Tafamidis treatment delays structural and functional changes of the left ventricle in patients with transthyretin amyloid cardiomyopathy.

AIMS: Tafamidis improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, it is not yet known whether tafamidis affects cardiac amyloid deposition and structural changes in the myocardium. We aimed to determine disease-modifying effects on myocardial amyloid progression and to identify imaging parameters that could be applied for specific therapy monitoring. METHODS AND RESULTS: ATTR-CM patients underwent serial cardiac magnetic resonance (CMR) imaging using T1 mapping techniques to derive extracellular volume (ECV). Patients receiving tafamidis 61 mg (n = 35) or 20 mg (n = 15) once daily showed stable measurements at follow-up (FU) {61 mg: 9.0 [interquartile range (IQR) 7.0-11.0] months, 20 mg: 11.0 (IQR 8.0-18.0) months} in left ventricular (LV) ejection fraction (LVEF; 61 mg: 47.6% vs. 47.5%, P = 0.935; 20 mg: 52.4% vs. 52.1%, P = 0.930), LV mass index (LVMI; 61 mg: 110.2 vs. 106.2 g/m2, P = 0.304; 20 mg: 114.5 vs. 115.4 g/m2, P = 0.900), and ECV (61 mg: 47.5% vs. 47.7%, P = 0.861; 20 mg: 56.7% vs. 57.5%, P = 0.759), whereas treatment-naïve ATTR-CM patients (n = 19) had clear signs of disease progression at the end of the observation period [12.0 (IQR 10.0-21.0) months; LVEF: 53.3% vs. 45.7%, P = 0.031; LVMI: 98.9 vs. 106.9 g/m2, P = 0.027; ECV: 49.3% vs. 54.6%, P = 0.023]. Between-group comparison at FU revealed positive effects in tafamidis 61 mg-treated compared to treatment-naïve patients (LVEF: P = 0.035, LVMI: P = 0.036, ECV: P = 0.030), while those treated with 20 mg showed no difference in the above LV measurements when compared with treatment-naïve (P = 0.120, P = 0.287, P = 0.158). However, both treatment groups showed clinically beneficial effects compared to the natural course [61 mg, 6-min walk distance (6-MWD): P = 0.005, N-terminal prohormone of brain natriuretic peptide (NT-proBNP): P = 0.002; 20 mg, 6-MWD: P = 0.023, NT-proBNP: P = 0.003]. CONCLUSION: Tafamidis delays myocardial amyloid progression in ATTR-CM patients, resulting in structural, functional, and clinical benefits compared to the natural course. Serial CMR including measurement of ECV may be appropriate for disease-specific therapy monitoring.

Renin Feedback Is an Independent Predictor of Outcome in HFpEF.

Drugs which interact with the renin angiotensin aldosterone system (RAAS) aim to reduce the negative effects of angiotensin (Ang) II. Treatment with these drugs anticipate a compensatory up-regulation of renin; however, it has been shown that there is a large variability in circulating plasma renin (PRA), even in patients with optimal medical therapy in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Our aim was to measure plasma renin activity (PRA-S), its response to RAAS inhibitor (RAASi) therapies and its effects on outcome in patients with HF with preserved ejection fraction (HFpEF). For this purpose, 150 HFpEF patients were included into a prospective single-center registry. Equilibrium (eq) angiotensin metabolites were measured from serum samples using mass spectroscopy. PRA-S (eqAng I + eqAng II) was calculated and compared in respect to the primary endpoint defined as all-cause death. PRA-S in patients with RAASi therapy was not significantly higher than in patients without RAASi (p = 0.262). Even after adjusting for confounding factors, PRA-S remained predictive for all-cause death in the multivariable model with a hazard ratio of 2.14 (95%CI 1.20-3.82, p = 0.010). We conclude that high PRA-S is associated with poor prognosis in patients with HFpEF, regardless of RAASi treatment, which could ultimately result in hyperactivated RAAS and consecutive negative effects on the cardiovascular and renal system, leading to poor outcome in patients with HFpEF.

Target site pharmacokinetics of linezolid after single and multiple doses in diabetic patients with soft tissue infection.

The underlying pathology of diabetic wounds, i.e. impairment of macro- and microcirculation, might also impact target site penetration of antibacterial drugs. To compare tissue concentrations of linezolid in infected and not infected tissue 10 patients suffering from type 2 diabetes with foot infection were included in the study. Tissue penetration of linezolid was assessed using in vivo microdialysis at the site of infection as well as in non-inflamed subcutaneous adipose tissue. All patients were investigated after receiving a single dose of linezolid and five patients in addition at steady state. After a single dose of linezolid significantly higher area under the concentration vs. time curve over 8 hours (AUC0-8 ) and maximum concentrations (Cmax )-values were observed in plasma (65.5 ± 21.2 mg*h/L and 16.4 ± 4.6 mg/L) as compared to inflamed (36.3 ± 22.9 mg*h/L and 6.6 ± 3.6 mg/L) and non-inflamed tissue (33.0 ± 17.7 mg*h/L and 6.7 ± 3.6 mg/L). Multiple administrations of linezolid led to disappearance of significant differences in Cmax and AUC0-8 between plasma, inflamed, and non-inflamed tissue. Approximately 2-fold increase of Cmax and AUC0-8 -values in tissue was observed at steady state as compared to the first administration. Penetration of linezolid is not impaired in diabetic foot infection but equilibrium between plasma and tissue might be delayed.

Prasugrel reduces agonists' inducible platelet activation and leukocyte-platelet interaction more efficiently than clopidogrel.

AIMS: The antiplatelet effects of clopidogrel and prasugrel have mainly been compared using different platelet reactivity tests. Further, data on the impact of both drugs on thrombin-inducible platelet activation are scarce. We therefore investigated the influence of clopidogrel and prasugrel on different flow cytometric parameters of platelet activation as well as on platelet function assessed by leukocyte-platelet interaction. METHODS: Baseline, ADP and thrombin receptor-activating peptide (TRAP)-6 inducible P-selectin expression, activation of glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregate (MPA) formation were determined by flow cytometry in 84 clopidogrel- and 21 prasugrel-treated patients undergoing percutaneous coronary intervention with stent implantation. RESULTS: Baseline expressions of P-selectin and activated GPIIb/IIIa did not differ significantly between clopidogrel- and prasugrel-treated patients (both P > 0.2). After activation with ADP or TRAP-6, patients with clopidogrel therapy exhibited significantly higher platelet surface expressions of P-selectin and activated GPIIb/IIIa than prasugrel-treated patients (all P ≤ 0.001). Further, high P-selectin and high GPIIb/IIIa were significantly more frequent in clopidogrel-treated patients than in patients on prasugrel therapy (all P = 0.01). Likewise, the formation of MPA without addition of agonists did not differ significantly between patients receiving clopidogrel and patients on prasugrel therapy (P = 0.2). After activation with ADP or TRAP-6, clopidogrel-treated patients showed a significantly more pronounced formation of MPA than patients-receiving prasugrel (both P = 0.02). CONCLUSIONS: Prasugrel reduces ADP and TRAP-6 inducible platelet activation, and leukocyte-platelet interaction more efficiently than clopidogrel.

High-shear- and-thrombin-inducible platelet adhesion and aggregation in patients undergoing percutaneous coronary intervention. Effects of unfractionated heparin versus bivalirudin.

Thrombin-generation and activation of platelets during percutaneous coronary intervention (PCI) play a key role for early thrombotic events. Heparin and bivalirudin are approved anticoagulants for PCI. We examined the specific effects of these anticoagulants on platelet adhesion and aggregation under high shear conditions, and the presence of excess thrombin. To simulate in vivo conditions that may precipitate a bleeding/thrombotic event, we added thrombin in vitro to blood samples from 89 stable patients who had been randomly assigned to receive heparin or bivalirudin for elective PCI and examined thrombin-inducible platelet adhesion and aggregation under high shear conditions. Platelet adhesion increased by 10% of baseline with heparin, but decreased by 20% with bivalirudin (p=0.0047). Thrombin-inducible platelet adhesion and size of aggregates was equally inhibited by heparin and bivalirudin. Thus, under high shear conditions and excessive thrombin generation as they occur in atherosclerotic vascular compartments and acute vascular syndromes, heparin and bivalirudin inhibit thrombin-induced platelet adhesion and aggregation to a similar extent, while they have opposite effects on platelet adhesion in the absence of thrombin.

Regulation of PAR-1 in patients undergoing percutaneous coronary intervention: effects of unfractionated heparin and bivalirudin.

Aims We examined the specific effects of unfractionated heparin and bivalirudin on thrombin-inducible platelet PAR-1 in patients undergoing percutaneous coronary intervention (PCI). Methods and results To simulate in vivo conditions that may precipitate a bleeding event, we added thrombin in vitro to blood samples from 89 patients who had been randomly assigned to receive heparin or bivalirudin for elective PCI and examined thrombin-inducible PAR-1 expression. Thrombin-inducible cleavage of PAR-1 was inhibited by heparin, but not affected by bivalirudin (P = 0.0001). Further, PAR-1 internalization was more effectively inhibited by heparin than bivalirudin (P = 0.002). Conclusion Heparin has stronger inhibitory effects on thrombin-dependent PAR-1 cleavage and internalization, thus providing a biological explanation for lower clinical bleeding rates with bivalirudin.