Association of haemolysis markers, blood viscosity and microcirculation function with organ damage in sickle cell disease in sub-Saharan Africa (the BIOCADRE study).

Sickle cell anaemia (SCA) is a monogenic disease with a highly variable clinical course. We aimed to investigate associations between microvascular function, haemolysis markers, blood viscosity and various types of SCA-related organ damage in a multicentric sub-Saharan African cohort of patients with SCA. In a cross-sectional study, we selected seven groups of adult patients with SS phenotype in Dakar and Bamako based on the following complications: leg ulcer, priapism, osteonecrosis, retinopathy, high tricuspid regurgitant jet velocity (TRV), macro-albuminuria or none. Clinical assessment, echocardiography, peripheral arterial tonometry, laboratory tests and blood viscosity measurement were performed. We explored statistical associations between the biological parameters and the six studied complications. Among 235 patients, 58 had high TRV, 46 osteonecrosis, 43 priapism, 33 leg ulcers, 31 retinopathy and 22 macroalbuminuria, whereas 36 had none of these complications. Multiple correspondence analysis revealed no cluster of complications. Lactate dehydrogenase levels were associated with high TRV, and blood viscosity was associated with retinopathy and the absence of macroalbuminuria. Despite extensive phenotyping of patients, no specific pattern of SCA-related complications was identified. New biomarkers are needed to predict SCA clinical expression to adapt patient management, especially in Africa, where healthcare resources are scarce.

Relationship between accessory renal arteries and resistant hypertension: A cohort study.

BACKGROUND: Resistant hypertension (RHT) is a major health care concern affecting 20 to 30% of hypertensive patients and increasing cardiovascular risk. Recent renal denervation trials have suggested a high prevalence of accessory renal arteries (ARA) in RHT. Our objective was to compare the prevalence of ARA in RHT vs. non-resistant hypertension (NRHT). METHODS: Eighty-six patients with essential hypertension who benefited from an abdominal CT-scan or MRI during their initial workup were retrospectively recruited in 6 French ESH (European Society of Hypertension) centers. At the end of a follow-up period of at least 6 months, patients were classified between RHT or NRHT. RHT was defined as uncontrolled blood pressure despite the optimal doses of three antihypertensive agents of which one is a diuretic or similar, or controlled by ≥ 4 medications. Blinded independent central review of all radiologic renal artery charts was performed. RESULTS: Baseline characteristics were: age 50±15 years, 62% males, BP 145±22/87±13mmHg. Fifty-three (62%) patients had RHT and 25 (29%) had at least one ARA. Prevalence of ARA was comparable between RHT (25%) and NRHT patients (33%, P=0.62), but there were more ARA per patient in NRHT (2±0.9) vs. RHT (1.3±0.5, P=0.05), and renin levels were higher in ARA group (51.6±41.7 mUI/L vs. 20.4±25.4 mUI/L, P=0.001). ARA were similar in diameter or length between the 2 groups. CONCLUSIONS: In this retrospective series of 86 essential hypertension patients, we found no difference in the prevalence of ARA in RHT and NRHT. More comprehensive studies are needed to answer this question.

Low grade intravascular hemolysis associates with peripheral nerve injury in type 2 diabetes.

Type 2 diabetes (T2D) induces hyperglycemia, alters hemoglobin (Hb), red blood cell (RBC) deformability and impairs hemorheology. The question remains whether RBC breakdown and intravascular hemolysis (IVH) occur in T2D patients. We characterized RBC-degradation products and vesiculation in a case-control study of 109 T2D patients and 65 control subjects. We quantified heme-related absorbance by spectrophotometry and circulating extracellular vesicles (EV) by flow cytometry and electron microscopy. Heme-related absorbance was increased in T2D vs. control plasma (+57%) and further elevated in obese T2D plasma (+27%). However, large CD235a+ EV were not increased in T2D plasma. EV from T2D plasma, or shed by isolated T2D RBC, were notably smaller in diameter (-27%) and carried heme-related absorbance. In T2D plasma, higher heme-related absorbance (+30%) was associated to peripheral sensory neuropathy, and no other vascular complication. In vitro, T2D RBC-derived EV triggered endothelial stress and thrombin activation in a phosphatidylserine- and heme-dependent fashion. We concluded that T2D was associated with low-grade IVH. Plasma absorbance may constitute a novel biomarker of peripheral neuropathy in T2D, while flow cytometry focusing on large EV may be maladapted to characterize RBC EV in T2D. Moreover, therapeutics limiting IVH or neutralizing RBC breakdown products might bolster vasculoprotection in T2D.

Exposure to inorganic particles in paediatric sarcoidosis: the PEDIASARC study.

Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.

A short course of corticosteroids reduces the risk of mechanical ventilation and death in patients with moderate to severe COVID 19 pneumonia: results of a retrospective monocentric cohort.

BACKGROUND: Reduced mortality at 28 days in patients treated with corticosteroids was demonstrated, but this result was not confirmed by certain large epidemiological studies. Our aim was to determine whether corticosteroids improve the outcomes of our patients hospitalized with COVID-19 pneumonia. METHODS: Our retrospective, single centre cohort study included consecutive patients hospitalized for moderate to severe COVID-19 pneumonia between March 15 and April 15 2020. An early short course of corticosteroids was given during the second phase of the study. The primary composite endpoint was the need for mechanical ventilation or mortality within 28 days of admission. A multivariate logistic regression model was used to estimate the propensity score, i.e. the probability of each patient receiving corticosteroid therapy based on the initial variables. RESULTS: About 120 consecutive patients were included, 39 in the "corticosteroids group", 81 in the "no corticosteroids group"; their mean ages (±SD) were 66.4 ± 14.1 and 66.1 ± 15.2 years, respectively. Mechanical ventilation-free survival at 28 days was higher in the "corticosteroids group" than in the "no corticosteroids group" (71% and 29% of cases, respectively, p < .0001). The effect of corticosteroids was confirmed with HR .28 (95%CI .10-.79), p = .02. In older and comorbid patients who were not eligible for intensive care, the effect of corticosteroid therapy was also beneficial (HR .36 (95%CI .16-.80), p = .01). CONCLUSION: A short course of corticosteroids reduced the risks of death or mechanical ventilation in patients with moderate to severe COVID-19 pneumonia in all patients and also in older and comorbid patients not eligible for intensive care.

Venous thrombosis and predictors of relapse in eosinophil-related diseases.

Eosinophils have widespread procoagulant effects. Eosinophilic cardiovascular toxicity mostly consists of endomyocardial damage or eosinophilic vasculitis, while reported cases of venous thrombosis (VT) are scarce. We aimed to report on the clinical features and treatment outcomes of patients with unexplained VT and eosinophilia, and to identify predictors of relapse. This retrospective, multicenter, observational study included patients aged over 15 years with VT, concomitant blood eosinophilia ≥ 1G/L and without any other moderate-to-strong contributing factors for VT. Fifty-four patients were included. VT was the initial manifestation of eosinophil-related disease in 29 (54%) patients and included pulmonary embolism (52%), deep venous thrombosis (37%), hepatic (11%) and portal vein (9%) thromboses. The median [IQR] absolute eosinophil count at VT onset was 3.3G/L [1.6-7.4]. Underlying eosinophil-related diseases included FIP1L1-PDGFRA-associated chronic myeloid neoplasm (n = 4), Eosinophilic Granulomatosis with Polyangiitis (n = 9), lymphocytic (n = 1) and idiopathic (n = 29) variants of hypereosinophilic syndrome. After a median [IQR] follow-up of 24 [10-62] months, 7 (13%) patients had a recurrence of VT. In multivariate analysis, persistent eosinophilia was the sole variable associated with a shorter time to VT relapse (HR 7.48; CI95% [1.94-29.47]; p = 0.015). Long-term normalization of eosinophil count could prevent the recurrence of VT in a subset of patients with unexplained VT and eosinophilia ≥ 1G/L.

High prevalence of early asymptomatic venous thromboembolism in anticoagulated COVID-19 patients hospitalized in general wards.

Coronavirus disease 2019 (COVID-19) is associated with coagulation activation and high incidence of venous thromboembolism (VTE) in severe patients despite routine thromboprophylaxis. Conflicting results exist regarding the epidemiology of VTE for unselected anticoagulated COVID-19 patients hospitalized in general wards. The aim of this study was to evaluate the prevalence of asymptomatic deep venous thrombosis (DVT) in unselected patients with COVID-19 recently hospitalized in general wards. We performed a systematic complete doppler ultrasound (CDU) at a median 4 days after admission in 42 consecutive COVID-19 patients hospitalized in general wards of our university hospital, irrespective of D-Dimer level, and retrospectively collected clinical, biological and outcome data from electronic charts. Thromboprophylaxis was systematically applied following a French national proposal. In our population, the prevalence of asymptomatic DVT was 19% (8/42 patients), with distal thrombosis in 7/8 cases and bilateral DVT in 4/8 cases. Symptomatic pulmonary embolism was detected in 4 (9.5%) patients, associated to DVT in one case. Compared to patients without DVT, patients with DVT were older and experienced poorer outcomes. In conclusion, prevalence of asymptomatic DVT is high in the first days of hospitalization of unselected COVID-19 patients in general wards and may be related to poor prognosis. Individualized assessment of thromboprophylaxis and early systematic screening for DVT is warranted in this context.

Management of the antiplatelet therapy during the diagnosis of venous thromboembolism disease: A national survey of French general practitioners' compared to the French vascular physicians' management.

INTRODUCTION: Approximately 15% of patients treated by anticoagulant for a venous thromboembolic event are also treated with antiplatelet therapy; and this association increases the risk of bleeding. The aim of this survey was to evaluate general practitioner's management of antiplatelet therapy at the initiation of anticoagulation, and at six months compared to French vascular physicians' management. METHODS: A questionnaire including 4 clinical situations was established and the physicians were asked to detail antiplatelet and anticoagulant therapy management. From September 2017 to December 2017, an e-mail invitation and a reminder were sent to members of the departmental councils who participated; 218 questionnaires were obtained. RESULTS: Overall, 91.3% of physicians considered that there was an increased risk of bleeding when antiplatelet therapy is associated with anticoagulation. After initiating anticoagulation, 67% of respondents continued antiplatelet therapy, while 30% stopped. Three strategies were used: 49.0% of physicians maintained concomitant antiplatelet therapy with full-dose anticoagulant, both at anticoagulant initiation and at 6 months; 23% of physicians stopped antiplatelet therapy and prescribed full-dose anticoagulant at initiation and at 6 months; 12.4% of physicians prescribed antiplatelet therapy associated with reduced-dose anticoagulation at 6 months regardless of the strategy at anticoagulant initiation. CONCLUSION: One third of general practitioners stopped antiplatelet therapy at the initiation of an anticoagulation for a venous thromboembolic event. Prospective controlled trials are needed to clarify the best way to treat these patients in this situation.

Thoracic aorta involvement in giant cell arteritis: a case-control analysis of morphological data at diagnosis.

OBJECTIVES: Giant cell arteritis (GCA) is a cause of potentially fatal aortic aneurysms. Descriptive data on thoracic aorta measurements at the beginning of the disease are lacking. We aimed to compare aortic diameters between a recently diagnosed GCA population and an age- and sex-matched control group. METHODS: Patients with GCA and with an available thoracic CT concomitant with diagnosis were included. Controls were patients matched for age and sex and hospitalised in the same care centre for pneumonia. The main criteria were the anteroposterior and lateral diameters of the ascending thoracic aorta, which were measured by a blinded evaluator. RESULTS: 90 cases and 90 controls were included. Each group comprised 30 males and 60 females for a mean age of 75.1±9 and 75.7±10.1 years old. At the time of GCA diagnosis no difference was found between the two groups (anteroposterior diameter 37.1±5 mm for cases vs. 36.7±5 mm for controls, p=0.6; lateral diameter 36.6±5 mm for cases vs. 35.9±4 mm for controls, p=0.3). Thoracic aorta diameter was not significantly higher in patients with aortitis at diagnosis (n=44) than in cases without aortitis (n=46). CONCLUSIONS: Morphologic comparison of thoracic aorta at diagnosis of GCA with an age- and sex-matched control population showed no significant difference. Morphologic evaluation of aorta cannot predict accurately the occurrence of aortic aneurysm. Systematic follow-up according to current recommendations is thus justified.

Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles.

In hemolytic diseases, such as sickle cell disease (SCD), intravascular hemolysis results in the release of hemoglobin, heme, and heme-loaded membrane microvesicles in the bloodstream. Intravascular hemolysis is thus associated with inflammation and organ injury. Complement system can be activated by heme in vitro. We investigated the mechanisms by which hemolysis and red blood cell (RBC) degradation products trigger complement activation in vivo. In kidney biopsies of SCD nephropathy patients and a mouse model with SCD, we detected tissue deposits of complement C3 and C5b-9. Moreover, drug-induced intravascular hemolysis or injection of heme or hemoglobin in mice triggered C3 deposition, primarily in kidneys. Renal injury markers (Kim-1, NGAL) were attenuated in C3-/- hemolytic mice. RBC degradation products, such as heme-loaded microvesicles and heme, induced alternative and terminal complement pathway activation in sera and on endothelial surfaces, in contrast to hemoglobin. Heme triggered rapid P selectin, C3aR, and C5aR expression and downregulated CD46 on endothelial cells. Importantly, complement deposition was attenuated in vivo and in vitro by heme scavenger hemopexin. In conclusion, we demonstrate that intravascular hemolysis triggers complement activation in vivo, encouraging further studies on its role in SCD nephropathy. Conversely, heme inhibition using hemopexin may provide a novel therapeutic opportunity to limit complement activation in hemolytic diseases.

Arterial Stiffness Impairment in Sickle Cell Disease Associated With Chronic Vascular Complications: The Multinational African CADRE Study.

BACKGROUND: Although a blood genetic disease, sickle cell disease (SCD) leads to a chronic vasculopathy with multiple organ involvement. We assessed arterial stiffness in SCD patients and looked for associations between arterial stiffness and SCD-related vascular complications. METHODS: The CADRE (Coeur Artères et Drepanocytose, ie, Heart Arteries and Sickle Cell Disease) study prospectively recruited pediatric and adult SCD patients and healthy controls in Cameroon, Ivory Coast, Gabon, Mali, and Senegal. Patients underwent clinical examination, routine laboratory tests (complete blood count, serum creatinine level), urine albumin/creatinine ratio measure, and a measure of carotid-femoral pulse wave velocity (cf-PWV) and augmentation index (AI) at a steady state. The clinical and biological correlates of cf-PWV and AI were investigated by using a multivariable multilevel linear regression analysis with individuals nested in families further nested in countries. RESULTS: Included were 3627 patients with SCD and 943 controls. Mean cf-PWV was lower in SCD patients (7.5±2.0 m/s) than in controls (9.1±2.4 m/s, P<0.0001), and lower in SS-Sß(0) than in SC-Sß(+) phenotypes. AI, corrected for heart rate, increased more rapidly with age in SCD patients and was higher in SCD than in control adults. cf-PWV and AI were independently associated with age, sex, height, heart rate, mean blood pressure, hemoglobin level, country, and hemoglobin phenotype. After adjustment for these correlates, cf-PWV and AI were associated with the glomerular filtration rate and osteonecrosis. AI was also associated with stroke, pulmonary hypertension, and priapism, and cf-PWV was associated with microalbuminuria. CONCLUSIONS: PWV and AI are deeply modified in SCD patients in comparison with healthy controls. These changes are independently associated with a lower blood pressure and a higher heart rate but also with the hemoglobin phenotype. Moreover, PWV and AI are associated with several SCD clinical complications. Their prognostic value will be assessed at follow-up of the patients.

Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease.

Intravascular hemolysis describes the relocalization of heme and hemoglobin (Hb) from erythrocytes to plasma. We investigated the concept that erythrocyte membrane microparticles (MPs) concentrate cell-free heme in human hemolytic diseases, and that heme-laden MPs have a physiopathological impact. Up to one-third of cell-free heme in plasma from 47 patients with sickle cell disease (SCD) was sequestered in circulating MPs. Erythrocyte vesiculation in vitro produced MPs loaded with heme. In silico analysis predicted that externalized phosphatidylserine (PS) in MPs may associate with and help retain heme at the cell surface. Immunohistology identified Hb-laden MPs adherent to capillary endothelium in kidney biopsies from hyperalbuminuric SCD patients. In addition, heme-laden erythrocyte MPs adhered and transferred heme to cultured endothelial cells, inducing oxidative stress and apoptosis. In transgenic SAD mice, infusion of heme-laden MPs triggered rapid vasoocclusions in kidneys and compromised microvascular dilation ex vivo. These vascular effects were largely blocked by heme-scavenging hemopexin and by the PS antagonist annexin-a5, in vitro and in vivo. Adversely remodeled MPs carrying heme may thus be a source of oxidant stress for the endothelium, linking hemolysis to vascular injury. This pathway might provide new targets for the therapeutic preservation of vascular function in SCD.

Combinations of inhibitors of the renin-angiotensin system with calcium channel blockers for the treatment of hypertension: focus on perindopril/amlodipine.

BACKGROUND: Combination antihypertensive therapy with an inhibitor of the renin-angiotensin system (RAS) and a calcium channel blocker (CCB) is a rational approach to achieve blood pressure (BP) goals in patients with hypertension, and may provide additional cardiovascular protection compared to other strategies in special populations. This article reviews the rationale for, and evidence supporting, the use of newer fixed-dose combinations of RAS inhibitors and CCBs, with particular emphasis on perindopril/amlodipine. METHODS: A literature search was performed in Medline and EMBASE databases to identify articles published up to May 2010 describing the impact of combination treatment with angiotensin receptor blocker (ARB)/CCB or angiotensin-converting enzyme (ACE) inhibitor/CCB based antihypertensive strategies on BP or clinical outcomes. FINDINGS: A substantial body of evidence supports the BP-lowering efficacy of RAS inhibitor/CCB combination therapy in patients with hypertension. RAS inhibitors and CCBs represent two different and complementary mechanisms of actions; their use in combination is associated with effective BP lowering with favourable tolerability and fewer adverse metabolic effects than some other combination therapies. Currently, intervention studies demonstrating the impact of ARB/CCB combinations on cardiovascular mortality and morbidity are lacking. However, evidence from large outcome trials supports the use of ACE inhibitor/CCB combinations for reducing the risk of cardiovascular and renal events, particularly in high-risk patients. There is also evidence that the benefits of ACE inhibitor/CCB combinations may extend beyond those solely associated with brachial BP lowering, by an additional impact on central BP haemodynamics. CONCLUSIONS: RAS inhibitor/CCB combination therapy is an effective antihypertensive therapy. Strong evidence supports the antihypertensive efficacy of ACE inhibitor/CCB combinations with cardioprotective and renoprotective properties. In particular, evidence suggests that fixed-dose perindopril/amlodipine effectively decreases BP and currently is the only RAS inhibitor/CCB combination proven to decrease all-cause and cardiovascular mortality as well as major cardiovascular events, and thus is a valuable option for the management of hypertension, especially in high-risk patients.

Heart protection: a key target in the management of patients with diabetes.

Cardiovascular disease is responsible for 70% of all mortality among patients with type 2 diabetes and is also a major contributor to diabetes-related healthcare costs. The ADVANCE trial clearly demonstrated that a simple and easily applicable pharmacological strategy based on perindopril/indapamide fixed combination could substantially reduce total and cardiovascular mortality (-14% and -18%, respectively). The observed benefits were largely caused by a substantial decrease in systolic blood pressure (SBP), confirming the need to have ambitious therapeutic goals in such high-risk patients. This point is of importance because most of the patients included in the trial were being treated for hypertension, and baseline brachial SBP and diastolic blood pressure at inclusion were very close to normal. Previous mechanistic studies have highlighted the positive effect of perindopril/indapamide fixed combination on large artery function as well as on microvascular structure. For example, in the REASON trial, in patients treated with perindopril/indapamide, the decrease in central aortic SBP, which closely correlated with the decrease in left ventricular hypertrophy, reflected a significant improvement in large artery function and a changing pattern in both peripheral reflection coefficients and structural arteriolar network. These data are supported by those from other studies, which show increases in coronary blood flow reserve with perindopril/indapamide treatment. In conclusion, normalization of SBP, pulse pressure, arterial function and myocardial perfusion, a haemodynamic profile known to improve survival in the hypertensive populations at high cardiovascular risk, seems to be more easily achieved when a strategy based on the perindopril/indapamide combination is applied.

Effective systolic blood pressure reduction with olmesartan medoxomil/amlodipine combination therapy: post hoc analysis of data from a randomized, double-blind, parallel-group, multicentre study.

BACKGROUND AND OBJECTIVE: Systolic blood pressure (SBP) strongly predicts cardiovascular risk and is an important factor to evaluate in studies of antihypertensive treatments. A recent randomized controlled study has shown that the angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) olmesartan medoxomil (hereafter olmesartan) combined with the calcium channel antagonist (calcium channel blocker) amlodipine can control SBP in a majority of patients with moderate-to-severe hypertension. The aim of this report is to present results from a post hoc analysis of this study to further evaluate the effects of this combination on SBP. METHODS: A post hoc analysis of changes in seated SBP (SeSBP) levels in patients treated with olmesartan 40 mg plus amlodipine 5 or 10 mg was carried out to investigate the distribution of SeSBP changes produced by this combination. Patients who reached the end of the 52-week study were categorized by size of SeSBP reduction from baseline as follows: 15 to 30 to 45 mmHg. RESULTS: In 578 patients who received olmesartan/amlodipine 40 mg/5 mg or 40 mg/10 mg and completed the study, the mean SeSBP reduction from baseline was 31.18 mmHg, and the proportions of patients with SeSBP reductions 15 to 30 to 45 mmHg were 12.8%, 36.0%, 35.3% and 15.9%, respectively. In patients who received olmesartan/amlodipine 40 mg/10 mg, the proportion of patients in the 45 mmHg group was larger (21.6%). Moreover, patients in the >45 mmHg category showed the greatest reduction in SeSBP from baseline (53.5 mmHg for olmesartan/amlodipine 40 mg/10 mg recipients). Categorical analysis of patients treated with olmesartan/amlodipine 40 mg/10 mg in a separate, factorial study showed similar results: SeSBP reductions of 15 to 30 to 45 mmHg were seen in 17%, 34%, 36% and 14% of patients, respectively. CONCLUSION: Treatment with a combination based upon olmesartan 40 mg plus amlodipine 5 or 10 mg effectively reduces elevated SeSBP, particularly in patients with high levels of SeSBP.

Blood pressure control, risk factors and cardiovascular prognosis in patients with diabetes: 30 years of progress.

Hypertension is a major co-morbidity for type 2 diabetes, and an important modifiable risk factor for vascular events. Therefore, treatment of diabetes and its risk factors is important to minimize complications, and much progress has been made over the past 30 years. The UKPDS trial showed that intensive glycaemic and blood pressure control reduced the risk of vascular events. In the HOT study, the addition of aspirin to patients with diabetes and controlled hypertension decreased the risk of myocardial infarction. Blood pressure control with angiotensin-converting enzyme inhibitors in MICRO-HOPE also showed significant reductions in the risk of vascular complications, and blockers of the renin-angiotensin system produced substantial renal protective effects in patients with hypertension and diabetes. Statin therapy in the HPS and CARDS studies was effective in the primary prevention of cardiovascular disorders. Finally, an intensive multifactorial intervention achieved sustained reduction in the risk of vascular complications and death in patients with type 2 diabetes in the Steno-2 study. Nevertheless, the major coronary event risk remains high in type 2 diabetes patients, and the results of the ADVANCE trial provided a step forward in treatment.