Prediction of cardiac worsening through to cardiogenic shock in patients with acute heart failure

Aims: Acute heart failure (AHF) can result in worsening of heart failure (WHF), cardiogenic shock (CS), or death. Risk factors for these adverse outcomes are not well characterized. This study aimed to identify predictors for WHF or new‐onset CS in patients hospitalized for AHF. Methods and results: Prospective cohort study enrolling consecutive patients with AHF admitted to a large tertiary care centre with follow‐up until death or discharge. WHF was defined by the RELAX‐AHF‐2 criteria. CS was defined as SCAI stages B–E. Potential predictors were assessed by fitting logistic regression models adjusted for age and sex. N = 233 patients were enrolled, median age was 78 years, and 80 were women (35.9%). Ischaemic cardiomyopathy was present in 82 patients (40.8%). Overall, 96 (44.2%) developed WHF and 18 (9.7%) CS. In‐hospital death (8/223, 3.6%) was related to both events (WHF: OR 6.64, 95% CI 1.21–36.55, P = 0.03; CS: OR 38.27, 95% CI 6.32–231.81, P < 0.001). Chronic kidney disease (OR 2.20, 95% CI 1.25–3.93, P = 0.007), logarithmized serum creatinine (OR 2.90, 95% CI 1.51–5.82, P = 0.002), cystatin c (OR 1.86, 95% CI 1.27–2.77, P = 0.002), tricuspid valve regurgitation (OR 2.08, 95% CI 1.11–3.94, P = 0.023) and logarithmized pro‐adrenomedullin (OR 3.01, 95% CI 1.75–5.38, P < 0.001) were significant predictors of WHF. Chronic kidney disease (OR 3.17, 95% CI 1.16–9.58, P = 0.03), cystatin c (OR 1.88, 95% CI 1.00–3.53, P = 0.045), logarithmized pro‐adrenomedullin (OR 2.90, 95% CI 1.19–7.19, P = 0.019), and tricuspid valve regurgitation (OR 10.44, 95% CI 2.61–70.00, P = 0.003) were significantly with new‐onset CS. Conclusions: Half of patients admitted with AHF experience WHF or new‐onset CS. Chronic kidney disease, tricuspid valve regurgitation, and elevated pro‐adrenomedullin concentrations predict these events. They could potentially serve as early warning signs for further deterioration in AHF patients

Pro‐adrenomedullin associates with congestion in acute heart failure patients

Aim: Congestion is a major determinant of outcomes in acute heart failure. Its assessment is complex, making sufficient decongestive therapy a challenge. Residual congestion is frequent at discharge, increasing the risk of re‐hospitalization and death. Mid‐regional pro‐adrenomedullin mirrors vascular integrity and may therefore be an objective marker to quantify congestion and to guide decongestive therapies in patients with acute heart failure. Methods and results: Observational, prospective, single‐centre study in unselected patients presenting with acute heart failure. This study aimed to assess adrenomedullin's association with congestion and clinical outcomes: in‐hospital death, post‐discharge mortality and in‐hospital worsening heart failure according to RELAX‐AHF‐2 trial criteria. Pro‐adrenomedullin was quantified at baseline and at discharge. Congestion was assessed applying clinical scores. Cox and logistic regression models with adjustment for clinical features were fitted. N = 233, median age 77 years (IQR 67, 83), 148 male (63.5%). Median pro‐adrenomedullin 2.0 nmol/L (IQR 1.4, 2.9). Eight patients (3.5%) died in hospital and 100 (44.1%) experienced in‐hospital worsening heart failure. After discharge, 60 patients (36.6%) died over a median follow‐up of 1.92 years (95% CI: 1.76, 2.46). Pro‐adrenomedullin concentrations (logarithmized) were significantly associated with congestion, both at enrolment (β = 0.36 and 0.81 depending on score, each P < 0.05) and at discharge (β = 1.12, P < 0.001). Enrolment of pro‐adrenomedullin was associated with in‐hospital worsening heart failure [OR 4.23 (95% CI: 1.87, 9.58), P < 0.001], and pro‐adrenomedullin at discharge was associated with post‐discharge death [HR 3.93 (1.86, 8.67), P < 0.001]. Conclusion: Elevated pro‐adrenomedullin is associated with in‐hospital worsening heart failure and with death during follow‐up in patients with acute heart failure. Further research is needed to validate this finding and to explore the ability of pro‐adrenomedullin to guide decongestive treatment

Association of systemic inflammation with shock severity, 30-day mortality, and therapy response in patients with cardiogenic shock

Background: Mortality in cardiogenic shock (CS) remains high even when mechanical circulatory support (MCS) restores adequate circulation. To detect a potential contribution of systemic inflammation to shock severity, this study determined associations between C-reactive protein (CRP) concentrations and outcomes in patients with CS. Methods: Unselected, consecutive patients with CS and CRP measurements treated at a single large cardiovascular center between 2009 and 2019 were analyzed. Adjusted regression models were fitted to evaluate the association of CRP with shock severity, 30-day in-hospital mortality and treatment response to MCS. Results: The analysis included 1116 patients [median age: 70 (IQR 58–79) years, 795 (71.3%) male, lactate 4.6 (IQR 2.2–9.5) mmol/l, CRP 17 (IQR 5–71) mg/l]. The cause of CS was acute myocardial infarction in 530 (48%) patients, 648 (58%) patients presented with cardiac arrest. Plasma CRP concentrations were equally distributed across shock severities (SCAI stage B–E). Higher CRP concentrations were associated with 30-day in-hospital mortality (8% relative risk increase per 50 mg/l increase in CRP, range 3–13%; p < 0.001), even after adjustment for CS severity and other potential confounders. Higher CRP concentrations were only associated with higher mortality in patients not treated with MCS [hazard ratio (HR) for CRP > median 1.50; 95%-CI 1.21–1.86; p < 0.001], but not in those treated with MCS (HR for CRP > median 0.92; 95%-CI 0.67–1.26; p = 0.59; p-interaction = 0.01). Conclusion: Elevated CRP concentrations are associated with increased 30-day in-hospital mortality in unselected patients with cardiogenic shock. The use of mechanical circulatory support attenuates this association

Therapeutic miR-21 Silencing Ameliorates Diabetic Kidney Disease in Mice

Diabetic nephropathy is the main cause of end-stage renal disease. MicroRNAs are powerful regulators of the genome, and global expression profiling revealed miR-21 to be among the most highly regulated microRNAs in kidneys of mice with diabetic nephropathy. In kidney biopsies of diabetic patients, miR-21 correlated with tubulointerstitial injury. In situ PCR analysis showed a specific enrichment of miR-21 in glomerular cells. We identified cell division cycle 25a (Cdc25a) and cyclin-dependent kinase 6 (Cdk6) as novel miR-21 targets in mesangial cells. miR-21-mediated repression of Cdc25a and Cdk6 resulted in impaired cell cycle progression and subsequent mesangial cell hypertrophy. miR-21 increased podocyte motility by regulating phosphatase and tensin homolog (Pten). miR-21 antagonism in vitro and in vivo in streptozotocin-induced diabetic mice decreased mesangial expansion, interstitial fibrosis, macrophage infiltration, podocyte loss, albuminuria, and fibrotic- and inflammatory gene expression. In conclusion, miR-21 antagonism rescued various functional and structural parameters in mice with diabetic nephropathy and, thus, might be a viable option in the treatment of patients with diabetic kidney disease

Antagonism of profibrotic microRNA-21 improves outcome of murine chronic renal allograft dysfunction

Chronic renal allograft dysfunction (CAD) is a major limiting factor of long-term graft survival. It is characterized by interstitial fibrosis and tubular atrophy. The underlying pathomechanisms are incompletely understood. MicroRNAs are powerful regulators of gene expression and may have an impact on various diseases by direct mRNA decay or translational inhibition. A murine model of allogenic kidney transplantation was used resulting in CAD at 6 weeks after kidney transplantation. We identified fibrosis-associated miR-21a-5p by whole miRNAome expression analysis to be among the most highly upregulated miRNAs. In vitro in renal fibroblasts, miR-21a-5p was transcriptionally activated by interleukin 6-induced signal transducer and activator of transcription 3. Co-culture of LPS-activated macrophages with renal fibroblasts increased expression levels of miR-21a-5p and markers of fibrosis and inflammation. In addition, mature miR-21a-5p was secreted by macrophages in small vesicles, which were internalized by renal fibroblasts, thereby promoting profibrotic and proinflammatory effects. Notch2 receptor was identified as a potential target of miR-21a-5p and validated by luciferase gene reporter assays. Therapeutic silencing of miR-21a-5p in mice after allogenic kidney transplantation resulted in an amelioration of CAD, as indicated by a reduction in fibrosis development, inflammatory cell influx, tissue injury and BANFF lesion scoring. In a life-supporting model, miR-21a-5p antagonism had beneficial effects on kidney function. miR-21a-5p silencing may therefore be a viable therapeutic option in the treatment of patients following kidney transplantation to halt the development of CAD

Renal AAV2-Mediated Overexpression of Long Non-Coding RNA H19 Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p

BACKGROUND Renal ischemia-reperfusion (I/R) injury is a major cause of AKI. Noncoding RNAs are intricately involved in the pathophysiology of this form of AKI. Transcription of hypoxia-induced, long noncoding RNA H19, which shows high embryonic expression and is silenced in adults, is upregulated in renal I/R injury. METHODS Lentivirus-mediated overexpression, as well as antisense oligonucleotide-based silencing, modulated H19 in vitro. In vivo analyses used constitutive H19 knockout mice. In addition, renal vein injection of adeno-associated virus 2 (AAV2) carrying H19 caused overexpression in the kidney. Expression of H19 in kidney transplant patients with I/R injury was investigated. RESULTS H19 is upregulated in kidney biopsies of patients with AKI, in murine ischemic kidney tissue, and in cultured and ex vivo sorted hypoxic endothelial cells (ECs) and tubular epithelial cells (TECs). Transcription factors hypoxia-inducible factor 1-α, LHX8, and SPI1 activate H19 in ECs and TECs. H19 overexpression promotes angiogenesis in vitro and in vivo. In vivo, transient AAV2-mediated H19 overexpression significantly improved kidney function, reduced apoptosis, and reduced inflammation, as well as preserving capillary density and tubular epithelial integrity. Sponging of miR-30a-5p mediated the effects, which, in turn, led to target regulation of Dll4, ATG5, and Snai1. CONCLUSIONS H19 overexpression confers protection against renal injury by stimulating proangiogenic signaling. H19 overexpression may be a promising future therapeutic option in the treatment of patients with ischemic AKI