Paul Christian Schulze

Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.

Background— Although metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid metabolic regulation in the disease remains understudied. Methods and Results— Transcriptomic and metabolomic analyses were performed in mouse failing heart induced by pressure overload. Suppression of branched-chain amino acid (BCAA) catabolic gene expression along with concomitant tissue accumulation of branched-chain &agr;-keto acids was identified as a significant signature of metabolic reprogramming in mouse failing hearts and validated to be shared in human cardiomyopathy hearts. Molecular and genetic evidence identified the transcription factor Krüppel-like factor 15 as a key upstream regulator of the BCAA catabolic regulation in the heart. Studies using a genetic mouse model revealed that BCAA catabolic defect promoted heart failure associated with induced oxidative stress and metabolic disturbance in response to mechanical overload. Mechanistically, elevated branched-chain &agr;-keto acids directly suppressed respiration and induced superoxide production in isolated mitochondria. Finally, pharmacological enhancement of branched-chain &agr;-keto acid dehydrogenase activity significantly blunted cardiac dysfunction after pressure overload. Conclusions— BCAA catabolic defect is a metabolic hallmark of failing heart resulting from Krüppel-like factor 15–mediated transcriptional reprogramming. BCAA catabolic defect imposes a previously unappreciated significant contribution to heart failure.

Multibiomarker analysis in patients with acute myocardial infarction

Novel biomarkers representing different pathobiological pathways and their role in patients with acute myocardial infarction (AMI) were studied.

Arginase Inhibition Reverses Monocrotaline-Induced Pulmonary Hypertension

Pulmonary hypertension (PH) is a heterogeneous disorder associated with a poor prognosis. Thus, the development of novel treatment strategies is of great interest. The enzyme arginase (Arg) is emerging as important player in PH development. The aim of the current study was to determine the expression of ArgI and ArgII as well as the effects of Arg inhibition in a rat model of PH. PH was induced in 35 Sprague–Dawley rats by monocrotaline (MCT, 60 mg/kg as single-dose). There were three experimental groups: sham-treated controls (control group, n = 11), MCT-induced PH (MCT group, n = 11) and MCT-induced PH treated with the Arg inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA; MCT/NorNoha group, n = 13). ArgI and ArgII expression was determined by immunohistochemistry and Western blot. Right ventricular systolic pressure (RVPsys) was measured and lung tissue remodeling was determined. Induction of PH resulted in an increase in RVPsys (81 ± 16 mmHg) compared to the control group (41 ± 15 mmHg, p = 0.002) accompanied by a significant elevation of histological sum-score (8.2 ± 2.4 in the MCT compared to 1.6 ± 1.6 in the control group, p < 0.001). Both, ArgI and ArgII were relevantly expressed in lung tissue and there was a significant increase in the MCT compared to the control group (p < 0.01). Arg inhibition resulted in a significant reduction of RVPsys to 52 ± 19 mmHg (p = 0.006) and histological sum-score to 5.8 ± 1.4 compared to the MCT group (p = 0.022). PH leads to increased expression of Arg. Arg inhibition leads to reduction of RVPsys and diminished lung tissue remodeling and therefore represents a potential treatment strategy in PH.

Specifics of fetuin-A levels in distinct types of chronic heart failure

Fetuin‐A has been described to correlate inversely with vascular calcification both in animal models but also in patients with heart and renal disease. In this current study, we sought to investigate whether fetuin‐A might be a useful marker for the discrimination of ischemic (ICM) from dilated cardiomyopathy (DCM).

Increased Number of Mast Cells in Atherosclerotic Lesions Correlates with the Presence of Myeloid but not Plasmacytoid Dendritic Cells as well as Pro-inflammatory T Cells

BACKGROUNDnAtherosclerosis is an inflammatory disease of the vessel wall promoted by different immune cells and inflammatory mediators.nnnMETHODSnIn this study, 26 human plaques and 12 control vessels without atherosclerosis were immunohistochemically stained to analyze the emergence of mast cells dependent on plaque morphology and to correlate mast cell occurrence with the emergence of myeloid as well as plasmacytoid dendritic cells. Also, mast cell emergence was correlated with the number of pro-inflammatory T cells. For this, plaques were classified as stable or unstable according to established histological criteria.nnnRESULTSnAs expected, atherosclerotic lesions showed significantly higher numbers of tryptase+, chymase+, and cathepsin G+ mast cells compared to control vessels, particularly in lesions with unstable morphology. As a novel finding, we detected significant correlations between mast cells and myeloid dendritic cells (fascin, CD83, r > 0.3, p < 0.01), but not plasmacytoid dendritic cells (CD123, CD304). Also, we observed significant correlations of mast cells and different subgroups of pro-inflammatory T cells (CD3, CD8, CD161, CD25; r > 0.35, p < 0.05).nnnCONCLUSIONSnOverall, the higher number of mast cells in plaques, particularly with unstable morphology, suggests that mast cells might be involved in the progression of atherosclerosis. The correlation of mast cells with other immune cells that are pivotal in atherogenesis, e.g., myeloid dendritic cells and pro-inflammatory T cells, also suggests an interplay leading to plaque destabilization. Therefore, modulating local mast cell function and invasion into the plaque might be a therapeutic tool for plaque stabilization.

Insulin like growth factor binding protein 2 (IGFBP-2) for risk prediction in patients with severe aortic stenosis undergoing Transcatheter Aortic Valve Implantation (TAVI)

INTRODUCTIONnSevere aortic stenosis (AS) caused by degenerative calcification is the most frequent acquired valvular heart disease worldwide and mortality rates are considerably high. Transcatheter Aortic Valve Implantation (TAVI) is a well-established method for valve replacement in high risk patients with AS. However, there is a lack of reliable predictors for patients undergoing TAVI since commonly used scores were developed for surgical populations.nnnMATERIALS AND METHODSn208 patients subjected to TAVI were included in this study. Plasma samples were obtained before TAVI and were evaluated for IGFBP-2 using commercially available ELISA kits. IGFBP-2 levels were analyzed for their ability for risk prediction after TAVI.nnnRESULTSnIGFBP-2 levels measured before TAVI correlated significantly with left ventricular ejection fraction, EUROSCORE and other functional and prognostic parameters like the 6-minute walking test. When patients were retrospectively divided in two groups with a cut-off of serum IGFBP-2 levels of 275u202fng/ml, IGFBP-2 was a strong predictor for 30-day and one-year mortality (3% vs. 11%, pu202f=u202f0.05 and 18.2% vs. 46.2%; pu202f<u202f0.001 respectively). Compared to an EUROSCORE above 20 or an STS score cut-off above 8, IGFBP-2 plasma levels above 275u202fng/ml outperformed the established risk score for prediction of one-year mortality as assessed by NRI (0.65 95% CI 0.37-0.94; pu202f<u202f0.001 and 0.54 95% CI 0.25-0.82; pu202f<u202f0.001, respectively).nnnCONCLUSIONSnOur results indicate that IGFBP-2 could serve as new outcome predictor for patients undergoing TAVI procedure. By providing additional information to the commonly used EUROSCORE, IGFPB-2 analysis could further assist Heart Team decision making.

The Lactate/Albumin Ratio: A Valuable Tool for Risk Stratification in Septic Patients Admitted to ICU

The lactate/albumin ratio has been reported to be associated with mortality in pediatric patients with sepsis. We aimed to evaluate the lactate/albumin ratio for its prognostic relevance in a larger collective of critically ill (adult) patients admitted to an intensive care unit (ICU). A total of 348 medical patients admitted to a German ICU for sepsis between 2004 and 2009 were included. Follow-up of patients was performed retrospectively between May 2013 and November 2013. The association of the lactate/albumin ratio (cut-off 0.15) and both in-hospital and post-discharge mortality was investigated. An optimal cut-off was calculated by means of Youden’s index. The lactate/albumin ratio was elevated in non-survivors (p < 0.001). Patients with an increased lactate/albumin ratio were of similar age, but clinically in a poorer condition and had more pronounced laboratory signs of multi-organ failure. An increased lactate/albumin ratio was associated with adverse in-hospital mortality. An optimal cut-off of 0.15 was calculated and was associated with adverse long-term outcome even after correction for APACHE2 and SAPS2. We matched 99 patients with a lactate/albumin ratio >0.15 to case-controls with a lactate/albumin ratio <0.15 corrected for APACHE2 scores: The group with a lactate/albumin ratio >0.15 evidenced adverse in-hospital outcome in a paired analysis with a difference of 27% (95%CI 10–43%; p < 0.01). Regarding long-term mortality, again, patients in the group with a lactate/albumin ratio >0.15 showed adverse outcomes (p < 0.001). An increased lactate/albumin ratio was significantly associated with an adverse outcome in critically ill patients admitted to an ICU, even after correction for confounders. The lactate/albumin ratio might constitute an independent, readily available, and important parameter for risk stratification in the critically ill.

Increased Serum Levels of Fetal Tenascin-C Variants in Patients with Pulmonary Hypertension: Novel Biomarkers Reflecting Vascular Remodeling and Right Ventricular Dysfunction?

Pulmonary vascular remodeling is a pathophysiological feature that common to all classes of pulmonary hypertension (PH) and right ventricular dysfunction, which is the major prognosis-limiting factor. Vascular, as well as cardiac tissue remodeling are associated with a re-expression of fetal variants of cellular adhesion proteins, including tenascin-C (Tn-C). We analyzed circulating levels of the fetal Tn-C splicing variants B+ and C+ Tn-C in serum of PH patients to evaluate their potential as novel biomarkers reflecting vascular remodeling and right ventricular dysfunction. Serum concentrations of B+ and C+ Tn-C were determined in 80 PH patients and were compared to 40 healthy controls by enzyme-linked immunosorbent assay. Clinical, laboratory, echocardiographic, and functional data were correlated with Tn-C levels. Serum concentrations of both Tn-C variants were significantly elevated in patients with PH (p < 0.05). Significant correlations could be observed between Tn-C and echocardiographic parameters, including systolic pulmonary artery pressure (B+ Tn-C: r = 0.31, p < 0.001, C+ Tn-C: r = 0.26, p = 0.006) and right atrial area (B+ Tn-C: r = 0.46, p < 0.001, C+ Tn-C: r = 0.49, p < 0.001), and laboratory values like BNP (B+ Tn-C: r = 0.45, p < 0.001, C+ Tn-C: r = 0.42, p < 0.001). An inverse correlation was observed between Tn-C variants and 6-minute walk distance as a functional parameter (B+ Tn-C: r = −0.54, p < 0.001, C+ Tn-C: r = −0.43, p < 0.001). In a multivariate analysis, B+ Tn-C, but not C+ Tn-C, was found to be an independent predictor of pulmonary hypertension. Both fetal Tn-C variants may represent novel biomarkers that are capable of estimating both pulmonary vascular remodeling and right ventricular load. The potential beneficial impact of Tn-C variants for risk stratification in patients with PH needs further investigation.

Extravascular lung water index and Halperin score to predict outcome in critically ill patients

SummaryObjectiveThe aim of this study was to describe real world extravascular lung water index (EVLWI) measurements obtained by pulse index continuous cardiac output (PiCCO) on the day of admission. These were then related to axa0radiologic score for lung edema, Halperin score and both the Halperin score and EVLWI were assessed for prediction of in-hospital mortality in critically ill patients.Methods and resultsA total of 311 patients admitted to axa0tertiary medical university hospital between February 2004 and December 2010 were included in this retrospective analysis and of these 177 patients were intubated. In-hospital mortality was assessed by logistic regression. In the overall cohort, EVLWI and the Halperin score correlated poorly (ru202f=u20090.17; pu202f=u20090.02). In intubated patients, EVLWI and Halperin score did not correlate (ru202f=u20090.09; pu202f=u20090.39), whereas in patients who were not intubated there was axa0moderate association (ru202f=u20090.30; pu202f=u20090.007).In the overall cohort, (a)xa0EVLWI (hazard ratio [HR]xa01.10, 95% confidence interval [CI] 1.02–1.19; pu202f=u20090.01; area under the curve [AUC]xa00.63, 95% CI 0.54–0.71) but not (b)xa0Halperin score (HRxa01.00, 95% CI 0.996–1.004; pu202f=u20090.94; AUCxa00.52, 95% CI 0.45–0.58) was associated with in-hospital mortality There was axa0robust association of EVLWI (HRxa01.12, 95% CI 1.01–1.25; pu202f=u20090.03) but not Halperin score (HRxa01.003, 95% CI 0.997–1.009; pu202f=u20090.30) with mortality in non-intubated patients. In intubated patients, neither EVLWI (HRxa00.997 95% CI 0.990–1.003; pu202f=u20090.33) nor Halperin score (HRxa01.08; 95% CI 0.88–1.32; pu202f=u20090.47) was associated with mortality.ConclusionThe EVLWI correlated moderately with axa0radiologic score for lung edema, the Halperin score, in non-intubated but not in intubated patients. The EVLWI at admission was associated with in-hospital mortality in our patient collective of critically ill patients and might constitute not only axa0tool for risk stratification but most importantly axa0valuable treatment goal.

What’s new in heart failure therapy 2018?

Even though significant progress has been made over the past 3 decades, heart failure remains one of the leading causes of mortality and morbidity in developed countries and contributes significantly to the economic burden of modern health care systems. Especially in patients with preserved ejection fraction, valid therapeutic options are missing due to a lack of evidence. In face of a very heterogeneous condition with an ongoing debate over aetiology and pathophysiology, clinicians face a challenge in providing optimal care for these patients. Recent data suggest that the optimal treatment of the underlying conditions as well as comorbidities that are associated with heart failure might play an ever increasing role in improving outcomes. This focused review summarizes and reviews current data for the treatment of heart failure with both preserved and reduced ejection fractions based on the latest recommendations covering medical therapy and interventional strategies.