Transcatheter aortic valve replacement (TAVI) is an alternative treatment for patients with symptomatic severe aortic stenosis ineligible for surgical aortic valve replacement (SAVR) or at increased perioperative risk. Due to continually emerging evidence, we performed a systematic review and meta-analysis comparing benefits and harms of TAVI, SAVR, medical therapy, and balloon aortic valvuloplasty. We searched MEDLINE, Embase, and Cochrane CENTRAL from 2002 to June 6, 2017. We dually screened abstracts and full-text articles for randomized controlled trials (RCTs) and propensity score-matched observational studies. Two investigators independently rated the risk of bias of included studies and determined the certainty of evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). If data permitted, we performed meta-analyses using random- and fixed-effects models. Out of 7755 citations, we included six RCTs (5862 patients) and 13 observational studies (6376 patients). In meta-analyses, patients treated with SAVR or TAVI had similar risks for mortality at 30 days (relative risk [RR] 1.05; 95% confidence interval [CI] 0.82 to 1.33) and 1 year (RR 1.02; 95% CI 0.93 to 1.13). TAVI had significantly lower risks for major bleeding but increased risks for major vascular complications, moderate or severe paravalvular aortic regurgitation, and new pacemaker implantation compared to SAVR. Comparing TAVI to medical therapy, mortality did not differ at 30 days but was significantly reduced at 1 year (RR 0.51; 95% CI 0.34 to 0.77). Given similar mortality risks but different patterns of adverse events, the choice between TAVI and SAVR remains an individual one.

Aim: GDF‐15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF‐15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF‐15 to other cardiac biomarkers and the general association of GDF‐15 on prognosis in an unselected cohort of treatment‐naïve cancer patients.Methods: We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF‐15 concentrations were determined alongside other cardiac and routine laboratory markers. All‐cause mortality was defined as primary endpoint.Results: GDF‐15 levels were 338 ng/L (IQR:205‐534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF‐15 [435 ng/L (IQR:279‐614) vs 266 ng/L (IQR:175‐427), P < .001]. GDF‐15 correlated positively with inflammatory status reflected by CRP, SAA and IL‐6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT‐proBNP, hsTnT, MR‐proADM and CT‐proET‐1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF‐15 was significantly associated with all‐cause mortality after multivariate adjustment [adj.HR for ln(GDF‐15) 1.78, 95%CI:1.47‐2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF‐15 with outcome in myelodysplastic and myeloproliferative disease.Conclusions: Elevated plasma GDF‐15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment‐naïve cancer patients. GDF‐15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF‐15 represents a promising target for our pathophysiologic understanding in cardio‐oncology linking conditions of both cardiac and neoplastic disease.

Background: Neutrophils are critically involved in the immune response. Inflammatory stimuli alter the expression status of their surface molecule toolset, while inflammation-stimulated granulopoiesis might also influence their maturation status. Data on neutrophil status in heart failure with reduced ejection fraction (HFrEF) are scarce. The present study aims to evaluate the role of neutrophil CD11b, CD66b and CD64 expression in HFrEF. Methods: A total of 135 HFrEF patients and 43 controls were recruited. Mean fluorescence intensity of the activation/maturation markers CD11b, CD66b and CD64 was measured on neutrophils by flow cytometry. CD10 (neprilysin) expression was simultaneously determined. Results: Neutrophil CD64 expression was higher in HFrEF compared with controls, while CD11b/CD66b levels were similar. Neutrophil CD11b and CD66b showed a significant direct correlation to neutrophil CD10 expression (rs = 0.573, p < 0.001 and rs = 0.184, p = 0.033). Neutrophil CD11b and CD66b correlated inversely with heart failure severity reflected by NT-proBNP and NYHA class (NT-proBNP: rs = −0.243, p = 0.005 and rs = −0.250, p = 0.004; NYHA class: p = 0.032 and p = 0.055), whereas no association for CD64 could be found. Outcome analysis did not reveal a significant association between the expression of CD11b, CD66b and CD64 and all-cause mortality (p = ns). Conclusions: The results underline the potential role of neutrophils in HFrEF disease pathophysiology and risk stratification and should stimulate further research, characterizing subpopulations of neutrophils and searching for key molecules involved in the downward spiral of inflammation and heart failure.

Aims: The clinically investigated rationale for neprilysin (NEP)‐inhibition by angiotensinreceptor‐NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi.Methods: Seventy‐four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin‐converting‐enzyme inhibitor(ACEi)/angiotensin‐receptor blocker (ARB) therapy served as control. Plasma bioactive‐ADM (bio‐ADM), mid‐regional‐pro‐ADM (MR‐proADM), B‐typenatriuretic peptide (BNP) and N‐terminal‐pro‐BNP (NT‐proBNP) were determined at baseline, short‐term, 1‐year and 2‐year follow up.Results: Following ARNi initiation both bio‐ADM and MR‐proADM concentrations were significantly increased at early and long‐term follow up (bio‐ADM [pg/mL]: 26.0 [interquartile range {IQR}: 17.7–37.5] vs. 50.8 [IQR: 36.5–78.1] vs. 54.6 [IQR: 42.0–97.1] vs. 57.4 [IQR: 48.5–161.6]; MR‐proADM [nmol/L]: 0.87 [IQR: 0.64–1.12] vs. 1.25 [IQR: 0.93–1.79] vs. 1.42 [IQR: 0.95–1.90] vs. 1.60 [IQR: 1.12–2.46], P < .0001 for all). The ratios bio‐ADM/MR‐proADM and BNP/NT‐proBNP increased during ARNi‐therapy proving improved availability of bioactive peptides. The proportional increase of bio‐ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin–angiotensin system blocker therapy, i.e. ACEi or ARB (P > .05 for all), indicating that activation of the ADM‐axis arises particularly from NEPinhibition.Conclusion: The significant increase of MR‐proADM and bio‐ADM together with an elevated bioADM/MR‐proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM‐axis represents a so far unrecognized effect of ARNi.

Significant expression of neprilysin (NEP) is found on neutrophils, which present the transmembrane integer form of the enzyme. This study aimed to investigate the relationship of neutrophil transmembrane neprilysin (mNEP) with disease severity, adverse remodeling, and outcome in HFrEF. In total, 228 HFrEF, 30 HFpEF patients, and 43 controls were enrolled. Neutrophil mNEP was measured by flow-cytometry. NEP activity in plasma and blood cells was determined for a subset of HFrEF patients using mass-spectrometry. Heart failure (HF) was characterized by reduced neutrophil mNEP compared to controls (p < 0.01). NEP activity on peripheral blood cells was almost 4-fold higher compared to plasma NEP activity (p = 0.031) and correlated with neutrophil mNEP (p = 0.006). Lower neutrophil mNEP was associated with increasing disease severity and markers of adverse remodeling. Higher neutrophil mNEP was associated with reduced risk for mortality, total cardiovascular hospitalizations, and the composite endpoint of both (p < 0.01 for all). This is the first report describing a significant role of neutrophil mNEP in HFrEF. The biological relevance of neutrophil mNEP and exact effects of angiotensin-converting-enzyme inhibitors (ARNi) at the neutrophil site have to be determined. However, the results may suggest early initiation of ARNi already in less severe HF disease, where effects of NEP inhibition may be more pronounced.

Background: Secondary mitral regurgitation (sMR) drives adverse cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF). Progression in severity over time contributes to a transition towards more advanced HF stages. Early identification of patients at risk for sMR progression remains challenging. We therefore sought to assess a broad spectrum of neurohumoral biomarkers in patients with HFrEF to explore their ability to predict progression of sMR.Methods: A total of 249 HFrEF patients were enrolled. Biomarkers encompassing key neurohumoral pathways in heart failure were sampled at baseline, and sMR progression was assessed over 3 years of follow‐up.Results: Of 191 patients with nonsevere sMR at baseline, 18% showed progressive sMR within three years after study enrolment. Progression of sMR was associated with higher levels of MR‐proADM (adj.OR 2.25, 95% CI 1.29‐3.93; P = .004), MR‐proANP (adj.OR 1.84, 95% CI 1.14‐3.00; P = .012), copeptin (adj.OR 1.66, 95% CI 1.04‐2.67; P = .035) and CT‐pro‐ET1 (adj.OR 1.68, 95% CI 1.06‐2.68; P = .027) but not with NT‐proBNP (P = .54).Conclusion: Increased plasma levels of neurohumoral cardiac biomarkers are predictors of sMR progression in patients with HFrEF and add easily available incremental prognostic information for risk stratification. Importantly, NT‐proBNP was not useful to predict progressive sMR in the present analysis. On the contrary, MR‐proANP, primarily produced in the atria, copeptin partly triggered by intra‐cardiac and intra‐arterial pressures and MR‐proADM, a marker of forward failure and peripheral released vasoactive CT‐proET1, increase based on a progressive loading burden by sMR and may thus serve as better predictors of sMR progression.