Renin-angiotensin system is involved in embryonic emergence of hematopoietic stem/progenitor cells.

Angiotensin-converting enzyme (ACE), a key element of the renin-angiotensin system (RAS), has recently been identified as a new marker of both adult and embryonic human hematopoietic stem/progenitor cells (HSPCs). However, whether a full renin-angiotensin pathway is locally present during the hematopoietic emergence is still an open question. In the present study, we show that this enzyme is expressed by hematopoietic progenitors in the developing mouse embryo. Furthermore, ACE and the other elements of RAS-namely angiotensinogen, renin, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors-are expressed in the paraaortic splanchnopleura (P-Sp) and in its derivative, the aorta-gonad-mesonephros region, both in human and mouse embryos. Their localization is compatible with the existence of a local autocrine and/or paracrine RAS in these hemogenic sites. in vitro perturbation of the RAS by administration of a specific AT1 receptor antagonist inhibits almost totally the generation of blood CD45-positive cells from dissected P-Sp, implying that angiotensin II signaling is necessary for the emergence of hematopoietic cells. Conversely, addition of exogenous angiotensin II peptide stimulates hematopoiesis in culture, with an increase in the number of immature c-Kit+ CD41+ CD31+ CD45+ hematopoietic progenitors, compared to the control. These results highlight a novel role of local-RAS during embryogenesis, suggesting that angiotensin II, via activation of AT1 receptor, promotes the emergence of undifferentiated hematopoietic progenitors.

Association between overall fruit and vegetable intake, and fruit and vegetable sub-types and blood pressure: the PRIME study (Prospective Epidemiological Study of Myocardial Infarction).

Increased fruit and vegetable (FV) intake is associated with reduced blood pressure (BP). However, it is not clear whether the effect of FV on BP depends on the type of FV consumed. Furthermore, there is limited research regarding the comparative effect of juices or whole FV on BP. Baseline data from a prospective cohort study of 10 660 men aged 50-59 years examined not only the cross-sectional association between total FV intake but also specific types of FV and BP in France and Northern Ireland. BP was measured, and dietary intake assessed using FFQ. After adjusting for confounders, both systolic BP (SBP) and diastolic BP (DBP) were significantly inversely associated with total fruit, vegetable and fruit juice intake; however, when examined according to fruit or vegetable sub-type (citrus fruit, other fruit, fruit juices, cooked vegetables and raw vegetables), only the other fruit and raw vegetable categories were consistently associated with reduced SBP and DBP. In relation to the risk of hypertension based on SBP >140 mmHg, the OR for total fruit, vegetable and fruit juice intake (per fourth) was 0·95 (95 % CI 0·91, 1·00), with the same estimates being 0·98 (95 % CI 0·94, 1·02) for citrus fruit (per fourth), 1·02 (95 % CI 0·98, 1·06) for fruit juice (per fourth), 0·93 (95 % CI 0·89, 0·98) for other fruit (per fourth), 1·05 (95 % CI 0·99, 1·10) for cooked vegetable (per fourth) and 0·86 (95 % CI 0·80, 0·91) for raw vegetable intakes (per fourth). Similar results were obtained for DBP. In conclusion, a high overall intake of fruit, vegetables and fruit juice was inversely associated with SBP, DBP and risk of hypertension, but this differed by FV sub-type, suggesting that the strength of the association between FV sub-types and BP might be related to the type consumed, or to processing or cooking-related factors.

Association of low plasma antioxidant levels with all-cause mortality and coronary events in healthy middle-aged men from France and Northern Ireland in the PRIME study.

BACKGROUND: The main underlying risk factors associated with coronary heart disease (CHD) are modifiable and oxidative injury and systemic inflammatory damage represent key aetiological factors associated with the development and progression of CHD and premature mortality. OBJECTIVE: To examine associations of plasma antioxidant status with all-cause mortality and fatal or non-fatal cardiovascular events. DESIGN: The PRIME study prospectively evaluated 9709 men aged 50-59 years between 1991 and 1993 in Northern Ireland and France who were free of CHD at recruitment and followed annually for deaths and cardiovascular events for 10 years. Serum concentrations of vitamin C, retinol, two forms of vitamin E (α- and γ-tocopherol) and six carotenoids were quantified by high-performance liquid chromatography. Baseline conventional risk factors were considered, as well as socioeconomic differences and lifestyle behaviours including diet, smoking habit, physical activity, and alcohol consumption through Cox regression analyses. RESULTS: At 10 years, there were 538 deaths from any cause and 440 fatal or non-fatal cardiovascular events. After adjustment for country, age, systolic blood pressure, diabetes, body mass index, cholesterol, high density lipoprotein cholesterol, triglycerides, height, total physical activity, alcohol consumption and smoking habit, higher levels of all antioxidants were associated with significantly lower risk of all-cause mortality, with the exception of γ-tocopherol. Only retinol was significantly associated with decreased risk of cardiovascular events in a fully adjusted model. CONCLUSIONS: Low antioxidant levels contribute to the gradient of all-cause mortality and cardiovascular incidence independent of lifestyle behaviours and traditional cardiovascular and socioeconomic risk factors.

Angiotensin-converting enzyme (CD143) specifies emerging lympho-hematopoietic progenitors in the human embryo.

Adult-type lympho-myeloid hematopoietic progenitors are first generated in the aorta-gonad-mesonephros region between days 27 and 40 of human embryonic development, but an elusive blood forming potential is present earlier in the underlying splanchnopleura. In the present study, we show that angiotensin-converting enzyme (ACE, also known as CD143), a recently identified cell-surface marker of adult human hematopoietic stem cells, is already expressed in all presumptive and developing blood-forming tissues of the human embryo and fetus: para-aortic splanchnopleura, yolk sac, aorta-gonad-mesonephros, liver, and bone marrow (BM). Fetal liver and BM-derived CD34(+)ACE(+) cells, but not CD34(+)ACE(-) cells, are endowed with long-term culture-initiating cell potential and sustain multilineage hematopoietic cell engraftment when transplanted into NOD/SCID mice. Furthermore, from 23-26 days of development, ACE expression characterizes rare CD34(-)CD45(-) cells concentrated in the hemogenic portion of the para-aortic splanchnopleura. ACE(+) cells sorted from the splanchnopleura generated colonies of hematopoietic cells more than 40 times more frequently than ACE(-) cells. These data suggest that, in addition to being a marker of adult human hematopoietic stem cells, ACE identifies embryonic mesodermal precursors responsible for definitive hematopoiesis, and we propose that this enzyme is involved in the regulation of human blood formation.

Regional and temporal differences in the associations between cardiovascular disease and its classic risk factors: an analysis of 49 cohorts from 11 European countries.

AIMS: The regional and temporal differences in the associations between cardiovascular disease (CVD) and its classic risk factors are unknown. The current study examined these associations in different European regions over a 30-year period. METHODS AND RESULTS: The study sample comprised 553 818 individuals from 49 cohorts in 11 European countries (baseline: 1982-2012) who were followed up for a maximum of 10 years. Risk factors [sex, smoking, diabetes, non-HDL cholesterol, systolic blood pressure (BP), and body mass index (BMI)] and CVD events (coronary heart disease or stroke) were harmonized across cohorts. Risk factor-outcome associations were analysed using multivariable-adjusted Cox regression models, and differences in associations were assessed using meta-regression. The differences in the risk factor-CVD associations between central Europe, northern Europe, southern Europe, and the UK were generally small. Men had a slightly higher hazard ratio (HR) in southern Europe (P = 0.043 for overall difference), and those with diabetes had a slightly lower HR in central Europe (P = 0.022 for overall difference) compared with the other regions. Of the six CVD risk factors, minor HR decreases per decade were observed for non-HDL cholesterol [7% per mmol/L; 95% confidence interval (CI), 3-10%] and systolic BP (4% per 20 mmHg; 95% CI, 1-8%), while a minor HR increase per decade was observed for BMI (7% per 10 kg/m2; 95% CI, 1-13%). CONCLUSION: The results demonstrate that all classic CVD risk factors are still relevant in Europe, irrespective of regional area. Preventive strategies should focus on risk factors with the greatest population attributable risk.

All classic cardiovascular disease (CVD) risk factors are still relevant in Europe, irrespective of regional area. The differences in the associations of CVD risk factors with overt CVD between regions of Europe are generally small. Minor temporal hazard decreases were observed for non-HDL cholesterol and systolic blood pressure, while a minor hazard increase was observed for body mass index.

Long-term follow-up of survivors of a first acute coronary syndrome: Results from the French MONICA registries from 2009 to 2017.

AIM: The objectives of the study were to characterize the long-term risk of first recurrence of acute coronary syndrome (ACS) among survivors of an incident ACS, as a function of the STEMI/NSTEMI/UA diagnosis. METHODS: Men and women (aged 35-74) hospitalized between 2009 and 2016 for an incident ACS in the French MONICA registries and still alive on discharge were followed-up until December 2017. Recurrent events were defined as the first (non-fatal or fatal) ACS occurring after hospital discharge from the incident event. RESULTS: The study comprised 15,739 incident ACSs with 63,777 patient-years of follow-up. The cumulative probability [95% confidence interval] of recurrent ACS was 6.7% [6.3-7.1%] at 1 year and 18.4% [17.4-19.5%] at 9 years. The cumulative probability of fatal recurrent ACS was 1.4% [1.2-1.5%] at 1 year and 4.3% [3.6-4.9%] at 9 years. The risk of recurrence did not depend on the type of the incident ACS after adjustment for confounding factors. The most frequent forms of recurrence were NSTEMI and UA. The presence of a major complication (OR = 1.59) and an impaired left ventricular ejection fraction (LVEF) (OR > 1.26) increased the risk of recurrence. The annual 1-year recurrence rates decreased from 7.4% in 2009 to 4.0% in 2016 (p < 0.001). CONCLUSION: The recurrence rate after an incident ACS remained high in France, and the risk of recurrence did not depend on the etiology of the first event. Our results emphasize the importance of targeting patients with a major complication and/or an impaired LVEF who are at a higher risk of recurrence.

Sex differences in time trends in acute coronary syndrome management and in 12-month lethality: Data from the French MONICA registries.

BACKGROUND: Sex differences in clinical presentation, patient care and fatal outcomes after an acute coronary syndrome (ACS) have been reported. However, recent improvements in the care and treatment of ACSs have not been assessed with regard to possible sex differences. AIM: To assess sex differences in trends between 2006 and 2016 in the characteristics of ACSs, their management, and the associated mortality. METHODS: We assessed all men and women (aged 35-74) covered by the MONICA registries in north, east and south-west France and having been hospitalized for an incident (first) ACS during a 12-month period in 2006 or a 6-month period in 2016. We analyzed the patients' clinical, biochemical, electrocardiographic and care-related data, and their vital status 28 days and 12 months after the ACS. RESULTS: In 2006, women were older (<0.0001) and had more atypical symptoms than men (p < 0.01). These differences were no longer statistically significant in 2016. Medical care improved in both men and women. However, revascularization treatment, prescriptions of platelet aggregation inhibitors, statins, and functional rehabilitation were still more frequently provided to men than to women (p < 0.01) in 2016, independently of confounders. The 28-day or 12-month case fatality was not different between men and women in both 2006 and 2016. CONCLUSIONS: The results of the present study evidenced an improvement over time in the management of ACS. However, although there were no longer sex differences in the patients' age and clinical presentation, women with ACS were still less likely than men to receive revascularization and pharmacological treatments in 2016.

Trends of in-hospital and out-of-hospital coronary heart disease mortality in French registries during the period 2000 to 2016.

PURPOSE: To estimate trends of in- and out-of-hospital Acute Coronary Events (ACE) mortality rates from 2000 to 2016 and their respective contributions to total ACE mortality in France. METHODS: All fatal coronary events occurring between January 2000 and December 2016 were recorded for patients age 35-74 in the French MONICA registries. Trends in age-standardized and crude mortality rates were expressed as annual percentage changes (APC). RESULTS: Between 2000 and 2016, 20,822 fatal events were recorded, of which 69.4% were out-of-hospital. Almost 90% of out-of-hospital deaths occurred at home. Decreases in ACE mortality were greater inside than outside the hospital (APC: -4.3% vs. -2.9% in men; -5.0% vs. -3.2% in women), resulting in a higher contribution of out-of-hospital mortality to overall ACE mortality, from 65.3% in 2000 to 71.4% in 2016. This trend was more pronounced for elderly than younger patients. CONCLUSIONS: Between 2000 and 2016, ACE mortality declined in France. This trend was more pronounced for in- than for out-of-hospital. These results underline the importance of out-of-hospital mortality in driving ACE mortality rates and the need to further investigate ways to reduce it.

Comparison of clinical profiles and care for patients with incident versus recurrent acute coronary syndromes in France: Data from the MONICA registries.

BACKGROUND: Recurrence is common after an acute coronary syndrome (ACS). In order to better assess the prognosis for patients with ACS, we compared clinical profiles, treatments, and case fatality rates for incident vs. recurrent ACS. METHODS: We enrolled 1,459 men and women (age: 35-74) living in three geographical areas covered by French MONICA registries and who had been admitted to hospital for an ACS in 2015/2016. We recorded and compared the clinical characteristics and medical care for patients with an incident vs. a recurrent ACS. RESULTS: Overall, 431 (30%) had a recurrent ACS. Relative to patients with an incident ACS, patients with recurrence were older (p<0.0001), had a greater frequency of NSTEMI or UA (p<0.0001), were less likely to show typical symptoms (p = 0.045), were more likely to have an altered LVEF (p<0.0001) and co-morbidities. Angioplasty was less frequently performed among patients with recurrent than incident NSTEMI (p<0.05). There were no intergroup differences in the prescription of the recommended secondary prevention measures upon hospital discharge, except for functional rehabilitation more frequently prescribed among incident patients (p<0.0001). Although the crude 1-year mortality rate was higher for recurrent cases (14%) than for incident cases (8%) (p<0.05), this difference was no longer significant after adjustment for age, sex, region, diagnosis category and LVEF. CONCLUSION: Compared with incident patients, recurrent cases were more likely to have co-morbidities and to have suboptimal treatments prior to hospital stay, reinforcing the need for secondary prevention.

Comparison of Short- and Long-Term Prognosis between ST-Elevation and Non-ST-Elevation Myocardial Infarction.

BACKGROUND: Available data comparing long-term prognosis according to the type of acute coronary syndrome (ACS) are scarce, contradictory, and outdated. Our aim was to compare short- and long-term mortality in ST-elevated (STEMI) and non-ST-elevated myocardial infarction (non-STEMI) ACS patients. METHODS: Patients presenting with an inaugural ACS during the year 2006 and living in one of the three areas in France covered by the Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) registry were included. RESULTS: A total of 1822 patients with a first ACS-1121 (61.5%) STEMI and 701 (38.5%) non-STEMI-were included in the study. At the 28-day follow-up, the mortality rates were 6.7% and 4.7% (p = 0.09) for STEMI and non-STEMI patients, respectively, and after adjustment of potential confounding factors, the 28-day probability of death was significantly lower for non-STEMI ACS patients (Odds Ratio = 0.58 (0.36-0.94), p = 0.03). At the 10-year follow-up, the death rates were 19.6% and 22.8% (p = 0.11) for STEMI and non-STEMI patients, respectively, and after adjustment of potential confounding factors, the 10-year probability of death did not significantly differ between non-STEMI and STEMI events (OR = 1.07 (0.83-1.38), p = 0.59). Over the first year, the mortality rate was 7.2%; it then decreased and stabilized at 1.7% per year between the 2nd and 10th year following ACS. CONCLUSION: STEMI patients have a worse vital prognosis than non-STEMI patients within 28 days following ACS. However, at the 10-year follow-up, STEMI and non-STEMI patients have a similar vital prognosis. From the 2nd year onwards following the occurrence of a first ACS, the patients become stable coronary artery disease patients with an annual mortality rate in the 2% range, regardless of the type of ACS they initially present with.

Coronary heart disease incidence still decreased between 2006 and 2014 in France, except in young age groups: Results from the French MONICA registries.

BACKGROUND: Over the past few decades decreases in coronary heart disease morbidity and mortality rates have been observed throughout the western world. We sought to determine whether the acute coronary event rates had decreased between 2006 and 2014 among French adults, and whether there were sex and age-specific differences. METHODS: We examined the French MONICA population-based registries monitoring the Lille urban area in northern France, the Bas-Rhin county in north-eastern France and the Haute Garonne county in south-western France. All acute coronary events among men and women aged 35-74 were collected. RESULTS: Over the study period, the age-standardised attack rates decreased in both men (annual percentage change -1.5%, P = 0.0006) and women (annual percentage change -2.1%, P = 0.002). Also, the age-standardised incidence rates decreased in both men (annual percentage change -0.9%, P = 0.03) and women (annual percentage change -1.8%, P = 0.002) due to decreases in the 65-74 year age group. In men, age-standardised mortality rates decreased by 3.5% per year (P = 0.0004), especially in the 55-64 and 65-74 year age groups. In women, these rates decreased by 4.3% per year (P = 0.0009), particularly in the 35-44 and 65-74 year age groups. We also observed significant decreases in case fatality among both men (annual percentage change -1.7%, P < 0.0001) and women (annual percentage change -1.9%, P = 0.009). CONCLUSIONS: Downward trends in acute coronary event attack, incidence and mortality rates were observed between 2006 and 2014 in men and women. This effect was age dependent and was primarily due to decreases in the 65-74 year age group. There were no substantial declines in the younger age groups except for mortality in young women. Prevention measures still need to be strengthened, particularly in young adults.

Intra-aortic clusters undergo endothelial to hematopoietic phenotypic transition during early embryogenesis.

Intra-aortic clusters (IACs) attach to floor of large arteries and are considered to have recently acquired hematopoietic stem cell (HSC)-potential in vertebrate early mid-gestation embryos. The formation and function of IACs is poorly understood. To address this issue, IACs were characterized by immunohistochemistry and flow cytometry in mouse embryos. Immunohistochemical analysis revealed that IACs simultaneously express the surface antigens CD31, CD34 and c-Kit. As embryos developed from 9.5 to 10.5 dpc, IACs up-regulate the hematopoietic markers CD41 and CD45 while down-regulating the endothelial surface antigen VE-cadherin/CD144, suggesting that IACs lose endothelial phenotype after 9.5 dpc. Analysis of the hematopoietic potential of IACs revealed a significant change in macrophage CFC activity from 9.5 to 10.5 dpc. To further characterize IACs, we isolated IACs based on CD45 expression. Correspondingly, the expression of hematopoietic transcription factors in the CD45(neg) fraction of IACs was significantly up-regulated. These results suggest that the transition from endothelial to hematopoietic phenotype of IACs occurs after 9.5 dpc.

Embryonic origin of human hematopoiesis.

Hematopoietic stem cells (HSC) are at the origin of the adult hematopoietic system. They give rise to all blood cells through a complex series of proliferation and differentiation events that occur throughout the lifespan of the individual. Because of their potential clinical importance in transplantation, recent research has focused on the developmental origins of embryonic HSC. During development in vertebrate embryos, two independent anatomical sites generate hematopoietic cells. The yolk sac is responsible for a first ephemeral hematopoiesis, characterized by the early appearance of hematopoietic progenitors with limited development ability that rapidly differentiate toward erythro-myeloid lineages. Self-renewing, multipotent adult-type HSC that also exhibit B and T lymphoid potentials emerge autonomously in the aorta/gonad/mesonephros (AGM) region inside the embryo. In this review, we provide a brief summary of recent developments regarding the origins of hematopoietic stem cells in the early human embryo. The recent discovery that angiotensin-converting enzyme (ACE) is a novel cell surface marker of human HSC is discussed in detail.