Linda Wilhelmina Van Laake

Heart transplantation (HTx) remains the gold standard treatment for selected patients with advanced heart failure and survival after transplantation has substantially improved over recent decades. As a consequence, the number of long-term HTx recipients continues to increase, and these patients are now frequently encountered in routine practice outside specialized transplant centers. Their management remains complex due to the use of chronic immunosuppression, transplant-specific complications, and a growing burden of comorbidities in the perspective of increasing longevity. Non-transplant cardiologists, general practitioners, and other healthcare professionals are therefore increasingly involved in their care but often have limited experience of post-transplant management. This clinical consensus statement from the Heart Failure Association (HFA) and the Association of Cardiovascular Nursing & Allied Professions (ACNAP) of the ESC provides practical support and a structured framework for healthcare providers involved in the care of HTx recipients outside dedicated transplant centers. The document reviews key aspects of post-transplant management, including outlining principles of care according to time from transplantation, essential knowledge around immunosuppressive therapy and drug monitoring, recognition and initial management of rejection, infection prophylaxis and treatment, and surveillance of long-term complications such as cardiac allograft vasculopathy, malignancy, chronic kidney disease, and metabolic disorders. In addition, specific clinical situations frequently encountered in practice—including fertility and pregnancy, non-cardiac surgery, rehabilitation, and palliative care—are discussed. Particular emphasis is placed on the organization of shared-care models between transplant centers and community providers and on identifying clinical scenarios requiring early referral. Through providing practical recommendations and a structured framework for follow-up, this document aims to support non-specialist clinicians in the safe management of HTx recipients and to facilitate timely collaboration with transplant centers.

Cardiogenic shock is a complex clinical syndrome with a high mortality risk. As heterogeneity of patient presentation is high and diagnosis not standardized, a timely diagnosis and thus initiation of treatment are oftentimes not achieved, further worsening the prognosis of affected patients. We therefore propose standardized criteria for the diagnosis of cardiogenic shock, based on three essential pillars: (i) an evidence of end-organ hypoperfusion at rest, (ii) which is primarily caused by haemodynamic abnormalities and a direct consequence of (iii) an underlying cardiac dysfunction commensurate with the state of shock.

Left ventricular assist device (LVAD) support has been shown to induce the reversal of neurohormonal changes and myocardial recovery. This study aimed to evaluate the prevalence, predictors, and clinical impact of left ventricular (LV) recovery after LVAD implantation using data from the European Registry for Patients with Mechanical Circulatory Support. Patients with at least one available left ventricular ejection fraction (LVEF) measurement at both baseline and post-LVAD implantation were enrolled. Left ventricular recovery was classified as 'no recovery' if LVEF increase was <5%, 'mild' if LVEF increased by 5%-15% with peak LVEF 15% with peak LVEF <50%, and 'full' if LVEF increased by ≥5% with peak LVEF ≥50%. A total of 1550 patients with a median age of 57 (48-64) years were included. LV recovery occurred mostly within the first year, with marginal probabilities of no, mild, intermediate, and full recovery at 4 years being 51% [95% confidence interval (CI) 48-54%), 41% (95% CI 38-43%), 8% (95% CI 7-9%), and 1% (95% CI 0-1%), respectively]. INTERMACS Classes 2, 3, and 4 [compared with Class 1; hazard ratio (HR) .72, .64, and .51, respectively] were associated with a lower hazard of attaining any LV recovery, whereas renin-angiotensin system inhibitor use was associated with a higher hazard of attaining any LV recovery (HR 1.17; 95% CI 1.00-1.37). Each 10% higher LVEF value during follow-up was associated with an estimated 14% lower instantaneous hazard of all-cause mortality (HR .86; 95% credible interval .75-.98). The cumulative incidence of the composite major adverse cardiovascular event endpoint, including cardiovascular death, late right heart failure, and arrhythmia beyond the first year, was lower across higher LV recovery categories defined according to the LVEF value at 1 year (Gray's test, P = .042). This multicentre European study shows that LV recovery mostly occurs within the first year after LVAD implantation and is associated with better clinical outcomes. Renin-angiotensin system inhibitor use was associated with both any and intermediate/full LV recovery, while combination neurohormonal blockade strategies yielded directionally favourable but imprecise estimates, warranting further study during LVAD support.

Objective: Atrial fibrillation (AF) is a common arrhythmia affecting a large fraction of patients in intensive care units (ICUs). Predicting patients at risk of AF in the ICU is a challenging task and is not commonly practiced but could have clinical implications considering that AF is a proxy for poorer outcomes. Our goal is to develop a real-time AF prediction model using ICU numerical data to improve alarm quality, helping clinicians to identify at-risk patients and intervene before AF onset, thereby potentially improving clinical outcomes. Methods: We employed AmsterdamUMCdb, Europe’s first openly accessible ICU dataset. The dataset includes static features, including demographics, as well as dynamic bedside monitoring data, like blood pressure and respiratory rate, along with detailed records of medication and fluid administration. To enhance generalizability across diverse ICU patients, we trained a long short-term memory (LSTM) model combined with a Model-Agnostic Meta-Learning (MAML) approach. Model performance was tested on an imbalanced test set, reflective of the real-world ratio of AF to non-AF patients. Direct external validation was performed using the MIMIC-IV database to test generalizability across different clinical settings. Results: The LSTM-MAML model achieved an AUC of 0.92, accuracy of 0.89, and precision of 0.29 on the internal validation set. In external validation with MIMIC-IV, it showed near-equivalent performance with an AUC of 0.89, accuracy of 0.85, and precision of 0.18. Conclusions: The real-time prediction model demonstrated predictive value for AF and has potential for future clinical benefits. However, for clinical implementation, further refinement is necessary to improve its performance in identifying patients at risk for AF.

Introduction: Little is known about the management and disease trajectories of heart failure (HF) patients in the pre-hospital setting when experiencing exacerbating symptoms. Shortness of breath (SOB) is a main reason for contacting out-of-hours primary care (OHS-PC). We aim to describe the care trajectories of these patients with HF at the OHS-PC with exacerbating symptom SOB and to assess 6-month outcomes regarding mortality and hospital admissions. Methods: We included patients who contacted Dutch OHS-PC for SOB between September 2020 and August 2021. We selected those in whom HF was considered to be the cause for consultation and further clinical evaluation. We applied descriptive analyses to characterize these patients and their disease trajectories following this OHS-PC contact and compared patients referred to the Emergency Department (ED) to those who remained in primary care. Results: Of 1833 calls for SOB, 102 (5.1%) concerned patients with HF, who had a mean age of 79.6 ± 11.1 years, and 53% were women. Ten (9.8%) patients were directly referred to the ED. The remaining 92 (90.2%) were first assessed by a general practitioner (GP): 62 (60.8%) received a home visit, 15 (14.7%) were seen at the OHS-PC clinic, and 15 (14.7%) received a telephone advice only. Of these 92 patients, 41 (44.6%) patients were subsequently referred to the ED, and 39 (42.4%) were kept at home and received loop diuretics (newly initiated or increased dose). Of the 51 patients referred to the ED (directly or after assessment with the GP), 42 patients (82.4%, P-value < .001) were admitted. Six-month all-cause mortality of the 102 patients was 32.3%. Conclusion: At the OHS-PC, one in every 20 contacts for SOB is a HF patient who has a high 6-month mortality risk. Patients were directly referred to the hospital or received initiation or up-titration of loop diuretics.

Genetic cardiomyopathies consist of a heterogeneous group of myocardial disorders caused by variants that disrupt key regulators of cardiac structure and function. Variants in PLN, encoding phospholamban (PLN), the main inhibitor of the sarco/endoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a), have been linked to both dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Among these, the PLN Arg14del (R14del) variant is the most prevalent. PLN R14del cardiomyopathy is characterized by the accumulation of large perinuclear PLN aggregates in cardiomyocytes of end-stage heart failure tissue. However, the mechanisms driving PLN aggregate formation and their role in disease progression remain unresolved. Using a humanized plna R14del zebrafish model, left ventricular tissue from end-stage PLN R14del cardiomyopathy patients and pharmacological modeling in wild type (WT) cardiac slices, we demonstrate that previously described PLN aggregates represent accumulated sarcoplasmic reticulum (SR)-derived PLN-containing vesicles that form due to impaired SERCA2a activity and increased cytosolic Ca²⁺ levels. Furthermore, these SR-derived vesicles often localize adjacent to lysosomes. Interestingly, Ca ²⁺ dysregulation in plna R14del hearts leads to reduced lysosomal function, resulting in SR-derived vesicle accumulation at the microtubule organizing center (MTOC). This perinuclear accumulation induces microtubule aster formation and subsequent cellular disorganization, including sarcomere misalignment and nuclear deformation. Strikingly, reactivation of lysosomal function through fasting reduces SR-derived vesicle accumulation, restores microtubule integrity, and rescues cellular organization in plna R14del zebrafish hearts. Together, these findings identify impaired lysosomal clearance of SR-derived vesicles and the resulting microtubule disorganization as key pathological mechanisms driving PLN R14del cardiomyopathy. Additionally, our results highlight lysosomal reactivation as a promising potential therapeutic strategy to halt or reverse PLN R14del cardiomyopathy progression. Main findings: PLN aggregates in PLN R14del cardiomyopathy represent SR-derived vesicles formed due to Ca²⁺ dysregulation. These SR-derived vesicles often localize perinuclearly at the microtubule organizing center (MTOC), where they are positioned adjacent to lysosomes. Ca ²⁺ dysregulation leads to lysosomal dysfunction which drives vesicle accumulation responsible for microtubule remodeling and pathological cellular rearrangements. Lysosomal reactivation restores vesicle clearance and rescues cardiomyocyte structure.

Introduction: The accessibility of left ventricular assist device (LVAD) therapy is a crucial factor in the survival and quality of life of patients suffering from advanced heart failure. However, there is a lack of clarity regarding the utilization of this therapy across regions in the Netherlands as well as whether any disparities exist based on socioeconomic status (SES). This study aimed to determine the utilization of LVAD therapy at a regional level using administrative data and to identify potential disparities based on SES by comparing postal code data to demographic governmental data. Methods: All patients aged 16 or older who underwent a primary LVAD implantation between 2015 and 2024 were included. The data was visualized with a heatmap using Python. Results: A total of 710 patients received an LVAD during the study period. LVAD utilization was lower in the southernmost regions compared to the northernmost regions and varied in the central regions. An ANOVA test between SES groups did not show significant differences in LVAD utilization ( p = 0.20). Conclusion: The findings of this study indicate that there are notable variations in the utilization of LVAD therapy across different geographical regions in the Netherlands. Nevertheless, no differences in LVAD use were found between areas with different SES categories. Future research should focus on identifying the underlying factors associated with referral for advanced heart failure therapies to ensure equitable access to LVAD therapy.

The adult mammalian heart has a limited regenerative capacity. Following injury, cardiomyocytes undergo a hypertrophic response accompanied by polyploidization, which has been described as a barrier to proliferation and regeneration of the heart ^1,2 . However, the unique molecular programs of polyploidy, or genome multiplied cardiomyocytes, and their influence on the disease-related myocardial remodelling process remains unclear. Here, we integrate single-nuclei and high-resolution spatial multi-omics across human, rat, and mouse hearts to define novel cardiac cell states and their tissue niches in ischemic and non-ischemic heart disease. Computational analysis across scales allowed us to generate detailed networks of the cardiac tissue remodelling process as well as tissue and sub-cellular environments uniquely enriched in polyploid cardiomyocytes or their diploid origins. We identify a conserved, dichotomous transcriptional program distinguishing diploid from polyploid cardiomyocytes. Polyploid cardiomyocytes demonstrated rewired metabolic and chromatin-remodeling transcriptional programs and recapitulate the gene signature of immature human fetal cardiomyocytes. Notably, we observe that polyploid cardiomyocytes—rather than the general myocyte population—are the primary sites of enrichment for major heart-failure drug targets, including the mineralocorticoid, β1-adrenergic, and glucagon-like peptide-1 receptors. Based on our cross-species dataset we further identified TNIK, a Wnt-pathway regulator expressed in polyploid cardiomyocytes across species, as a potential therapeutic target and demonstrate that pharmacological TNIK inhibition improves cardiac function after myocardial infarction in rats. Together, this species-spanning, disease-resolved study redefines cardiomyocyte heterogeneity in heart disease and suggests a therapeutic path to heart failure treatment by targeting polyploid cardiomyocytes.