Comparison of transcatheter aortic valve implantation with other approaches to treat aortic valve stenosis: a systematic review and meta-analysis

Abstract Background 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. Methods 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. Results 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). Conclusions Given similar mortality risks but different patterns of adverse events, the choice between TAVI and SAVR remains an individual one

The inflammation‐based modified Glasgow prognostic score is associated with survival in stable heart failure patients

Abstract Aims The progression of heart failure is presumably dependent on the individual inflammatory host response. The combination of the inflammatory markers, albumin, and C‐reactive protein, termed modified Glasgow prognostic score (mGPS), has been derived from cancer patients and validated in multiple cohorts. This study aimed to investigate the impact of the easily available mGPS on survival of stable patients with heart failure with reduced ejection fraction (HFrEF). Methods and results Patients with stable HFrEF undergoing routine ambulatory care between January 2011 and November 2017 have been identified from a prospective registry at the Medical University of Vienna. Comorbidities, laboratory data as well as the nutritional risk index at baseline were assessed. All‐cause mortality was defined as the primary study end point. The mGPS was calculated, and its association with heart failure severity and impact on overall survival were determined. Data were analysed for a total of 443 patients. The mGPS was 0 for 352 (80%), 1 for 76 (17%), and 2 for 14 (3%) patients, respectively. Elevation of mGPS was associated with worsening of routine laboratory parameters linked to prognosis, especially NT‐proBNP [median 1830 pg/mL (IQR 764–3455) vs. 4484 pg/mL (IQR 1565–8003) vs. 6343 pg/mL (IQR 3750–15401) for mGPS 0, 1, and 2, respectively; P < 0.001] and nutritional risk index. In the Cox regression analysis, the increase of mGPS was associated with adverse outcome in the univariate analysis [crude hazard ratio 3.00 (95% CI 2.14–4.21), P < 0.001] and after adjustment for multiple covariates as age, gender, body mass index, and glomerular filtration rate as well as heart failure severity reflected by NT‐proBNP and New York Heart Association class [adj. hazard ratio 1.87 (95% CI 1.19–2.93), P = 0.006]. Conclusions Enhanced inflammation and nutritional depletion are more common in advanced heart failure. The inflammation‐based score mGPS predicts survival in HFrEF patients independently of NT‐proBNP emphasizing the significance of the individual pro‐inflammatory response on prognosis

Parameters associated with therapeutic response using peritoneal dialysis for therapy refractory heart failure and congestive right ventricular dysfunction.

BACKGROUND:In patients with refractory heart failure (HF) peritoneal dialysis (PD) is associated with improved functional status and decrease in hospitalization. However, previous studies did not focus on right ventricular dysfunction as an important pathophysiologic component of cardiorenal syndrome. METHODS:In a prospective cohort study PD was started in 40 patients with refractory right HF (with/without left HF). Refractoriness to conservative therapy was defined as persistent right heart congestion/ascites with intensified diuretic treatment and/or ≥2 hospitalizations within 6 months because of cardiac decompensation despite optimal medical treatment, and/or acute renal failure during intensified conservative treatment of cardiac decompensations. RESULTS:Patient survival was 55.0% at 1 year, 35.0% at 2 years and 27.5% at 3 years. The number of hospitalization days declined after initiation of PD for both cardiac [13 (IQR 1-53) days before vs. 1 (IQR 0-12) days after start of PD, p<0.001] and unplanned reasons [12 (IQR 3-44) days before vs. 1 (IQR 0-33) days after start of PD, p = 0.007]. Using a combined endpoint including survival time of ≥1 year and either improvement in quality of life or decline in hospitalizations we found that patients with extended ascites, higher systolic pulmonary artery pressure, more marked impairment of right ventricular function and tricuspid valve insufficiency, higher residual renal function as well as those who could perform PD without assistance have benefited most from this therapy. CONCLUSIONS:Patients with more pronounced backward failure, less marked residual renal functional impairment and those not depending on assistance for therapy are likely to profit most from PD

Neprilysin inhibition does not alter dynamic of proenkephalin‐A 119‐159 and pro‐substance P in heart failure

Abstract Aims As NEP degrades many substrates, the specific therapeutic mechanism of NEP inhibition with angiotensin receptor neprilysin inhibitor (ARNi) in heart failure with reduced ejection fraction (HFrEF) is not entirely evident. The aim of this study was to investigate the response of two substrates of NEP—the tachykinin and enkephalin systems—to the initiation of ARNi therapy in HFrEF. Methods and results Between 2016 and 2018, 141 consecutive patients with stable HFrEF [74 with initiation of ARNi and 67 controls on continuous angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy] were prospectively enrolled. Plasma proenkephalin‐A 119‐159 (PENK) and pro‐substance P (pro‐SP) were serially determined. Proenkephalin‐A 119‐159 and pro‐SP correlated strongly with each other (rs = 0.67, P  0.05 between groups). Conclusions Although enkephalins and SP are known substrates of NEP, NEP inhibition by ARNi does not clearly affect the circulating precursors PENK and pro‐SP in HFrEF

Natural history of functional tricuspid regurgitation : implications of quantitative doppler assessment

OBJECTIVES This study sought to define the relationship between functional tricuspid regurgitation (TR) and mortality in patients with heart failure with reduced ejection fraction (HFrEF); and to establish the prognostic value of quantitative measures of TR severity (i.e., effective regurgitant orifice area [EROA] and regurgitant volume). BACKGROUND The significance of TR in chronic heart failure is controversial. Earlier studies have shown an independent impact of TR on mortality, whereas more recent evidence suggests myocardial impairment to be the driving force of mortality rather than TR itself. Earlier studies have used qualitative measures of TR severity, hence the prognostic value of more quantitative measures of TR severity (i.e., EROA and regurgitant volumes) remains unclear. METHODS We enrolled 382 patients with HFrEF on guideline-directed medical therapy and assessed TR EROA and regurgitant volume by Doppler/2-dimensional echocardiography. All-cause mortality was defined as the primary study endpoint. RESULTS TR severity was associated with the HFrEF phenotype with more symptoms (p = 0.004), higher neurohumoral activation (p = 0.2 cm(2), and the regurgitant volume >= 20 ml with sustained excess mortality thereafter. CONCLUSIONS This large-scale outcome study demonstrates the prognostic value of quantitative Doppler-echocardiographic measures of TR severity in HFrEF. The thresholds for EROA and TR regurgitant volume associated with mortality in our study fall within current ranges defining nonsevere TR. This may potentially impact therapeutic decision making, particularly timing of intervention. (C) 2019 by the American College of Cardiology Foundation

An Integrated Imaging and Circulating Biomarker Approach for Secondary Tricuspid Regurgitation

Secondary tricuspid regurgitation (sTR) is frequent among patients with heart failure with reduced ejection fraction (HFrEF), however it confers considerable diagnostic challenges. The assessment of neurohumoral activation may constitute a valuable supplement to the current imaging-based diagnostic process. This study sought to investigate the expression of complementary biomarkers in sTR and to evaluate the effectiveness of integrating their assessment into the diagnostic process. We enrolled 576 HFrEF patients recording echocardiographic and biochemical measurements, i.e., N-terminal pro-B-type natriuretic peptide, mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin, C-terminal pro-endothelin-1 (CT-pro-ET1), and copeptin. Plasma levels of the aforementioned neurohormones were significantly elevated with increasing sTR severity (p &lt; 0.001 for all). CT-pro-ET1 and MR-proANP were the closest related to severe sTR (adj. OR 1.46; 95%CI 1.11&ndash;1.91, p = 0.006 and adj. OR 1.45, 95%CI 1.13&ndash;1.87, p = 0.004, respectively). In patients with moderate-to-severe sTR, adding selected biomarkers (i.e., CT-pro-ET1 and MR-proANP) resulted in a substantial improvement in the discriminatory power regarding long-term mortality (C-statistic: 0.54 vs. 0.65, p &lt; 0.001; continuous NRI 57%, p &lt; 0.001). Circulating biomarkers closely relate to sTR severity and correlate with hemodynamic and morphologic mechanisms of sTR. Specifically, MR-proANP and CT-pro-ET1 are closely linked to the presence of severe sTR, and a combined assessment with the guideline recommended echocardiographic grading significantly improves individual risk stratification

Relevance of Neutrophil Neprilysin in Heart Failure

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 &lt; 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 &lt; 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

European Journal of Clinical Investigation / GDF15 in solid vs nonsolid treatmentnaïve malignancies

Aim GDF15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF15 to other cardiac biomarkers and the general association of GDF15 on prognosis in an unselected cohort of treatmentnaïve cancer patients. Methods We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF15 concentrations were determined alongside other cardiac and routine laboratory markers. Allcause mortality was defined as primary endpoint. Results GDF15 levels were 338 ng/L (IQR:205534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF15 [435 ng/L (IQR:279614) vs 266 ng/L (IQR:175427), P < .001]. GDF15 correlated positively with inflammatory status reflected by CRP, SAA and IL6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NTproBNP, hsTnT, MRproADM and CTproET1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF15 was significantly associated with allcause mortality after multivariate adjustment [adj.HR for ln(GDF15) 1.78, 95%CI:1.472.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF15 with outcome in myelodysplastic and myeloproliferative disease. Conclusions Elevated plasma GDF15 is associated with progressing disease severity and poor prognosis in solid tumours of treatmentnaïve cancer patients. GDF15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF15 represents a promising target for our pathophysiologic understanding in cardiooncology linking conditions of both cardiac and neoplastic disease.(VLID)510161

Principal morphomic and functional components of secondary mitral regurgitation

Objectives: The aim of this work was to identify the key morphological and functional features in secondary mitral regurgitation (sMR) and their prognostic impact on outcome. Background: Secondary sMR in patients with heart failure and reduced ejection fraction typically results from distortion of the underlying cardiac architecture. The morphological components which may account for the clinical impact of sMR have not been systematically assessed or correlated with clinical outcomes. Methods: Morphomic and functional network profiling were performed on a cohort of patients with stable heart failure optimized on guideline-based medical therapy. Principal component (PC) analysis and subsequent cluster analysis were used to condense the morphomic and functional data first into PCs with varimax rotation (PCVmax) and second into homogeneous clusters. Clusters and PCs were tested for their correlations with clinical outcomes. Results: Morphomic and functional data from 383 patients were profiled and subsequently condensed into PCs. PCVmax 1 describes high loadings of left atrial morphological information, and PCVmax 2 describes high loadings of left ventricular (LV) topology. Based on these components, 4 homogeneous clusters were derived. sMR was most prominent in clusters 3 and 4, with the morphological difference being left ventricular size (median end-diastolic volume 188 mL [interquartile range: 160 mL-224 mL] vs 315 mL [264 mL-408 mL]; P &lt; 0.001). Clusters were associated with mortality (P &lt; 0.001), but sMR remained independently associated with mortality after adjusting for the clusters (adjusted HR: 1.42; 95% CI: 1.14–1.77; P &lt; 0.01). The detrimental association of sMR with mortality was mainly driven by cluster 3 (HR: 2.18; 95% CI: 1.32-3.60; P = 0.002), the “small LV cavity” phenotype. Conclusions: These results challenge the current perceptions that sMR in heart failure with reduced ejection fraction results exclusively from global or local LV remodeling and are suggestive of a potential role of the left atrial component. The association of sMR with mortality cannot be purely attributed to cardiac morphology alone, supporting other complementary key aspects of mitral valve closure consistent with the force balance theory. Unsupervised clustering supports the association of sMR with mortality predominantly driven by the small LV cavity phenotype, as previously suggested by a conceptional framework and termed disproportionate sMR