Brigitte Jude

Acquired von Willebrand Syndrome After Continuous-Flow Mechanical Device Support Contributes to a High Prevalence of Bleeding During Long-Term Support and at the Time of Transplantation

OBJECTIVES The objective of the study was to determine the prevalence of bleeding during continuous-flow left ventricular assist device support and to identify potential mechanisms for those bleeding events. BACKGROUND Bleeding is frequently reported with continuous-flow left ventricular assist devices and may result from anticoagulation coupled with bleeding diathesis such as acquired von Willebrand syndrome. Accordingly, the prevalence of coagulation abnormalities including laboratory assessment for von Willebrand syndrome, bleeding events during device support, and at heart transplantation were evaluated. METHODS A retrospective study in all HeartMate II (HM II) (Thoratec Corp., Pleasanton, California) patients who underwent implantation between April 1, 2004, and August 1, 2009, was performed. Bleeding was defined as the need for transfusion >7 days after device insertion of 1 U of packed red blood cells. Transfusion at heart transplantation was compared with that in HeartMate XVE patients. RESULTS Seventy-nine HM II devices were implanted. Anticoagulation included warfarin in 68.3%, aspirin in 55.7%, and dipyridamole in 58.2% of the patients. Of the patients, 44.3% had bleeding episodes at 112 ± 183 days after left ventricular assist device implantation, with 50% experiencing an event within 2 months. Gastrointestinal bleeding was the most frequent event. At the index event, the international normalized ratio averaged 1.67 ± 0.53, and the platelet count was 237 ± 119 × 10(9)/l. Comparison of the transfusion requirements at heart transplantation of 35 HM II patients with 62 HeartMate XVE patients demonstrated twice the transfusion requirements in HM II patients (packed red blood cells, 6.3 ± 0.8 U vs. 3.8 ± 0.5 U; platelets, 12.5 ± 5.4 U vs. 8.6 ± 6.4 U; fresh frozen plasma, 9.6 ± 4.9 U vs. 4.9 ± 3.6 U; and cryoprecipitate, 4.3 ± 3.6 U vs. 2.2 ± 3.5 U; p < 0.05 for all). High molecular weight von Willebrand factor multimers were measured in 31 HM II patients and were reduced in all patients; 18 of these 31 (58%) patients had bleeding. CONCLUSIONS Patients with the HM II had a high incidence of bleeding events during device support and at heart transplantation. All HM II patients had reduced high molecular weight von Willebrand factor multimers. The role of these abnormalities in the high incidence of bleeding deserves further investigation. Furthermore, alterations in anticoagulation should be considered during device support and before surgery in patients supported with the HM II.

High-dose tranexamic acid reduces blood loss in postpartum haemorrhage

IntroductionOur purpose in conducting this study was to determine whether administration of high-dose tranexamic acid (TA) at the time of diagnosis of postpartum haemorrhage (PPH) could reduce blood loss.MethodsThis was a randomised, controlled, multicentred, open-label trial. Women with PPH >800 mL following vaginal delivery were randomly assigned to receive TA (loading dose 4 g over 1 hour, then infusion of 1 g/hour over 6 hours) or not. In both groups, packed red blood cells (PRBCs) and colloids could be used according to French guidelines. The use of additional procoagulant treatments was permitted only in cases involving intractable bleeding. The primary objective was to assess the efficacy of TA in the reduction of blood loss in women with PPH, and the secondary objectives were the effect of TA on PPH duration, anaemia, transfusion and the need for invasive procedures.ResultsA total of 144 women fully completed the protocol (72 in each group). Blood loss between enrolment and 6 hours later was significantly lower in the TA group than in the control group (median, 173 mL; first to third quartiles, 59 to 377) than in controls (221 mL; first to third quartiles 105 to 564) (P = 0.041). In the TA group, bleeding duration was shorter and progression to severe PPH and PRBC transfusion was less frequent than in controls (P < 0.03). Invasive procedures were performed in four women in the TA group and in seven controls (P = NS). PPH stopped after only uterotonics and PRBC transfusion in 93% of women in the TA group versus 79% of controls (P = 0.016). Mild, transient adverse manifestations occurred more often in the TA group than in the control group (P = 0.03).ConclusionsThis study is the first to demonstrate that high-dose TA can reduce blood loss and maternal morbidity in women with PPH. Although the study was not adequately powered to address safety issues, the observed side effects were mild and transient. A larger international study is needed to investigate whether TA can decrease the need for invasive procedures and reduce maternal morbidity in women with PPH.Trial registrationControlled Trials ISRCTN09968140.

Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure

BACKGROUND Recent studies have demonstrated that aldosterone levels measured in patients with heart failure or acute myocardial infarction (MI) are associated with long-term mortality, but the association with aldosterone levels in patients with coronary artery disease (CAD) outside these specific settings remains unknown. In addition, no clear mechanism has been elucidated to explain these observations. The present study was designed to evaluate the relationship between the level of aldosterone and the risk of death and acute ischaemic events in CAD patients with a preserved left ventricular (LV) function and no acute MI. METHODS AND RESULTS In 799 consecutive CAD patients referred for elective coronary angioplasty measurements were obtained before the procedure for: aldosterone (median = 25 pg/mL), brain natriuretic peptide (BNP) (median = 35 pg/mL), hsC-reactive protein (median = 4.17 mg/L), and left ventricular ejection fraction (mean = 58%). Patients with acute MI or coronary syndrome (ACS) who required urgent revascularization were not included in the study. The primary endpoint, cardiovascular death, occurred in 41 patients during a median follow-up period of 14.9 months. Secondary endpoints-total mortality, acute ischaemic events (acute MI or ischaemic stroke), and the composite of death and acute ischaemic events-were observed in 52, 54, and 94 patients, respectively. Plasma aldosterone was found to be related to BMI, hypertension and NYHA class, and inversely related to age, creatinine clearance, and use of beta-blockers. Multivariate Cox model analysis demonstrated that aldosterone was independently associated with cardiovascular mortality (P = 0.001), total mortality (P = 0.001), acute ischaemic events (P = 0.01), and the composite of death and acute ischaemic events (P = 0.004). Reclassification analysis, using integrated discrimination improvement (IDI) and net reclassification improvement (NRI), demonstrated incremental predictive value of aldosterone (P < 0.0001). CONCLUSION Our results demonstrate that, in patients with CAD but without heart failure or acute MI, the level of aldosterone is strongly and independently associated with mortality and the occurrence of acute ischaemic events.

Atherosclerotic-like process in aortic stenosis: Activation of the tissue factor-thrombin pathway and potential role through osteopontin alteration

BACKGROUND We recently demonstrated in an experimental model the expression of tissue factor (TF) in aortic valves. Thrombin, generated at the end of the TF-initiated coagulation cascade, has been shown to cleave the anti-calcific osteopontin (OSP) liberating the pro-inflammatory OSP N-half. OBJECTIVES We hypothesized that TF might play an important role in calcific aortic valve stenosis (AS) through thrombin generation and hence evaluated the valvular expression of TF and its inhibitor (TF pathway inhibitor), α-thrombin, OSP and its thrombin-cleaved form (OSP N-half). METHODS Calcified aortic valves were obtained from patients undergoing valve replacement. Protein expression was evaluated by immunostaining and measured using ELISA kits. Transcripts were analyzed by RT-PCR. RESULTS We included 52 patients (31 men; age 70 ± 10 years; aortic valve area index 0.35 ± 0.13 cm(2)/m(2)). Immunohistochemistry revealed that TF, OSP and α-thrombin expressions were associated with calcifications at the aortic side of the leaflets. There was an overexpression in calcified regions as compared to non-calcified zones of TF (733.3 ± 70.5 pg/mg vs. 429.4 ± 73.2 pg/mg; p<0.0001), OSP (88.9 ± 12.7 ng/mg vs. 15.0 ± 3.3 ng/mg; p<0.0001) and OSP N-half (0.41 ± 0.06 pmol/mg vs. 0.056 ± 0.011 pmol/mg; p<0.0001). Additionally, both TF and α-thrombin expressions were associated with OSP N-half (r=0.52; p<0.0001 and r=0.33; p=0.019, respectively). CONCLUSIONS Aortic leaflet TF and α-thrombin expressions and their association with the thrombin-cleaved form of OSP, are a new and important feature of AS. We hypothesize that TF may be involved in the mineralization process of aortic valves by enhancing the generation of the pro-inflammatory OSP N-half through thrombin induction. This pathway deserves further studies to address its implication in the aortic valve calcification process.

Renal resistance index and its prognostic significance in patients with heart failure with preserved ejection fraction

BACKGROUND Functional renal impairment is a common feature of heart failure with preserved ejection fraction (HFpEF). The link between functional renal impairment and HFpEF remains incompletely understood. With hypertension and diabetes as frequent co-morbidities, patients with HFpEF are at risk of developing intra-renal vascular hemodynamic alterations that may lead to functional renal impairment and impact on prognosis. METHODS Renal resistive index (RRI) was non-invasively determined by Doppler ultrasonic examination in 90 HFpEF patients and 90 age- and sex-matched hypertensive patients without evidence of heart failure (HF) who served as controls. Clinical, laboratory and cardiac echocardiography data were obtained in HFpEF patients and controls. To investigate its possible clinical relevance, RRI was evaluated as a prognostic index of all-cause mortality and hospitalization for HF. RESULTS Mean RRI was substantially greater in HFpEF patients than in controls (P < 0.0001), while mean blood pressure, glomerular filtration rate, hemoglobin and serum protein levels were significantly lower in HFpEF patients than in controls. On multivariable analysis, mean RRI was independently associated with HFpEF. In addition, increased mean RRI was an independent predictor of poor outcome [hazard ratio = 1.06 95% confidence interval (1.01-1.10), P = 0.007] and remained significantly associated with the outcome after adjustment for univariate predictors that included low mean blood pressure, low hemoglobin concentration and low glomerular filtration rate. Conclusion. Patients with HFpEF exhibit intra-renal vascular hemodynamic alterations. The severity of intra-renal vascular hemodynamic alterations correlates with a poor outcome.

Prevalence and clinical significance of antiphospholipid antibodies in heart valve disease: A case-control study

The purposes of this study were (1) to assess the prevalence of antiphospholipid (aPL) antibodies in patients with non-specific heart valve disease referred for valve replacement and (2) to determine whether the presence of aPL antibodies carries a risk for thrombotic events during a postoperative follow-up in a prospective cohort. The sera of 89 consecutive patients and 80 matched control subjects were tested for antibodies to cardiolipin (immunoglobulin G and immunoglobulin M) and for lupus anticoagulant. The prevalence of aPL antibodies was significantly higher in patients (19 [21%] of 89) than in control subjects (7 [9%] of 80) (p < 0.05). Patients were divided into two subgroups according to the presence (subgroup A) or the absence (subgroup B) of aPL antibodies. No significant difference in age or sex ratio was observed between the two subgroups. A history of arterial thrombosis was more frequent in subgroup A (8 [42%] of 19) than in subgroup B (8 [11%] of 70) (p < 0.01). No significant difference with respect to the occurrence of thrombotic events was observed during a median follow-up period of 8.7 months. Thus a high prevalence of aPL antibodies was found in patients referred for heart valve replacement compared with matched control subjects. No increased risk has been demonstrated in the patients with aPL antibodies.

Measuring and targeting aldosterone and renin in atherosclerosis: A review of clinical data

Our understanding of the development and progression of atherosclerosis has increased substantially over the past decades. A significant role for the renin-angiotensin-aldosterone system (RAAS) in this process has gained appreciation in recent years. Preclinical and clinical studies have associated components of the RAAS with various cardiovascular disease conditions. Classically known for its contribution to hypertension, dysregulation of the system is now also believed to promote vascular inflammation, fibrosis, remodeling, and endothelial dysfunction, all intimately related to atherosclerosis. The reduction in cardiovascular mortality and morbidity, as seen with the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, supports the concept that RAAS is involved in the pathogenesis of atherosclerotic disease. However, the underlying molecular mechanisms of the pathophysiology remain to be completely understood. Evidence points toward additional benefit from therapeutic approaches aiming at more complete inhibition of the system and the possible utility of renin or aldosterone in the prediction of cardiovascular outcome. This review will summarize the current knowledge from clinical studies regarding the presumptive role of renin and aldosterone in the prediction and management of patients with atherosclerosis. For this purpose, a literature search was performed, focusing on available clinical data regarding renin or aldosterone and cardiovascular outcome.

Dietary Lipid Lowering Modifies Plaque Phenotype in Rabbit Atheroma After Angioplasty A Potential Role of Tissue Factor

Background—Tissue factor (TF), the main initiator of blood coagulation, is involved in cellular migration and angiogenesis processes. TF is expressed strongly in lipid-rich plaques and probably plays an important role in the thrombotic complications of plaque rupture. This study analyzes the effect of dietary lipid lowering on TF expression and cellular modifications in angioplasty-induced rabbit plaque rupture. Methods and Results—After experimental plaque rupture by balloon angioplasty in atheromatous rabbits, animals were assigned a 0.2% or a 2% cholesterol diet, and the TF content of arterial wall and the associated histological modifications were analyzed after 4 weeks. Early effects of lipid lowering were observed: The increase of TF expression in the vascular wall was stronger in the 2% than in the 0.2% cholesterol diet group (iliac arteries: 1226±308 versus 72±29 mU TF/g artery, P <0.005). Immunohistochemistry indicated that TF expression was associated with sprout of neovessels, which was more pronounced in the 2% than in the 0.2% cholesterol group. Conclusions—This study shows that dietary lipid lowering decreases the thrombotic potential of ruptured atherosclerotic plaques through TF decrease. Moreover, high TF expression is associated with marked angiogenesis in the vascular wall, which is reduced by lipid lowering. These results provide further arguments for strong dietary lipid lowering to reduce plaque instability and thrombogenicity.

Clinical and echocardiographic correlates of plasma B-type natriuretic peptide levels in patients with aortic valve stenosis and normal left ventricular ejection fraction.

Background: Several studies suggest that BNP testing may help define the timing of aortic valve surgery in patients with aortic valve stenosis (AVS) prior onset of overt LV systolic dysfunction. The aim of this study was to identify clinical and echocardiographic correlates of plasma BNP levels in a large cohort of patients with AVS and preserved LV ejection fraction. Method and results: One hundred thirty‐five consecutive patients were prospectively included in the present study (Mean age 73 ± 13 years old, 66 (49%) male). Eighty‐nine patients (66%) had severe AVS (aortic valve area <0.6 cm2/m2 BSA). Plasma BNP levels, clinical and comprehensive Doppler echocardiography evaluation was performed in all patients. Independent clinical correlates of plasma BNP levels (R2= 0.19) were older age (P < 0.0001) and presence of AVS symptoms (P = 0.004). Independent echocardiographic correlates of plasma BNP levels (R2= 0.38) were E/Ea ratio (P = 0.01), LV mass index (P = 0.018), left atrial surface (P < 0.0001) and systolic pulmonary artery pressure (sPAP; P = 0.004). Overall, independent correlates of plasma BNP levels (R2= 0.47) were older age (P = 0.001), known coronary artery disease (P = 0.047), increased LV mass index (P = 0.001), left atrial enlargement (P = 0.002), and increased sPAP (P = 0.003). Conclusions: In patients with AVS and normal LV ejection fraction, plasma BNP predominantly reflects the clinical and echocardiographic consequences of afterload burden imposed on the left ventricle rather than the severity of valve stenosis, per se. (Echocardiography 2011;28:695‐702)

The coronary artery disease-associated gene C6ORF105 is expressed in human macrophages under the transcriptional control of PPARγ.

Coronary artery disease (CAD) is a major cause of morbidity and mortality. Mutations in C6ORF105, associated with decreased gene expression, positively correlate with the risk of CAD in Chinese populations. Moreover, the C6ORF105‐encoded protein may play a role in coagulation. Here, we report that C6ORF105 gene expression is lower in circulating mononuclear cells from obese diabetic than lean subjects. Moreover, C6ORF105 is expressed in human macrophages and atherosclerotic lesions, where its expression positively correlates with expression of the transcription factor Peroxisome Proliferator‐Activated Receptor (PPAR)γ. Activation of PPARγ increases, in a PPARγ‐dependent manner, the expression of C6ORF105 in human macrophages and atherosclerotic lesions.