Disconnect between the effects of serelaxin on renal function and outcome in acute heart failure.

BACKGROUND: We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes. METHODS: We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure. RESULTS: Improvement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64-2.15, p < 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60-0.83, p < 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99-1.04), ACM HR 1.01 (0.99-1.03), HF/renal failure hospitalization HR 0.99 (0.97-1.00)]. CONCLUSIONS: Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF. Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.

Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial.

BACKGROUND: Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF. METHODS AND RESULTS: This was a post hoc analysis of 79 patients with acute HF included in the EMPA-RESPONSE-AHF trial, which compared sodium-dependent glucose-cotransporter protein 2 inhibitor treatment with empagliflozin for 30 days with placebo in patients with acute HF [NCT03200860]. Plasma concentrations of ketone bodies acetone, ß-hydroxybutyrate, and acetoacetate were measured at baseline and 5 different timepoints. Changes in ketone bodies over time were monitored using repeated measures analysis of variance. In the total cohort, median total ketone body concentration was 251 µmol/L (interquartile range, 178-377 µmol/L) at baseline, which gradually decreased to 202 µmol/L (interquartile range, 156-240 µmol/L) at day 30 (P = .041). Acetone decreased from 60 µmol/L (interquartile range, 34-94 µmol/L) at baseline to 30 µmol/L (interquartile range, 21-42 µmol/L) ( P < .001), whereas ß-hydroxybutyrate and acetoacetate remained stable over time. Higher acetone concentrations were correlated with higher N-terminal pro brain natriuretic peptide levels (r = 0.234; P = .039). Circulating ketone bodies did not differ between patients treated with empagliflozin or placebo throughout the study period. A higher acetone concentration at baseline was univariately associated with a greater risk of the composite end point, including in-hospital worsening HF, HF rehospitalizations, and all-cause mortality after 30 days. However, after adjustment for age and sex, acetone did not remain an independent predictor for the combined end point. CONCLUSIONS: Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization. Treatment with empagliflozin did not affect ketone body concentrations in patients with acute HF.

The Netherlands Heart Tissue Bank : Strengthening the cardiovascular research infrastructure with an open access Cardiac Tissue Repository.

AIM: Cardiac diseases remain a leading cause of cardiovascular disease (CVD) related hospitalisation and mortality. That is why research to improve our understanding of pathophysiological processes underlying cardiac diseases is of great importance. There is a strong need for healthy and diseased human cardiac tissue and related clinical data to accomplish this, since currently used animal and in vitro disease models do not fully grasp the pathophysiological processes observed in humans. This design paper describes the initiative of the Netherlands Heart Tissue Bank (NHTB) that aims to boost CVD-related research by providing an open-access biobank. METHODS: The NHTB, founded in June 2020, is a non-profit biobank that collects and stores biomaterial (including but not limited to myocardial tissue and blood samples) and clinical data of individuals with and without previously known cardiac diseases. All individuals aged ≥ 18 years living in the Netherlands are eligible for inclusion as a potential future donor. The stored samples and clinical data will be available upon request for cardiovascular researchers. CONCLUSION: To improve the availability of cardiac tissue for cardiovascular research, the NHTB will include extensive (cardiac) biosamples, medical images, and clinical data of donors with and without a previously known cardiac disease. As such, the NHTB will function as a translational bridge to boost a wide range of cardiac disease-related fundamental and translational studies.

Characteristics and outcomes of COVID-19 in heart transplantation recipients in the Netherlands.

BACKGROUND: Immunocompromised patients are at high risk of complicated severe acute respiratory coronavirus 2 infection. The aim of this retrospective study was to describe the characteristics and outcomes of heart transplantation (HTx) recipients with coronavirus disease 2019 (COVID-19) in the Netherlands. METHODS: HTx patients from one of the three HTx centres in the Netherlands with COVID-19 (proven by positive reverse-transcription polymerase chain reaction or serology test result) between February 2020 and June 2021 were included. The primary endpoint was all-cause mortality and the secondary endpoint was disease severity. RESULTS: COVID-19 was diagnosed in 54/665 HTx patients (8%), with a mean (±â€¯standard deviation (SD)) time after HTx of 11 ± 8 years. Mean (±â€¯SD) age was 53 ± 14 years and 39% were female. Immunosuppressive therapy dosage was reduced in 37% patients (20/54). Hospitalisation was required in 39% patients (21/54), and 13% patients (7/54) had severe COVID-19 (leading to intensive care unit (ICU) admission or death). In-hospital mortality was 14% (3/21), and all-cause mortality was 6%. Compared with patients with moderate COVID-19 (hospitalised without ICU indication), severe COVID-19 patients tended to be transplanted earlier and had a significantly higher mean (±â€¯SD) body mass index (26 ± 3 vs 30 ± 3 kg/m2, p = 0.01). Myocardial infarction, cellular rejection and pulmonary embolism were observed once in three different HTx patients. CONCLUSION: HTx patients were at increased risk of complicated COVID-19 with frequent hospitalisation, but the all-cause mortality was substantially lower than previously described (7-33%).

Listing criteria for heart transplantation in the Netherlands.

The updated listing criteria for heart transplantation are presented on behalf of the three heart transplant centres in the Netherlands. Given the shortage of donor hearts, selection of those patients who may expect to have the greatest benefit from a scarce societal resource in terms of life expectancy and quality of life is inevitable. The indication for heart transplantation includes end-stage heart disease not remediable by more conservative measures, accompanied by severe physical limitation while on optimal medical therapy, including ICD/CRT­D. Assessment of this condition requires cardiopulmonary stress testing, prognostic stratification and invasive haemodynamic measurements. Timely referral to a tertiary centre is essential for an optimal outcome. Chronic mechanical circulatory support is being used more and more as an alternative to heart transplantation and to bridge the progressively longer waiting time for heart transplantation and, thus, has become an important treatment option for patients with advanced heart failure.

Waiting list mortality and the potential of donation after circulatory death heart transplantations in the Netherlands.

BACKGROUND: With more patients qualifying for heart transplantation (HT) and fewer hearts being transplanted, it is vital to look for other options. To date, only organs from brain-dead donors have been used for HT in the Netherlands. We investigated waiting list mortality in all Dutch HT centres and the potential of donation after circulatory death (DCD) HT in the Netherlands. METHODS: Two different cohorts were evaluated. One cohort was defined as patients who were newly listed or were already on the waiting list for HT between January 2013 and December 2017. Follow-up continued until September 2018 and waiting list mortality was calculated. A second cohort of all DCD donors in the Netherlands (lung, liver, kidney and pancreas) between January 2013 and December 2017 was used to calculate the potential of DCD HT. RESULTS: Out of 395 patients on the waiting list for HT, 196 (50%) received transplants after a median waiting time of 2.6 years. In total, 15% died while on the waiting list before a suitable donor heart became available. We identified 1006 DCD donors. After applying exclusion criteria and an age limit of 50 years, 122 potential heart donors remained. This number increased to 220 when the age limit was extended to 57 years. CONCLUSION: Waiting list mortality in the Netherlands is high. HT using organs from DCD donors has great potential in the Netherlands and could lead to a reduction in waiting list mortality. Cardiac screening will eventually determine the true potential.

The value of 18F-FDG PET/CT for the diagnosis of device-related infections in patients with a left ventricular assist device: a systematic review and meta-analysis.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly used for the treatment of advanced heart failure. LVADs improve quality of life and decrease mortality, but the driveline carries substantial risk for major infections. These device-related LVAD and driveline infections are difficult to diagnose with conventional imaging. We reviewed and analysed the current literature on the additive value of 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) imaging for the diagnosis of LVAD-related infections." MATERIALS/METHODS: We performed a systematic literature review using several databases from their inception until the 31st of December, 2019. Studies investigating the diagnostic performance of FDG-PET/CT in patients with suspected LVAD infection were retrieved. After a bias risk assessment using QUADAS-2, a study-aggregate meta-analysis was performed on a per examination-based analysis. RESULTS: A total of 10 studies were included in the systematic review, eight of which were also eligible for study-aggregate meta-analysis. For the meta-analysis, a total of 256 FDG-PET/CT scans, examining pump/pocket and/or driveline infection, were acquired in 230 patients. Pooled sensitivity of FDG-PET/CT was 0.95 (95% confidence interval (CI) 0.89-0.97) and pooled specificity was 0.91 (95% CI 0.54-0.99) for the diagnosis of device-related infection. For pump/pocket infection, sensitivity and specificity of FDG-PET/CT were 0.97 (95%CI 0.69-1.00) and 0.93 (95%CI 0.64-0.99), respectively. For driveline infection, sensitivity and specificity were 0.96 (95%CI 0.88-0.99) and 0.99 (95%CI 0.13-1.00) respectively. Significant heterogeneity existed across studies for specificity, mostly caused by differences in scan procedures. Predefined criteria for suspicion of LVAD and/or driveline infection were lacking in all included studies. CONCLUSIONS: FDG-PET/CT is a valuable tool for assessment of device-related infection in LVAD patients, with high sensitivity and high, albeit variable, specificity. Standardization of FDG-PET/CT procedures and criteria for suspected device-related LVAD infections are needed for consistent reporting of FDG-PET/CT scans.

The role of long-term mechanical circulatory support in patients with advanced heart failure.

In patients with end-stage heart failure, advanced therapies such as heart transplantation and long-term mechanical circulatory support (MCS) with a left ventricular assist device (LVAD) have to be considered. LVADs can be implanted as a bridge to transplantation or as an alternative to heart transplantation: destination therapy. In the Netherlands, long-term LVAD therapy is gaining importance as a result of increased prevalence of heart failure together with a low number of heart transplantations due to shortage of donor hearts. As a result, the difference between bridge to transplantation and destination therapy is becoming more artificial since, at present, most patients initially implanted as bridge to transplantation end up receiving extended LVAD therapy. Following LVAD implantation, survival after 1, 2 and 3 years is 83%, 76% and 70%, respectively. Quality of life improves substantially despite important adverse events such as device-related infection, stroke, major bleeding and right heart failure. Early referral of potential candidates for long-term MCS is of utmost importance and positively influences outcome. In this review, an overview of the indications, contraindications, patient selection, clinical outcome and optimal time of referral for long-term MCS is given.

Sofosbuvir Add-on to Ribavirin Treatment for Chronic Hepatitis E Virus Infection in Solid Organ Transplant Recipients Does Not Result in Sustained Virological Response.

Ribavirin is effective for treating immunocompromised patients with chronic hepatitis E virus infection. However, ribavirin treatment is not always successful. We describe 3 solid organ transplant recipients treated with sofosbuvir and ribavirin after failing ribavirin monotherapy. Complete elimination of hepatitis E virus could not be achieved.

Presión intraabdominal y empeoramiento de la función renal durante las descompensaciones de la insuficiencia cardiaca. Un informe preliminar del estudio PIA / Intraabdominal pressure and worsening renal function during decompensations of heart failure. A preliminary report from the PIA study

Antecedentes: El aumento de la presión intraabdominal (PIA) que tiene lugar durante la insuficiencia cardiaca aguda parece estar directamente relacionado con un empeoramiento de la función renal, lo que conduce a peores resultados clínicos. Nuestro objetivo fue analizar la relación entre la PIA y los determinantes de la función renal para la insuficiencia cardiaca aguda descompensada (ICAD) durante el ingreso en un pabellón de medicina interna convencional. Pacientes y métodos: Estudio descriptivo y prospectivo. Se incluyó a aquellos pacientes con una tasa de filtración glomerular > 30mL/min/1,73 m2, dispuestos a participar en el estudio y que otorgaron su consentimiento informado. El protocolo (PI 15 0227) fue aprobado por el Comité de Ética de Aragón. Resultados: Presentamos los resultados de un análisis preliminar llevado a cabo con los primeros 28 pacientes incluidos en el estudio. Los pacientes se segregaron en 2grupos según la mediana de la PIA, alta (PIA > 15mmHg) y baja (PIA < 15mmHg), medida durante las primeras 24 h tras el ingreso por ICAD. Cada grupo estuvo integrado por 14pacientes. No hubo diferencias entre los grupos en cuanto a características clínicas de referencia, comorbilidades ni tratamiento. Los pacientes con PIA superior a los 15mmHg presentaron una tasa de filtración glomerular basal significativamente baja (70,7 vs. 44,4mL/min/1,73 m2 con p = 0,004; urea en sangre 36 vs. 83mg/dL con p = 0,002; creatinina sérica 0,87 vs. 1,3mg/dL con p = 0,004 y cistatina C 1,2 vs. 1,94mg/dL con p = 0,002). Además, estos pacientes mostraron las concentraciones de ácido úrico más altas (5,7 vs. 8,0; p = 0,046), las de hemoglobina resultaron más bajas (11,7 vs. 10,5g/L; p = 0,04) y la estancia hospitalaria más larga (6,5 vs. 9,6 días; p = 0,017). Conclusiones: El aumento de la PIA parece ser un hallazgo frecuente en pacientes ingresados por ICAD. Independientemente de la PIA, los pacientes comparten un perfil clínico similar, si bien el aumento de la PIA se asoció con un empeoramiento significativo de la función renal de referencia

Background: An increase in intraabdominal pressure (IAP) during acute heart failure, seems to be directly related to worsening renal function, which leads to worse clinical outcomes. We aimed to analyze the relationship between IAP and determinants of renal function during admission for acute decompensation of heart failure (ADHF) in a conventional Internal Medicine Ward. Patients and methods: Descriptive and prospective study. Patients admitted for ADHF with an estimated glomerular filtration rate > 30mL/min/1.73 m2, willing to participate and who gave their informed consent were included. Ethics Committee of Aragon approved the protocol (PI 15 0227). Results: We hereby report the results of an interim analysis of the first 28 patients included. Patients were divided in 2groups according to the median of IAP measured during the first 24h after admission for ADHF, namely high IAP (IAP>15mmHg) and low (IAP< 15mmHg). Fourteen patients were included in each group. No differences were found in baseline clinical characteristics, comorbidities or treatment between both groups. Patients with IAP above 15mmHg, showed a significant lower baseline estimated glomerular filtration rate (70.7 vs. 44.4mL/min/1.73 m2 with p=0.004], blood urea 36 vs. 83mg/dL with p=0.002]; serum creatinine 0.87 vs. 1.3mg/dL with p=0.004 and cystatin C 1.2 vs. 1.94mg/dL with p= 0.002. Additionally, these patients had higher uric acid (5.7 vs. 8.0, p=0.046), lower hemoglobin concentrations (11.7 vs. 10.5g/L, p=0.04) and longer length of hospital stay (6.5 vs. 9.6 days, p=0.017). Conclusions: The increase in IAP seems to be a frequent finding in patients admitted for ADHF. Patients share similar clinical profile irrespective of IAP, although the increase in IAP is associated with a significant baseline impairment of renal function

Intraabdominal pressure and worsening renal function during decompensations of heart failure. A preliminary report from the PIA study. / Presión intraabdominal y empeoramiento de la función renal durante las descompensaciones de la insuficiencia cardiaca. Un informe preliminar del estudio PIA.

BACKGROUND: An increase in intraabdominal pressure (IAP) during acute heart failure, seems to be directly related to worsening renal function, which leads to worse clinical outcomes. We aimed to analyze the relationship between IAP and determinants of renal function during admission for acute decompensation of heart failure (ADHF) in a conventional Internal Medicine Ward. PATIENTS AND METHODS: Descriptive and prospective study. Patients admitted for ADHF with an estimated glomerular filtration rate > 30mL/min/1.73 m2, willing to participate and who gave their informed consent were included. Ethics Committee of Aragon approved the protocol (PI 15 0227). RESULTS: We hereby report the results of an interim analysis of the first 28 patients included. Patients were divided in 2groups according to the median of IAP measured during the first 24h after admission for ADHF, namely high IAP (IAP>15mmHg) and low (IAP< 15mmHg). Fourteen patients were included in each group. No differences were found in baseline clinical characteristics, comorbidities or treatment between both groups. Patients with IAP above 15mmHg, showed a significant lower baseline estimated glomerular filtration rate (70.7 vs. 44.4mL/min/1.73 m2 with p=0.004], blood urea 36 vs. 83mg/dL with p=0.002]; serum creatinine 0.87 vs. 1.3mg/dL with p=0.004 and cystatin C 1.2 vs. 1.94mg/dL with p= 0.002. Additionally, these patients had higher uric acid (5.7 vs. 8.0, p=0.046), lower hemoglobin concentrations (11.7 vs. 10.5g/L, p=0.04) and longer length of hospital stay (6.5 vs. 9.6 days, p=0.017). CONCLUSIONS: The increase in IAP seems to be a frequent finding in patients admitted for ADHF. Patients share similar clinical profile irrespective of IAP, although the increase in IAP is associated with a significant baseline impairment of renal function.

Chronic kidney disease, worsening renal function and outcomes in a heart failure community setting: A UK national study.

BACKGROUND: Routine heart failure (HF) monitoring and management is in the community but the natural course of worsening renal function (WRF) and its influence on HF prognosis is unknown. We investigated the influence of routinely monitored renal decline and related comorbidities on imminent hospitalisation and death in the HF community population. METHODS: A nested case-control study within an incident HF cohort (N = 50,114) with 12-years follow-up. WRF over 6-months before first hospitalisation and 12-months before death was defined by >20% reduction in estimated glomerular filtration rate (eGFR). Additive interactions between chronic kidney disease (CKD) and comorbidities were investigated. RESULTS: Prevalence of CKD (eGFR<60 ml/min/1.73m2) in the HF community was 63%, which was associated with an 11% increase in hospitalisation and 17% in mortality. Both risk associations were significantly worse in the presence of diabetes. Compared to HF patients with eGFR,60-89, there was no or minimal increase in risk for mild to moderate CKD (eGFR,30-59) for both outcomes. Adjusted risk estimates for hospitalisation were increased only for severe CKD(eGFR,15-29); Odds Ratio 1.49 (95%CI;1.36,1.62) and renal failure(eGFR,<15); 3.38(2.67,4.29). The relationship between eGFR and mortality was U-shaped; eGFR, ≥90; 1.32(1.17,1.48), eGFR,15-29; 1.68(1.58,1.79) and eGFR,<15; 3.04(2.71,3.41). WRF is common and associated with imminent hospitalisation (1.50;1.37,1.64) and mortality (1.92;1.79,2.06). CONCLUSIONS: In HF, the risk associated with CKD differs between the community and the acute HF setting. In the community setting, moderate CKD confers no risk but severe CKD, WRF or CKD with other comorbidities identifies patients at high risk of imminent hospitalisation and death.

Predictors of outcome after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Special interest for the septal coronary anatomy.

BACKGROUND: Alcohol septal ablation (ASA) provides symptomatic relief in most but not all patients with hypertrophic obstructive cardiomyopathy (HOCM). Therefore we investigated predictors of outcome after ASA. METHODS: Clinical, echocardiographic, angiographic and procedural characteristics were analysed in 113 consecutive patients. Successful ASA was defined as NYHA ≤ 2 with improvement of at least 1 class combined with a resting gradient < 30 mmHg and provoked gradient < 50 mmHg at 4-month follow-up. RESULTS: In 37 patients ASA was not successful. In multivariate analysis, baseline gradient (OR 1.06 (1.01-1.11) per 5 mmHg, p = 0.024) and distance to the ablated septal branch (OR 1.09 (1.03-1.16) per mm, p = 0.004) were predictors of unsuccessful outcome. The combined presence of a non-ablated septal branch and a distance ≥ 19 mm to the ablated branch was a predictor of unsuccessful outcome (OR 5.88 (2.06-16.7), p < 0.001). CONCLUSIONS: Baseline gradient and a greater distance from the origin of the left anterior descending artery to the ablated septal branch combined with a non-ablated proximal septal branch are associated with an unsuccessful outcome after ASA.

Abnormal liver function in relation to hemodynamic profile in heart failure patients.

BACKGROUND: We studied the relation between liver function abnormalities and hemodynamic profile in patients with heart failure (HF). METHODS AND RESULTS: In 323 HF patients, liver function was determined by aspartate and alanine aminotransferase (AST, ALT), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase, and direct and total bilirubin (Bili dir, Bili tot). Central venous pressure (CVP) and cardiac index (CI) were determined invasively. Follow-up consisted of time to all-cause mortality. Mean age was 53 +/- 15 years, and 60% were male. In multivariable analysis, all liver function tests related to CVP, but higher CVP was predominantly related to GGT (r = 0.336, P < .001) and Bili dir (r = 0.370, P < .001). Only elevated AST (r =-0.177, P < .01), ALT (r = -0.130, P < .05), and Bili tot (r = -0.158, P < .01) were associated with both low CI and elevated CVP. The prognostic value of abnormal liver function tests was related to their interaction with CI and CVP. CONCLUSIONS: Elevated liver function tests mainly indicate higher CVP, whereas only the presence of elevated AST, ALT, or Bili dir may indicate a low CI. The absence of prognostic information in the presence of invasive hemodynamic measurements suggests that abnormal liver function tests in HF reflect a poor hemodynamic status.