Annika Weidenhammer

Background/Objectives: Real-world evidence shows alarmingly suboptimal utilization of guideline directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). One of the barriers of GDMT implementation appears to be concerns about the potential development of drug-related adverse events (AEs), particularly in high-risk patients. This study aimed to evaluate whether advanced HFrEF (AHF) patients can be up-titrated safely and whether AHF predisposes individuals to the occurrence of putatively drug-related AEs. Methods: A total of 373 HFrEF patients with documented baseline, 2 months, and 12 months visits were analyzed for utilization and target dosages (TDs) of HF drugs. Successful up-titration and AEs were evaluated for different stages of HF reflected by N-terminal pro-B type natriuretic peptide (NT-proBNP) (2000 pg/mL). Results: A stepwise increase in HF medications was observed for all drug classes during follow-up. At 12 months, 73%, 75%, 62%, 86%, and 45% of patients received ≥90% of TDs of beta-blockers (BBs), renin–angiotensin system inhibitors (RASis), mineralocorticoid receptor antagonists (MRAs), sodium–glucose cotransporter-2 inhibitors (SGLT2 i), and triple-therapy, respectively. Predictors of successful up-titration in logistic regression were baseline HF drug TDs, estimated glomerular filtration rate (eGFR), and potassium, but not NT-proBNP or age. The development of AEs was rare, with hyperkalemia as the most common event (34% at 12 months). AEs were comparable in all stages of HF. However, the development of hyperkalemia was more frequent in patients with higher NT-proBNP and also accounted for most cases of incomplete up-titration. Conclusions: This study suggests that with dedicated protocols and frequent visits, GDMT can be successfully implemented across all stages of HFrEF, including patients with AHF.

Background/Objectives. Real-world evidence shows alarmingly suboptimal utilization of GDMT in HFrEF. One of the barriers of GDMT implementation appears to be concerns about the potential development of drug-related ad-verse events (AEs), particularly in high-risk patients. This study aimed to evaluate whether advanced HfrEF (AHF) patients can be up-titrated safely and whether AHF predisposes to the occurrence of putatively drug-related AEs. Methods. A total of 373 HFrEF patients with documented baseline, 2 months and 12 months visits were analyzed for utilization and target dosages (TDs) of HF-drugs. Successful up-titration and AEs were evaluated for different stages of HF reflected by NT-proBNP (< 1000pg/ml, 1000-2000pg/ml, >2000pg/ml). Results. A stepwise increase in HF medications could be observed for all drug classes during follow-up. At 12 months 73%, 75%, 62%, 86% and 45% of pa-tients received ≥90% of TDs of beta-blockers (BB), renin-angiotensin system inhibitors (RASi), mineralocorticoid receptor antagonists (MRA), sodi-um-glucose cotransporter-2 inhibitors (SGLT2i), and triple-therapy, respec-tively. Predictors of successful up-titration in logistic regression were baseline HF-drug TDs, eGFR, and potassium, but not NT-proBNP or age. The devel-opment of AEs was rare, with hyperkalemia as the most common event (34% at 12 months). AEs were comparable in all stages of HF. However, develop-ment of hyperkalemia was more frequent in patients with higher NT-proBNP and also accounted for most cases for incomplete up-titration. Conclusion. This study suggests that with dedicated protocols and frequent visits GDMT can be successfully implemented across all stages of HFrEF, in-cluding patients with AHF.

Microvascular integrity is a critical factor in myocardial fluid homeostasis. The subtle equilibrium between capillary filtration and lymphatic fluid removal is disturbed during pathological processes leading to inflammation, but also in hypoxia or due to alterations in vascular perfusion and coagulability. The degradation of the glycocalyx as the main component of the endothelial filtration barrier as well as pericyte disintegration results in the accumulation of interstitial and intracellular water. Moreover, lymphatic dysfunction evokes an increase in metabolic waste products, cytokines and inflammatory cells in the interstitial space contributing to myocardial oedema formation. This leads to myocardial stiffness and impaired contractility, eventually resulting in cardiomyocyte apoptosis, myocardial remodelling and fibrosis. The following article reviews pathophysiological inflammatory processes leading to myocardial oedema including myocarditis, ischaemia-reperfusion injury and viral infections with a special focus on the pathomechanisms evoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, clinical implications including potential long-term effects due to viral persistence (long COVID), as well as treatment options, are discussed.

Microvascular integrity is a critical factor in myocardial fluid homeostasis. The subtle equilibrium between capillary filtration and lymphatic fluid removal is disturbed during pathological processes leading to inflammation, but also in hypoxia or due to alterations in vascular perfusion and coagulability. The degradation of the glycocalyx as the main component of the endothelial filtration barrier as well as pericyte disintegration result in accumulation of interstitial and intracellular water. Moreover, lymphatic dysfunction evokes an increase in metabolic waste products, cytokines and inflammatory cells in the interstitial space contributing to myocardial oedema formation. This leads to myocardial stiffness and impaired contractility eventually resulting in cardiomyocyte apoptosis, myocardial remodelling and fibrosis. The following article reviews pathophysiological inflammatory processes leading to myocardial oedema including myocarditis, ischaemia-reperfusion injury and viral infections with a special focus on the pathomechanisms evoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, clinical implications including potential long-term effects due to viral persistence (long-COVID), as well as treatment options are discussed.

Background: CILP-1 regulates myocardial fibrotic response and remodeling and was reported to indicate right ventricular dysfunction (RVD) in pulmonary hypertension (PH) and heart failure (HF). This study examines CILP-1 as a potential biomarker for RVD and prognosis in heart failure with reduced ejection fraction (HFrEF) patients on guideline-directed medical therapy. Methods: CILP-1 levels were measured in 610 HFrEF patients from a prospective registry with biobanking (2016–2022). Correlations with echocardiographic and hemodynamic data and its association with RVD and prognosis were analyzed. Results: The median age was 62 years (Q1–Q3: 52–72), 77.7% of patients were male, and the median NT-proBNP was 1810 pg/mL (Q1–Q3: 712–3962). CILP-1 levels increased with HF severity, as indicated by NT-proBNP and NYHA class (p < 0.0001, for both). CILP-1 showed a weak–moderate direct association with increased left ventricular filling pressures and its sequalae, i.e., backward failure (LA diameter r_s = 0.15, p = 0.001; sPAP r_s = 0.28, p = 0.010; RVF r_s = 0.218, p < 0.0001), but not with cardiac index (CI) and systemic vascular resistance (SVR). CILP-1 trended as a risk factor for all-cause mortality (crude HR for 500 pg/mL increase: 1.03 (95%CI: 1.00–1.06), p = 0.053) but lost significance when it was adjusted for NT-proBNP (adj. HR: 1.00 (95%CI: 1.00–1.00), p = 0.770). No association with cardiovascular hospitalization was observed. Conclusions: CILP-1 correlates with HFrEF severity and may indicate an elevated risk for all-cause mortality, though it is not independent from NT-proBNP. Increased CILP-1 is associated with backward failure and RVD rather than forward failure. Whether CILP-1 release in this context is based on elevated pulmonary pressures or is specific to RVD needs to be further investigated.

After spinal cord injury (SCI), the destruction of spinal parenchyma causes permanent deficits in motor functions, which correlates with the severity and location of the lesion. Despite being disconnected from their targets, most cortical motor neurons survive the acute phase of SCI, and these neurons can therefore be a resource for functional recovery, provided that they are properly reconnected and retuned to a physiological state. However, inappropriate re-integration of cortical neurons or aberrant activity of corticospinal networks may worsen the long-term outcomes of SCI. In this review, we revisit recent studies addressing the relation between cortical disinhibition and functional recovery after SCI. Evidence suggests that cortical disinhibition can be either beneficial or detrimental in a context-dependent manner. A careful examination of clinical data helps to resolve apparent paradoxes and explain the heterogeneity of treatment outcomes. Additionally, evidence gained from SCI animal models indicates probable mechanisms mediating cortical disinhibition. Understanding the mechanisms and dynamics of cortical disinhibition is a prerequisite to improve current interventions through targeted pharmacological and/or rehabilitative interventions following SCI.