potential sex differences.

Background/Introduction Despite improved surgical techniques and pump designs, LVAD therapy remains associated with high mortality and morbidity. CardioMEMS guided hemodynamic optimization shortly pre-LVAD surgery could improve the long-term post-surgery outcomes. Purpose The aim of this analysis was to investigate the feasibility of pre-operative optimization using the hemodynamic monitoring provided by the CardioMEMS in patients with an LVAD surgery, to improve the long-term outcome compared to a cohort of historical controls. Methods Ten consecutive chronic heart failure patients, with an INTERMACS Class 2–5, scheduled for (semi-) elective HeartMate 3 (HM3) LVAD surgery were enrolled in the HEMO-VAD pilot study. All patients received a CardioMEMS device prior to LVAD surgery. The daily hemodynamic readings were used to guide the patient optimization process pre- and post-operatively. Aims of hemodynamic optimization were the normalization of the mean pulmonary artery pressure (mPAP), decongesting of the right ventricle (RV) and optimization of the renal function. Patients were categorized into optimized patients (mPAP ≤25mmHg) and non-optimized mPAP (mPAP >25mmHg). Additionally, a historical cohort, consisting of 24 (semi-) elective HM3 LVAD recipients were included in this analysis. The outcome of this analysis was the event-free survival of the combined endpoint of all-cause mortality, RV failure, acute kidney injury (AKI) and/or renal replacement therapy (RRT) during the first 12 months post-LVAD surgery (time to first event analysis). Results The median age was 60.3 [51.6–66.3], 58.7 [53.4–61.9] and 60.1 [53.5–65.2] years in the optimized patients, non-optimized patients and historical controls, respectively (p=0.90). Of the optimized patients, 66.7% were men, compared to 75.0% and 100.0% of the non-optimized patients and historical controls, respectively (p=0.02). During the first year post-LVAD surgery, the combined endpoint occurred in 19 patients, five (83%) events occurred in the non-optimized patients, and 14 (58%) events in the historical controls, while no (0%) events occurred in the optimized patients (p=0.018) (Figure). Conclusion(s) This analysis demonstrated the feasibility of hemodynamic guided optimization pre-LVAD surgery using the CardioMEMS. The hemodynamic optimized patients were at very low risk for all-cause mortality, right-sided HF, and AKI/RRT compared to non-optimized patients or historical controls. Figure 1. Event-free survival for the combined endpoint (all-cause mortality, right ventricular failure, and acute kidney injury and/or renal replacement therapy). Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): This work was supported by Abbott with an independent research grant, partially covering personnel costs. This study was investigator-initiated and was designed, conducted, interpreted and reported independently of the funder

PURPOSE: Invasively measured fractional flow reserve (FFR) is associated with outcome in heart transplant (HTx) patients. Non-invasive coronary computed tomography angiography (CCTA)-derived FFR (FFRct) provides additional functional information from anatomical CT images. The anatomical model of the coronary arteries derived from CCTA is used to calculate the FFRct values at each point in the coronary arteries. We describe the first use of FFRct in a cohort of HTx patients. METHODS: HTx patients underwent CCTA with FFRct as part routine follow-up to screen for cardiac allograft vasculopathy (CAV). FFRct was performed off-site by a company. FFRct was measured distal to each coronary stenosis >30% and at the most distal location of each of the 3 major coronary arteries (right, left anterior descending and circumflex coronary artery). Overal distal FFRct was calculated as the mean of 3 vessels per patient. During 90-day follow-up, performance of additional tests for coronary assessment and revascularization were recorded. RESULTS: 73 patients (age 56 (42-65) years, 63% males) at 11 (8-16) years after HTx were included. In the 54 patients without a hemodynamically significant focal FFRct stenosis (FFRct >0.80), the distal left anterior descending artery FFRct was

PURPOSE: Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects heart transplant patients (HTx). Routine screening for CAV is warranted. We evaluated the feasibility and utility of cardiac CT to screen for CAV in 100 consecutive HTx patients at our center. METHODS: From Feb 2018 to Jan 2019 all consecutive HTxs who were more than five-years post-transplant were converted from using stress myocardial perfusion imaging to cardiac CT for the annual assessment of CAV. CAV was scored (0 (absent), 1 (mild), 2 (moderate), 3 (severe)) based on coronary CT angiography (CCTA) findings and compared with the most recently known CAV score before CCTA. RESULTS: CCTA was performed in 99 out of 100 patients who were planned for cardiac CT (56 (42-63) years, 65% men, and 11 (8-16) years post-transplant), 1 patient underwent only a calcium scan due to IV access problems. The median Agatston calcium score was 6 (0-85), and 38 patients had no detectable calcium. CCTA showed new obstructive coronary disease (>50% stenosis) in 20 patients. The CAV score was reclassified based on CCTA findings in 37 patients (p

Data on the risk of aortic root thrombosis in patients with aortic valve replacement (AVR) and left ventricular assist device (LVAD) surgery are scarce. Two out of nine patients receiving AVR concomitant with LVAD surgery and two out of two patients receiving AVR on LVAD support, at our centre, developed an aortic root thrombus, all diagnosed with computed tomography (CT) angiography. These results demonstrate that patients with concomitant AVR and LVAD surgery, or AVR on LVAD support, have an increased risk of aortic root thrombosis. Therefore, early anti‐thrombotic therapy and vigilant diagnostic follow‐up, using CT scans, are warranted to prevent thromboembolic events.

Background: Orthotopic heart transplantation (OHT) is the gold standard treatment in end-stage heart disease. Controversy remains whether bicaval OHT is superior to biatrial OHT in both early and late outcomes. This study aimed to provide an overview of the early and late outcomes in patients who underwent a bicaval or biatrial OHT. Methods: A systematic literature search was performed for articles published before December 2017. Studies comparing adult patients undergoing biatrial OHT and bicaval OHT were included. Early outcomes were pooled in odds ratios and late outcomes were pooled in rate ratios. Late survival was visualized by a pooled Kaplan-Meier curve. Results: A total of 36 publications were included in the meta-analysis, counting 3555 patients undergoing biatrial OHT and 3208 patients undergoing bicaval OHT. Early outcomes in mortality, tricuspid regurgitation, mitral regurgitation, and permanent pacemaker implantation differed significantly in favor of the bicaval OHT patients. Long-term survival was significantly better in patients undergoing bicaval vs biatrial OHT (hazard ratio, 1.32; 95% confidence interval, 1.1-1.6; P = .008). Also, late tricuspid regurgitation was less frequently seen in the bicaval OHT patients (rate ratio, 2.14; 95% CI, 1.17-3.94; P = .014). Conclusions. This systematic review with meta-analysis shows that bicaval OHT results in more favorable early and late outcomes for patients undergoing a bicaval OHT compared with a biatrial OHT. Therefore, bicaval OHT should be considered as preferable technique for OHT.

Coronary artery fistulae (CAF) represent an abnormal communication bypassing the myocardial capillary bed between a coronary artery and either a cardiac chamber (coronary-cameral CAF) or a vascular structure from systemic or pulmonary circulation (coronary-vascular CAF). CAF represent a congenital anomaly in 0.2% of the population, but are more frequently found in heart transplant recipients (8%), mostly as coronary-right ventricle (RV) CAF caused by endomyocardial biopsy used for monitoring of rejection1,2. Other complications of myocardial biopsy include perforation of the RV wall and tricuspid valve damage2. Several case reports have shown successful transcatheter closure of CAF3,4. We aimed to analyse ...

Purpose Acute kidney injury (AKI) frequently occurs after heart transplantation (HTx), but its relation to preoperative right heart hemodynamic (RHH) parameters remains unknown. Therefore, we aimed to determine their predictive properties for postoperative AKI severity within 30 days after HTx. Methods From 1984 to 2016, all consecutive HTx recipients (n = 595) in our tertiary referral center were included and analyzed for the occurrence of postoperative AKI staged by the kidney disease improving global outcome criteria. The effects of preoperative RHH parameters on postoperative AKI were calculated using logistic regression, and predictive accuracy was assessed using integrated discrimination improvement (IDI), net reclassification improvement (NRI), and area under the receiver operating characteristic curves (AUC). Results Postoperative AKI occurred in 430 (72%) patients including 278 (47%) stage 1, 66 (11%) stage 2, and 86 (14%) stage 3 cases. Renal replacement therapy (RRT) was administered in 41 (7%) patients. Patients with higher AKI stages had also higher baseline right atrial pressure (RAP; median 7, 7, 8, and in RRT 11 mmHg, p trend = 0.021), RAP-to-pulmonary capillary wedge pressure ratio (median 0.37, 0.36, 0.40, 0.47, p trend = 0.009), and lower pulmonary artery pulsatility index (PAPi) values (median 2.83, 3.17, 2.54, 2.31, p trend = 0.012). Higher RAP and lower PAPi values independently predicted AKI severity [adjusted odds ratio (OR) per doubling of RAP 1.16 (1.02–1.32), p = 0.029; of PAPi 0.85 (0.75–0.96), p = 0.008]. Based on IDI, NRI, and delta AUC, inclusion of these parameters improved the models’ predictive accuracy. Conclusions Preoperative PAPi and RAP strongly predict the development of AKI early after HTx and can be used as early AKI predictors. Electronic supplementary material The online version of this article (10.1007/s00134-018-5159-z) contains supplementary material, which is available to authorized users.

Renal dysfunction is an important component of chronic heart failure (CHF), but its single assessment does not sufficiently reflect clinically silent progression of CHF prior to adverse clinical outcome. Therefore, we aimed to investigate temporal evolutions of glomerular and tubular markers in 263 stable patients with CHF, and to determine if their patient-specific evolutions during this clinically silent period can dynamically predict clinical outcome. We determined the risk of clinical outcome (composite endpoint of Heart Failure hospitalization, cardiac death, Left Ventricular Assist Device placement, and heart transplantation) in relation to marker levels, slopes and areas under their trajectories. In each patient, the trajectories were estimated using repeatedly measured glomerular markers: creatinine/estimated glomerular filtration rate (eGFR), cystatin C (CysC), and tubular markers: urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1, plasma and urinary neutrophil gelatinase-associated lipocalin (NGAL). During 2.2 years of follow-up, we collected on average 8 urine and 9 plasma samples per patient. All glomerular markers predicted the endpoint (univariable hazard ratio [95% confidence interval] per 20% increase: creatinine: 1.18 [1.07-1.31], CysC: 2.41[ 1.81-3.41], and per 20% eGFR decrease: 1.13[1.05-1.23]). Tubular markers, NAG, and KIM-1 also predicted the endpoint (NAG: 1.06[1.01-1.11] and KIM-1: 1.08[1.04-1.11]). Larger slopes were the strongest predictors (creatinine: 1.57[1.39-1.84], CysC: 1.76 [1.52-2.09], eGFR: 1.59[1.37-1.90], NAG: 1.26[1.11-1.44], and KIM-1: 1.64[1.38-2.05]). Associations persisted after multivariable adjustment for clinical characteristics. Thus, during clinically silent progression of CHF, glomerular and tubular functions deteriorate, but not simultaneously. Hence, patient-specific evolutions of these renal markers dynamically predict clinical outcome in patients with CHF.

Aims Patients with a left ventricular assist device (LVAD) are challenging to evaluate using conventional imaging techniques, such as standard echocardiography (SE). The aim of this pilot study was to evaluate the potential of contrast echocardiography (CE) for the evaluation of the left ventricle (LV). Methods and results This prospective study included 14 ambulatory patients (mean age 58 ± 9 years, 79% male) with a LVAD (all HeartMate 3, Abbott Laboratories, Chicago, IL, USA). Nine (64%) patients had an ischaemic cardiomyopathy, and 5 (36%) had a non-ischaemic cardiomyopathy. All patients underwent SE and CE using intravenous administration of Sonovue contrast agent (Bracco, Milan, Italy). The echocardiograms were assessed by three observers, using a standard 17-segment model of the LV. Left ventricular end-diastolic volume (LVEDV) was assessed using the biplane Simpson method. The contrast agent was well tolerated by all patients, without any side effects. Overall, SE allowed visualization of 57% of LV segments (135/238) and CE allowed visualization of 79% of LV segments (187/238), P < 0.001. Per patient, SE resulted in visualization of 9.6 ± 5.2 segments and CE was able to visualize 13.4 ± 5.8 segments (P < 0.001). Administration of contrast agent significantly improved the assessment of LVEDV (feasibility SE: 36% vs. CE: 79%, P < 0.05). Conclusion Routine use of a contrast agent appears safe when used in patients having a new third generation LVAD and may enhance the diagnostic accuracy of transthoracic echocardiography in these patients. LV size determination can be obtained more often due to improved LV visualization using contrast agent.

Background We examined the prognostic information of detailed temporal patterns of N-terminal proBNP (NT-proBNP), high-sensitive troponin T (HsTNT), and C-reactive protein (CRP) in patients with chronic heart failure. Methods The first inclusion round (2011-2013, N = 263) from the ongoing Bio-SHiFT study was used. Biomarkers were measured at baseline and every 3 months. The primary end point (PE) comprised heart failure hospitalization, cardiovascular mortality, cardiac transplantation, and left ventricular assist device implantation. Associations between temporal biomarker patterns and the PE were investigated by joint modeling. Results Mean age was 67 ± 12 years, 72% were men, 95% had systolic dysfunction, and 73% were in New York Heart Association class I or II. Median follow-up was 2.2 (interquartile range 1.4-2.5) years. We used 2,022 blood samples (median 9 [interquartile range 5-10] per patient), and 70 (27%) patients reached the PE. Temporal patterns of NT-proBNP, HsTNT, and CRP level were associated with the PE (multivariable-adjusted hazard ratio per doubling of biomarker: NT-proBNP 2.28 (95% CI 1.82-2.86), HsTNT 2.05 (1.63-2.58), and CRP 1.65 (1.30-2.08). A combined 3-biomarker model demonstrated independent associations for the temporal patterns of NT-proBNP and CRP level (hazard ratios 2.06 [1.53-2.79] and 1.38 [1.01-1.89], respectively). Instantaneous change in biomarker level was also independently associated with the PE for NT-proBNP and CRP. Long-term biomarker elevation showed an association for NT-proBNP. Conclusions Temporal patterns representing evolution of level and rate of change in level of NT-proBNP and CRP, and long-term elevation of NT-proBNP were independently associated with adverse prognosis in patients with chronic heart failure. Individual patterns of change and combining multiple biomarkers could carry value for prognostication and for therapy guidance.