Factors associated with disease progression in early-diagnosed pulmonary arterial hypertension associated with systemic sclerosis: longitudinal data from the DETECT cohort

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc). In this longitudinal study, we aimed to identify factors associated with an unfavourable outcome in patients with SSc with early PAH (SSc-PAH) from the DETECT cohort. METHODS: Patients with SSc-PAH enrolled in DETECT were observed for up to 3 years. Associations between cross-sectional variables and disease progression (defined as the occurrence of any of the following events: WHO Functional Class worsening, combination therapy for PAH, hospitalisation or death) were analysed by univariable logistic regression. RESULTS: Of 57 patients with PAH (median observation time 12.6 months), 25 (43.9%) had disease progression. The following factors (OR (95% CI)) were associated with disease progression: male gender (4.1 (1.2 to 14.1)), high forced vital capacity % predicted/carbon monoxide lung diffusion capacity (DLCO)% predicted ratio (3.6 (1.2 to 10.7)), high Borg Dyspnoea Index (1.7 (1.1 to 2.6)) and low DLCO% predicted (non-linear relationship). CONCLUSION: More than 40% of early-diagnosed patients with SSc-PAH had disease progression during a short follow-up time, with male gender, functional capacity and pulmonary function tests at PAH diagnosis being associated with progression. This suggests that even mild PAH should be considered a high-risk complication of SSc

Heart Failure with Preserved and Reduced Ejection Fraction in Hemodialysis Patients: Prevalence, Disease Prediction and Prognosis

Background/Aims: Heart failure (HF) is a main cause of mortality of hemodialysis (HD) patients. While HF with reduced ejection fraction (HFrEF) is known to only affect a minority of patients, little is known about the prevalence, associations with clinical characteristics and prognosis of HF with preserved ejection fraction (HFpEF). Methods: We included 105 maintenance HD patients from the Medical University of Vienna into this prospective single-center cohort study and determined the prevalence of HFpEF (per the 2013 criteria of the European Society of Cardiology) and HFrEF (EF <45%), using standardized post-HD transthoracic echocardiography. We also assessed clinical, laboratory and volume status parameters (by bioimpedance spectroscopy). These parameters served to calculate prediction models for both disease entities, while clinical outcomes (frequency of cardiovascular hospitalizations and/or cardiac death) were assessed prospectively over 27±4 months of follow-up. Results: All but 4 patients (96%) had evidence of diastolic dysfunction. 70% of the entire cohort fulfilled HF criteria (81% HFpEF, 19% HFrEF). Age, female sex, body mass index, blood pressure and dialysis vintage were predictive of HFpEF (sensitivity 86%, specificity 63%; AUC 0.87), while age, female sex, NT pro-BNP, history of coronary artery disease and atrial fibrillation were predictive of HFrEF (sensitivity 85%, specificity 90%; AUC 0.95). Compared to patients without HF, those with HFpEF and HFrEF had a higher risk of hospitalization for cardiovascular reason and/or cardiac death (adjusted HR 4.31, 95% CI 0.46-40.03; adjusted HR 3.24, 95% CI 1.08-9.75, respectively). Conclusion: Diastolic dysfunction and HFpEF are highly prevalent in HD patients while HFrEF only affects a minority. Distinct patient-specific characteristics predict diagnosis of either entity with good accuracy

Fluid overload in hemodialysis patients: a cross-sectional study to determine its association with cardiac biomarkers and nutritional status

Abstract Background Chronic fluid overload is associated with higher mortality in dialysis patients; however, the link with cardiovascular morbidity has not formally been established and may be influenced by subclinical inflammation. We hypothesized that a relationship exists between fluid overload and [i] cardiovascular laboratory parameter as well as between fluid overload and [ii] inflammatory laboratory parameters. In addition, we aimed to confirm whether volume status correlates with nutritional status. Methods We recorded baseline characteristics of 244 hemodialysis patients at three hemodialysis facilities in Vienna (Austria) and determined associations with volume measurements using the body composition monitor (Fresenius/Germany). In one facility comprising 126 patients, we further analyzed cardiovascular, inflammatory and nutritional parameters. Results We detected predialysis fluid overload (FO) in 39% of all patients (n = 95) with FO defined as ≥15% of extracellular water (ECW). In this subgroup, the absolute FO was 4.4 +/-1.5 L or 22.9 ± 4.8% of ECW. A sub-analysis of patients from one center showed that FO was negatively associated with body mass index (r = -0.371; p = &lt;0.001), while serum albumin was significantly lower in fluid overloaded patients (p = 0.001). FO was positively associated with D-Dimer (r = 0.316; p = 0.001), troponin T (r = 0.325; p &lt; 0.001), and N-terminal pro-B-type natriuretic peptide (r = 0.436; p &lt; 0.001), but not with investigated inflammatory parameters. Conclusions Fluid overload in HD patients was found to be lower in patients with high body mass index, indicating that dry weight was inadequately prescribed and/or difficult to achieve in overweight patients. The association with parameters of cardiovascular compromise and/or damage suggests that fluid overload is a biomarker for cardiovascular risk. Future studies should determine if this applies to patients prior to end-stage renal disease. </jats:sec

Aortic stiffness in aortic stenosis assessed by cardiovascular MRI: a comparison between bicuspid and tricuspid valves

Objectives To compare aortic size and stiffness parameters on MRI between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) patients with aortic stenosis (AS). Methods MRI was performed in 174 patients with asymptomatic moderate-severe AS (mean AVAI 0.57 ± 0.14 cm2/m2) and 23 controls on 3T scanners. Valve morphology was available/analysable in 169 patients: 63 BAV (41 type-I, 22 type-II) and 106 TAV. Aortic cross-sectional areas were measured at the level of the pulmonary artery bifurcation. The ascending and descending aorta (AA, DA) distensibility, and pulse wave velocity (PWV) around the aortic arch were calculated. Results The AA and DA areas were lower in the controls, with no difference in DA distensibility or PWV, but slightly lower AA distensibility than in the patient group. With increasing age, there was a decrease in distensibility and an increase in PWV. After correcting for age, the AA maximum cross-sectional area was higher in bicuspid vs. tricuspid patients (12.97 [11.10, 15.59] vs. 10.06 [8.57, 12.04] cm2, p < 0.001), but there were no significant differences in AA distensibility (p = 0.099), DA distensibility (p = 0.498) or PWV (p = 0.235). Patients with BAV type-II valves demonstrated a significantly higher AA distensibility and lower PWV compared to type-I, despite a trend towards higher AA area. Conclusions In patients with significant AS, BAV patients do not have increased aortic stiffness compared to those with TAV despite increased ascending aortic dimensions. Those with type-II BAV have less aortic stiffness despite greater dimensions. These results demonstrate a dissociation between aortic dilatation and stiffness and suggest that altered flow patterns may play a role. Key Points • Both cellular abnormalities secondary to genetic differences and abnormal flow patterns have been implicated in the pathophysiology of aortic dilatation and increased vascular complications associated with bicuspid aortic valves (BAV). • We demonstrate an increased ascending aortic size in patients with BAV and moderate to severe AS compared to TAV and controls, but no difference in aortic stiffness parameters, therefore suggesting a dissociation between dilatation and stiffness. • Sub-group analysis showed greater aortic size but lower stiffness parameters in those with BAV type-II AS compared to BAV type-I

Anticoagulants and the Propagation Phase of Thrombin Generation

The view that clot time-based assays do not provide a sufficient assessment of an individual's hemostatic competence, especially in the context of anticoagulant therapy, has provoked a search for new metrics, with significant focus directed at techniques that define the propagation phase of thrombin generation. Here we use our deterministic mathematical model of tissue-factor initiated thrombin generation in combination with reconstructions using purified protein components to characterize how the interplay between anticoagulant mechanisms and variable composition of the coagulation proteome result in differential regulation of the propagation phase of thrombin generation. Thrombin parameters were extracted from computationally derived thrombin generation profiles generated using coagulation proteome factor data from warfarin-treated individuals (N = 54) and matching groups of control individuals (N = 37). A computational clot time prolongation value (cINR) was devised that correlated with their actual International Normalized Ratio (INR) values, with differences between individual INR and cINR values shown to derive from the insensitivity of the INR to tissue factor pathway inhibitor (TFPI). The analysis suggests that normal range variation in TFPI levels could be an important contributor to the failure of the INR to adequately reflect the anticoagulated state in some individuals. Warfarin-induced changes in thrombin propagation phase parameters were then compared to those induced by unfractionated heparin, fondaparinux, rivaroxaban, and a reversible thrombin inhibitor. Anticoagulants were assessed at concentrations yielding equivalent cINR values, with each anticoagulant evaluated using 32 unique coagulation proteome compositions. The analyses showed that no anticoagulant recapitulated all features of warfarin propagation phase dynamics; differences in propagation phase effects suggest that anticoagulants that selectively target fXa or thrombin may provoke fewer bleeding episodes. More generally, the study shows that computational modeling of the response of core elements of the coagulation proteome to a physiologically relevant tissue factor stimulus may improve the monitoring of a broad range of anticoagulants

Hemodynamic predictors of aortic dilatation in bicuspid aortic valve by velocity-encoded cardiovascular magnetic resonance

<p>Abstract</p> <p>Background</p> <p>Congenital Bicuspid Aortic Valve (BAV) is a significant risk factor for serious complications including valve dysfunction, aortic dilatation, dissection, and sudden death. Clinical tools for identification and monitoring of BAV patients at high risk for development of aortic dilatation, an early complication, are not available.</p> <p>Methods</p> <p>This paper reports an investigation in 18 pediatric BAV patients and 10 normal controls of links between abnormal blood flow patterns in the ascending aorta and aortic dilatation using velocity-encoded cardiovascular magnetic resonance. Blood flow patterns were quantitatively expressed in the angle between systolic left ventricular outflow and the aortic root channel axis, and also correlated with known biochemical markers of vessel wall disease.</p> <p>Results</p> <p>The data confirm larger ascending aortas in BAV patients than in controls, and show more angled LV outflow in BAV (17.54 ± 0.87 degrees) than controls (10.01 ± 1.29) (p = 0.01). Significant correlation of systolic LV outflow jet angles with dilatation was found at different levels of the aorta in BAV patients STJ: r = 0.386 (N = 18, p = 0.048), AAO: r = 0.536 (N = 18, p = 0.022), and stronger correlation was found with patients and controls combined into one population: SOV: r = 0.405 (N = 28, p = 0.033), STJ: r = 0.562 (N = 28, p = 0.002), and AAO r = 0.645 (N = 28, p < 0.001). Dilatation and the flow jet angle were also found to correlate with plasma levels of matrix metallo-proteinase 2.</p> <p>Conclusions</p> <p>The results of this study provide new insights into the pathophysiological processes underlying aortic dilatation in BAV patients. These results show a possible path towards the development of clinical risk stratification protocols in order to reduce morbidity and mortality for this common congenital heart defect.</p

Effect of ejection fraction on clinical outcomes in patients treated with omecamtiv mecarbil in GALACTIC-HF

Background: In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) (n = 8,256), the cardiac myosin activator, omecamtiv mecarbil, significantly reduced the primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death in patients with heart failure and reduced ejection fraction (EF) (≤35%). Objectives: The purpose of this study was to evaluate the influence of baseline EF on the therapeutic effect of omecamtiv mecarbil. Methods: Outcomes in patients treated with omecamtiv mecarbil were compared with placebo according to EF. Results: The risk of the PCE in the placebo group was nearly 1.8-fold greater in the lowest EF (≤22%) compared with the highest EF (≥33%) quartile. Amongst the pre-specified subgroups, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the PCE (interaction as continuous variable, p = 0.004). Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute treatment effect as baseline EF decreased, with a 17% relative risk reduction for the PCE in patients with baseline EF ≤22% (n = 2,246; hazard ratio: 0.83; 95% confidence interval: 0.73 to 0.95) compared with patients with EF ≥33% (n = 1,750; hazard ratio: 0.99; 95% confidence interval: 0.84 to 1.16; interaction as EF by quartiles, p = 0.013). The absolute reduction in the PCE increased with decreasing EF (EF ≤22%; absolute risk reduction, 7.4 events per 100 patient-years; number needed to treat for 3 years = 11.8), compared with no reduction in the highest EF quartile. Conclusions: In heart failure patients with reduced EF, omecamtiv mecarbil produced greater therapeutic benefit as baseline EF decreased. These findings are consistent with the drug’s mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients at greatest risk. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329