M E Safar

Université René Descartes - Paris 5, Lutetia Parisorum, Île-de-France, France

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Publications (805)3619.92 Total impact

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    ABSTRACT: In a population of 56,242 individuals living in France, we showed that individuals born in France have significantly different levels of blood pressure (BP) and cardiovascular (CV) risk factors than African and Asian populations born in their own country but living long-term in France (average duration of stay, 5-10 years). The objective of our study was to investigate the impact of country of birth on BP and CV risk factors in a subpopulation of 9245 patients selected solely on the diagnosis of hypertension, either alone or with simultaneous type 2 diabetes. In the subgroup of individuals with hypertension alone, brachial systolic, diastolic, mean and pulse pressure (PP), heart rate (HR), augmentation index and PP amplification were significantly higher in African-born than French- and Asian-born populations. In the subgroup of individuals with both hypertension and diabetes, only augmentation index, PP amplification and brachial and central PP, but not brachial systolic, diastolic, mean BP, and HR, were elevated when the African-born subgroup was compared to the French- and Asian-born populations. Increased body mass index (BMI), waist-hip ratio (WHR), and deprivation scores, but not increased plasma lipids or glycemia, were consistently associated with the African-born population. The combination of diabetes and hypertension in African populations was associated with increased aortic stiffness and PP, together with greater body weight and WHR. In individuals with increased PP and hence systolic hypertension, increased PP requires systolic BP to be reduced whereas notable reductions in diastolic BP may have deleterious consequences.
    Frontiers in Physiology 09/2015; 6:248. DOI:10.3389/fphys.2015.00248 · 3.53 Impact Factor
  • La Presse Médicale 09/2015; DOI:10.1016/j.lpm.2015.05.014 · 1.08 Impact Factor
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    ABSTRACT: Hypertension (HTN) in chronic kidney disease (CKD) is influenced by blood pressure (BP) and the progression of CKD, including hemodialysis and renal transplantation. To date, the efficacy of antihypertensive drug strategies has chiefly been assessed by measuring steady-state systolic, diastolic and mean arterial pressures (MAP). However, recently elucidated features of the BP curve have highlighted other important goals, that is, the specific roles of pulse pressure (PP), arterial stiffness, pulse wave velocity (PWV) and wave reflections as potentially deleterious factors affecting the progression of HTN and CKD. Pharmacological strategies to date have included progressive withdrawal of alpha-blocking agents; efficacy of beta-blockers for coronary prevention; use of angiotensin blockade in HTN with glomerular injury, using angiotensin-converting enzyme inhibition or receptor blockade, as mono but never double-blockade, to avoid major complications; development of combination therapies with diuretics and/or calcium channel blockers. Nowadays, most clinical trials show that SBP, DBP and MAP-lowering is an effective strategy, although results no longer show preference for any specific drug class.Studies of arterial stiffness in CKD have become crucial. In older individuals, PWV is considerably elevated. The 'stiffness gradient' disappears or is inverted (normally, aortic PWV is lower than brachial PWV). Despite BP-lowering, PP is insufficiently dampened, thus promoting microcirculatory damage, progression of arterial calcifications and disturbed wave reflections, which all increase the risk of mortality. In the absence of effective hemodialysis or graft, increased arterial stiffness is therefore a major cardiovascular risk factor in CKD.
    Journal of Hypertension 07/2015; DOI:10.1097/HJH.0000000000000711 · 4.72 Impact Factor
  • Harold Smulyan · Ari Lieber · Michel E Safar
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    ABSTRACT: In patients with both hypertension and type II diabetes, the systolic blood pressure (SBP) increases linearly with age, while that of diastolic blood pressure (DBP) declines curvilinearly as early as age 45, all suggesting the development of increased arterial stiffness. Increased stiffness is an important, independent, and significant risk predictor in subjects with hypertension and diabetes. In patients with both diseases, stiffness assessed at the same mean arterial pressure (MAP) was significantly higher in diabetic patients. Arterial stiffness is related to age, heart rate (HR), and MAP, but in diabetic patients, it also related to diabetes duration and insulin treatment (IT). In the metabolic syndrome (MetSyn), diabetes also acts on the small arteries through capillary rarefaction to reduce the effective length of the arterial tree, increases the reflected pulse wave and thus the pulse pressure (PP). These studies indicate that diabetes and hypertension additively contribute to increased pulsatility and suggest that any means to reduce stiffness would be beneficial in these conditions. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    American Journal of Hypertension 07/2015; DOI:10.1093/ajh/hpv107 · 2.85 Impact Factor
  • C Chi · C Tai · J Wang · A Protogerou · J Blacher · M E Safar · Y Zhang · Y Xu
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    ABSTRACT: Current clinical evidence and latest guidelines recommended the combination antihypertensive therapy with angiotensin-converting enzyme (ACE) inhibitor / angiotensin receptor blocker (ARB) and calcium channel blocker (CCB) in patients with grade 2 to 3 hypertension. However, data are scarce in the comparison between the ACE inhibitor / ARB + CCB (A+C) therapy and other combinations. We therefore conducted a meta-analysis to see if ACE inhibitor/ARB combined with CCB is superior to other combinations.(Figure is included in full-text article.) DESIGN AND METHOD:: A meta-analysis was conducted in 20,669 hypertensives from 9 randomized controlled trials and we compared the A+C therapy with other combinations, in terms of blood pressure (BP) reduction, clinical outcomes and adverse effects. BP reduction did not differ significantly between the A+C therapy and other combination therapies, neither in systolic nor in diastolic BP, with P = 0.43 and P = 0.41, respectively. However, A+C strategy, compared with other combination therapies, achieved a significantly lower incidence of cardiovascular composite endpoints, including cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke (Risk ratio [RR] and 95% confidential interval [CI]: 0.80 [0.70, 0.91], P < 0.001, see as Figure), but similar all-cause mortality (0.90 [0.77, 1.04], P = 0.15) and stroke rate (0.90 [0.77, 1.04], P = 0.09). Moreover, A+C combination therapy exhibited a 3.10 ml/min/1.73m2 greater estimated glomerular filtration rate than other combinations (P = 0.01). Lastly, A+C therapy showed a similar incidence of adverse effects as other combinations (P = 0.34), but had a significantly lower incidence of severe adverse effects (0.85 [0.73, 0.98], P = 0.03). In summary, clinical evidences favor A+C therapy, which is superior to other combinations, in current anti-hypertensive strategy, with greater clinical benefit in cardiovascular outcome and reservation of renal function.
    Journal of Hypertension 06/2015; 33 Suppl 1 - ESH 2015 Abstract Book:e19-e20. DOI:10.1097/01.hjh.0000467402.25796.00 · 4.72 Impact Factor
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    ABSTRACT: It was reported that, in addition to blood pressure (BP) level, BP variability could also provide prognostic value of target organ damage, cardiovascular and all-cause mortality. Therefore, evaluation of patients' BP variability could potentially offer guiding information on their clinical therapy. BP variability could be assessed by calculating standard deviation, coefficient of variation and other parameters of BP readings from 24-h ambulatory BP monitor, known as short-term BP variability. More recently, an emerging BP variability can be derived from regular home and office BP recordings for 1 week or several months, known as long-term BP variability. Although the cause and meaning of fluctuated BP was not well elucidated, several factors, including age, mean BP, heart rate variability and arterial stiffness, may influence patients' BP variability. Most clinical investigations indicated a significant prognostic value of either short- or long-term BP variability, with regards to target organ damage, cardiovascular events and mortality, but controversy exists in this field, especially its incremental prognostic value in addition to BP level. Till now, there is no solid evidence indicating any effective agent in terms of BP variability reduction, but some clinical studies favor CCB in reducing both short- and long-term BP variability. Further studies are warranted to investigate the standardized evaluation of patients' BP variation, its cause and added prognostic significance, as well as effective treatment.
  • A.D. Protogerou · M.E. Safar · G.E. Plante · J. Blacher
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    ABSTRACT: Arterial stiffening, especially of the large elastic arteries, is a fundamental vascular aging trait, which is, however, accelerated in the presence of genetic and environmental factors. It is an early marker of subclinical arterial disease but also a well-established biomarker of clinical cardiovascular disease events and cardiovascular disease mortality. Preventive strategies calcium channel blockade and allopurinol, a careful individualized de-stiffening strategy on the basis of sodium balance, in combination with the renin-angiotensin system blockade, appears to be the currently available optimal strategy.
  • A. Benetos · A. Aviv · P. Lacolley · M.E. Safar · V. Regnault
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    ABSTRACT: Increases in arterial stiffness and pulse pressure are typical features of the arterial stiffness during aging and are associated with increased risk of cardiovascular complications. Cellular and molecular determinants of arterial stiffness have not been completely elucidated. Clinically, the carotid-femoral pulse wave velocity (PWV) is the gold standard parameter of arterial stiffness. A recent genome-wide scan of the Framingham Heart Study population has shown that arterial stiffness and mean and pulsatile components of blood pressure are heritable and map to separate the genetic loci in humans, suggesting that distinct genes may modulate these two phenotypes. This chapter details the recent knowledge on the influence of genetic determinants and telomere length on the development of age-related phenotypes. Recent genetic studies have revealed specific genes contributing to arterial stiffening. Available data on genome-wide association (GWA) have been initiated on PWV and have identified common genetic variation in specific loci or single-nucleotide polymorphisms (SNP) significantly associated with PWV. Telomere length at birth is strongly determined genetically and is the main determinant of leukocytes' telomere length (LTL) later in life. Short LTL is associated with increased risk of stiffness and atherosclerosis of the carotid artery, atherosclerotic heart disease, and diminished survival in the elderly.
  • S.A. Bahous · S. Korjian · Y. Daaboul · J. Blacher · M.E. Safar
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    ABSTRACT: Renal transplantation is the best renal replacement modality for patients with end-stage renal disease in terms of patient survival and quality of life. Despite substantial improvement in recipient outcome, stiffness of the large arterial system and cardiovascular (CV) mortality remain high compared to age- and sex-matched subjects in the general population. In addition to traditional CV risk factors, transplantation-specific parameters emerge and are related to immune interactions, drug specifications, and donor characteristics. Some of these parameters appear to be modulators of risk factors and graft and recipient outcome. Acute rejection, for example, appears as a major and independent determinant of high arterial stiffness in recipients of kidney grafts. Furthermore, past history of CV events, low graft filtration function, and donor age determine long-term patient and graft outcome. Living kidney donors, on the other hand, are normally protected especially that they are carefully selected prior to transplantation. Despite a similar long-term outcome compared to the general population, donors may be at higher risk for stiffening of the large arterial system, especially if they cluster with time, CV comorbidities.
  • A. Benetos · S. Gautier · M.E. Safar
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    ABSTRACT: The 2013 ESC-ESH Guidelines for the management of arterial hypertension stated that in elderly (>80 years) individuals, lowering SBP to < 150mmHg is strongly evidence-based. These guidelines are mainly based on the results of the Hypertension in the Very Elderly (HYVET) study which showed the beneficial effect of decreasing SBP with antihypertensive treatment in patients older than 80 years. This trial was conducted in a highly selected population of robust elderly patients with very low comorbidities. Thus, despite the interest of these results, we believe that the question of the benefits of antihypertensive treatment in the very old is not unequivocally settled and may depend on the magnitude of co-morbidities, frailty and functional decline. The PARTAGE (Predictive values of blood pressure and arterial stiffness in institutionalized very aged population) multicenter study performed in very old, frail subjects living in nursing homes reported a 30% increase in all-cause mortality in patients ranked in the lowest tertile of SBP (<130mmHg) compared to the two upper tertiles. These results remained identical after adjusting for several confounders such as age, gender, history of previous CV disease, index of co-morbidity, cognitive function and autonomy status. These paradoxical results can be explained by the fact that in these very old frail subjects, a low SBP may not simply be a sign of so-called good arterial health, but often of malnutrition and of co-morbidities such as heart failure, neurological disorders etc., as well as other concomitant conditions associated with poor prognosis. Irrespective of the underlying explanation, the present results indicate that the BP levels in very old frail individuals are evidently not reliable. These findings raise the question as to relevance of BP levels as an indicator of the cardiovascular risk in these subjects. This is of major interest since iatrogenic-induced problems are also a major issue in geriatric subjects. In fact, at the present time, no study has provided evidence that higher morbidity-mortality rates in those with very low BP is due to low BP in itself or is just a sign of general bad health. Interventional clinical trials will provide critical information to guide physicians in order to fixe specific goals for treating hypertension and decreasing the risk of cardiovascular complications in these very old and frail individuals.
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    ABSTRACT: In recent clinical investigations, visit-to-visit systolic blood pressure (SBP) variability was proven as a predictor of cardiovascular events and all-cause mortality. However, inconsistent results exist in this association. A meta-analysis of 13 prospective studies was conducted to evaluate the prognostic value of visit-to-visit SBP variability by different parameters in 77,299 patients with a mean follow-up of 6.3 years. The pooled age- and mean SBP-adjusted hazard ratios (HRs) for all-cause mortality were 1.03 (95% confidence interval [CI], 1.02-1.04; P<.001) per 1-mm Hg increase in SBP standard deviation (SD) and 1.04 (1.02-1.06, P<.001) per 1% in SBP coefficient of variation, and the corresponding values of cardiovascular mortality were 1.10 (1.02-1.17, P<.001) and 1.01 (0.99-1.03, P=.32), respectively. Moreover, a 1-mm Hg increase in SD was significantly associated with stroke, with an HR of 1.02 (1.01-1.03, P<.001). Visit-to-visit SBP variability, independent of age and mean SBP, is a predictor of cardiovascular and all-cause mortality and stroke. ©2015 Wiley Periodicals, Inc.
    Journal of Clinical Hypertension 02/2015; 17(2). DOI:10.1111/jch.12484 · 2.85 Impact Factor
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    ABSTRACT: Background/Aims: Renal function decreases over time as a result of reduction in the number of functioning nephrons with age. In recipients and donors of kidney grafts, renal function decline may be linked differently to various parameters, namely arterial stiffness. Methods: We conducted a prospective cohort study including 101 recipients of kidney grafts and their donors aiming at determining the factors correlating with renal function decline over time. Aortic stiffness was evaluated by the non-invasive measurement of aortic pulse wave velocity. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation and the annualized change was determined. Results: Decline in renal function was estimated at 1-year post-transplantation and annually thereafter (median follow-up 8 years, range 3.6-18.3), as the mean of the annualized decrease in the glomerular filtration rate. In recipients, filtration rate decreased by 4.8 ± 19.7 mL/min/1.73m2 the first post-transplant year, and at a yearly rate of 2.2 ± 3.8 mL/min/1.73m2 thereafter. The first year decline was related to smoking and acute rejection. Later decline was significantly associated with donor age and aortic stiffness. In living donors, renal function decline after the first year corresponded to 0.7 mL/min/1.73m2, was significantly lower than that of recipients (p<0.001), and was determined by donor age at nephrectomy. Conclusion: Recipients of kidney grafts show a glomerular filtration rate decline over time that is significantly associated with donor age and aortic stiffness after the first post-transplant year, while donors demonstrate a lower decline that is mostly determined by age at nephrectomy.
    American Journal of Nephrology 12/2014; 41(1). DOI:10.1159/000371858 · 2.67 Impact Factor
  • Michel E Safar · Gérard E Plante · Albert Mimran
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    ABSTRACT: Classical studies indicate that the contribution of kidneys to hypertension is almost exclusively related to the association between mean arterial pressure (MAP) and vascular resistance. Recent reports including estimates of glomerular filtration rate (GFR) have shown that pulse pressure (PP) and pulse wave velocity, 2 major indices of arterial stiffness, now emerge as significant predictors of cardiovascular risk and age-associated decline in GFR. Such findings are mainly observed in patients with hypertension and renal failure and in atherosclerotic subjects undergoing coronary angiography. In such patients, amplification of PP between ascending and terminal aorta at the renal site is constantly increased over 10mm Hg (P < 0.001), whereas MAP level remains continuously unmodified. This PP amplification is significantly associated with presence of proteinuria. Furthermore, increases in plasma creatinine and aortic stiffness are independently and positively correlated (P < 0.001) both in cross-sectional and longitudinal studies. All these relationships associating PP, arterial stiffness, and renal function are mainly observed in patients 60 years of age or older. Furthermore, in renal transplant patients and their donors, subjects have been recruited for evaluations of arterial stiffness and posttransplant decline in GFR. Determinants of GFR decline were evaluated 1 and 9 years after transplantation. The first year GFR decline was related to smoking and acute rejection, whereas the later was significantly and exclusively associated with donor age and aortic stiffness. Thus, in hypertensive humans, the observed association between PP and GFR suggests that the 2 parameters are substantially mediated by arterial stiffness, not exclusively by vascular resistance. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    American Journal of Hypertension 12/2014; 28(5). DOI:10.1093/ajh/hpu206 · 2.85 Impact Factor
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    ABSTRACT: Aortic blood pressure (BP) and 24-h ambulatory BP are both better associated with target organ damage than office brachial BP. However, it remains unclear whether a combination of these two techniques would be the optimal methodology to evaluate patients' BP in terms of left ventricular diastolic dysfunction (LVDD) prevention. In 230 participants, office brachial and aortic BPs were measured by a validated BP monitor and a tonometry-based device, respectively. 24-h ambulatory brachial and aortic BPs were measured by a validated ambulatory BP monitor (Mobil-O-Graph, Germany). Systematic assessment of patients' LVDD was performed. After adjustment for age, gender, hypertension and antihypertensive treatment, septum and lateral E/Ea were significantly associated with office aortic systolic BP (SBP) and pulse pressure (PP) and 24-h brachial and aortic SBP and PP (P⩽0.04), but not with office brachial BP (P⩾0.09). Similarly, 1 standard deviation in SBP was significantly associated with 97.8±20.9, 86.4±22.9, 74.1±23.3 and 51.3±22.6 in septum E/Ea and 68.6±20.1, 54.2±21.9, 37.9±22.4 and 23.1±21.4 in lateral E/Ea, for office and 24-h aortic and brachial SBP, respectively. In qualitative analysis, except for office brachial BP, office aortic and 24-h brachial and aortic BPs were all significantly associated with LVDD (P⩽0.03), with the highest odds ratio in 24-h aortic SBP. Furthermore, aortic BP, no matter in the office or 24-h ambulatory setting, showed the largest area under receiver operating characteristic curves (P⩽0.02). In conclusion, 24-h aortic BP is superior to other BPs in the association with LVDD.Journal of Human Hypertension advance online publication, 13 November 2014; doi:10.1038/jhh.2014.101.
    Journal of Human Hypertension 11/2014; 29(7). DOI:10.1038/jhh.2014.101 · 2.70 Impact Factor
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    ABSTRACT: Although the clinical relevance of brachial blood pressure (BP) measurement for cardiovascular (CV) risk stratification is nowadays widely accepted, this approach can nevertheless present several limitations. Pulse pressure (PP) amplification accounts for the notable increase in PP from central to peripheral arterial sites. Target organs are more greatly exposed to central hemodynamic changes than peripheral organs. The pathophysiological significance of local BP pulsatility, which has a role in the pathogenesis of target organ damage in both the macro- and the microcirculation, may therefore not be accurately captured by brachial BP as traditionally evaluated with cuff measurements. The predictive value of central systolic BP and PP over brachial BP for major clinical outcomes has been demonstrated in the general population, in elderly adults and in patients at high CV risk, irrespective of the invasive or non-invasive methods used to assess central BP. Aortic stiffness, timing and intensity of wave reflections, and cardiac performance appear as major factors influencing central PP. Great emphasis has been placed on the role of aortic stiffness, disturbed arterial wave reflections and their intercorrelation in the pathophysiological mechanisms of CV diseases as well as on their capacity to predict target organ damage and clinical events. Comorbidities and age-related changes, together with gender-related specificities of arterial and cardiac parameters, are known to affect the predictive ability of central hemodynamics on individual CV risk.
    Current Pharmaceutical Design 10/2014; 21(6). DOI:10.2174/1381612820666141023164125 · 3.45 Impact Factor
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    ABSTRACT: Reduction strategies of blood pressure, as a modifiable cardiovascular risk, are currently based on office assessment of brachial artery blood pressure. However, antihypertensive treatment based on brachial BP values reduces cardiovascular risk but cannot completely reverse the hypertension-induced risk of morbidity events. As is well known, BP varies in different arterial systems and invasive and non-invasive studies have demonstrated that brachial BP does not necessarily reflect central aortic BP. Emerging evidences now suggest that central pressure may predict cardiovascular diseases better than brachial BP; moreover, it may differently respond to certain antihypertensive drugs. The potential effects beyond peripheral BP control may be due to specific protective properties of different antihypertensive drugs in affecting central aortic pressure and arterial stiffness. Although data on direct cardiovascular benefit impact of central blood pressure treatment in randomized clinical trials are still lacking, it is likely that the improvement of quality of care and the individualized assessment of the hypertension-associated cardiovascular risk are achievable with the use of central hemodynamics. Therefore, basing antihypertensive treatment guidance on central pressures rather than on peripheral blood pressure may be the key for future antihypertensive strategies.
    Current Pharmaceutical Design 10/2014; 21(6). DOI:10.2174/1381612820666141023164530 · 3.45 Impact Factor
  • Yi Zhang · Davide Agnoletti · Ji-Guang Wang · Yawei Xu · Michel E. Safar
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    ABSTRACT: Background The antihypertensive effect of indapamide has never been clearly understood, particularly in hypertensive patients with diabetes mellitus. Methods A total of 565 patients were randomly selected to receive either indapamide 1.5 mg or enalapril 10 mg daily for 12 months. Brachial blood pressure (BP) and plasma and urinary electrolytes were measured at baseline and at the end of follow-up. Sodium and potassium levels and excretion rates were measured in overnight urine collections. Results After 12 months’ treatment, similar significant reductions were observed in systolic and diastolic BP and pulse pressure levels in both treatment arms (P<0.001). However, age, body mass index (BMI), diabetes duration and plasma sodium reductions were shown to be major, independent factors influencing BP reduction with indapamide, but not with enalapril. Regression coefficients were positive for age and plasma sodium reductions (P≤0.009) but negative for BMI and diabetes duration (P≤0.008). Similar findings were observed for pulse pressure. These results were more notable in elderly patients, did not differ regardless of whether BP reduction was measured in absolute or percent values, and were associated with increased sodium and potassium excretion rates. Conclusions Indapamide is more effective than enalapril at reducing BP in elderly diabetic hypertensives with marked sodium retention.
    Journal of the American Society of Hypertension 10/2014; 9(1). DOI:10.1016/j.jash.2014.10.003 · 2.61 Impact Factor
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    ABSTRACT: During year 2013, several recommendations for the management of hypertension were published: recommendations of the French and European Societies of Hypertension and two recommendations from the USA, those from the ACC/AHA/CDC groups and those from the JNC 8. The recommendations of the JNC 8 are not, strictly speaking, the recommendations of JNC 8, since they are neither endorsed by their sponsor: the National Heart, Lung and Blood Institute (NHLBI), nor by any other supervisor. They only commit their authors. Just before the publication of the JNC 8, "competing" recommendations, jointly produced by the AHA, ACC and CDC, were jointly published in Hypertension and in the Journal of American College of Cardiology, with different preferred treatment choices and significantly different algorithms. The authors of the JNC 8 have only included in their literature review randomized controlled trials of sufficient power. Randomized controlled trials are clearly the gold standard of comparative trials in medicine, but can they summarize all the knowledge? The authors of the JNC 8 propose in subjects over 60, a therapeutic threshold and target blood pressure of 150/90mmHg. This original threshold is poorly supported by the evidence and possibly increases the risk of physicians' inertia. The issue of experts' conflicts of interest has greatly changed the rules of drafting guidelines for clinical practice. Knowing that the vast majority of clinical trials is promoted by drug industry, could guidelines be strictly without any conflict of interest? Finally, recommendations for practice should have as primary, if not unique, objective to improve the practice.
    La Presse Médicale 09/2014; 43(10). DOI:10.1016/j.lpm.2014.03.031 · 1.08 Impact Factor
  • Michel E Safar · Bernard I Levy
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    ABSTRACT: Background: Patho-physiological and pharmacological studies have consistently noticed that, with the exception of subjects with end-stage renal disease, total intravascular blood volume is not increased in patients with chronic hypertension. Methods: Because the mean circulatory pressure is enhanced in such subjects, it was postulated that the compliance of the cardiovascular system could be abnormally low in this particular population. This simple observation has influenced a great part of our experimental and clinical research directed toward subjects with hypertension and their relationship with the compliance of the vascular system. Results: These works started between 1970 and 1980 by methodological investigations and validations followed by analysis of clinical situations that showed that venous and mostly arterial stiffness were significantly increased in hypertensive patients independently of blood pressure level. During the same time, we assessed the role of endothelium on the large arterial wall mechanical properties in normotensive and hypertensive rats. Thereafter more specific directions have been developed, affecting large arteries structure and function and arterial wall remodeling, including their consequences on central and peripheral hemodynamics. In parallel, epidemiological studies identified the pulsatile hemodynamic parameters as major independent predictors of cardiovascular risks. Conclusions: The consequences of these alterations on clinical pharmacology and therapeutics in hypertension are analyzed in detail.
    American Journal of Hypertension 09/2014; 28(1). DOI:10.1093/ajh/hpu155 · 2.85 Impact Factor
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    M E Safar · J Blacher
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    ABSTRACT: In recent years, treatment strategies for hypertension have often focused on combination therapies that include diuretics and renin angiotensin aldosterone system blockers such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. However, in clinical practice, a significant number of patients do not respond completely to these combination treatments, and long-term reduction of cardiovascular risk remains insufficient. The particularly high residual cardiovascular risk of hypertensive patients, even when adequately treated with strategies based on renin angiotensin aldosterone system blockers, speaks in favor of new, innovative strategies. Thus, it has become relevant to consider whether it is always necessary to block plasma renin activation and whether other guideline-approved combinations should be considered routinely. Diuretic/calcium channel blocker combinations, which are supported by significant long-term evidence, are put forth as a preferred combination in the main guidelines, but are still underused by physicians who do not yet have easy access to such treatments. Fixed-dose indapamide sustained release/amlodipine is the first such single-pill combination to become available. Complementary mechanisms of action of these two molecules are expected to lead to greater and longer-term reductions in systolic blood pressure and pulse pressure and potentially to the reduction of cardiovascular risk.
    American Journal of Cardiovascular Drugs 08/2014; 15(1). DOI:10.1007/s40256-014-0087-y · 2.42 Impact Factor

Publication Stats

29k Citations
3,619.92 Total Impact Points


  • 2006–2015
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
    • University of Florida
      Gainesville, Florida, United States
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
  • 1997–2015
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • Tongji Medical University
      • Department of Cardiology
      Shanghai, Shanghai Shi, China
  • 2002–2013
    • University of New South Wales
      Kensington, New South Wales, Australia
    • Centre D'Investigations Préventives Et Cliniques
      Lutetia Parisorum, Île-de-France, France
    • Covance
      Princeton, New Jersey, United States
  • 2008–2012
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • St. James's Hospital
      Dublin, Leinster, Ireland
  • 2003–2011
    • State University of New York Upstate Medical University
      • • Division of Cardiology
      • • Department of Medicine
      Syracuse, NY, United States
    • Cea Leti
      Grenoble, Rhône-Alpes, France
  • 2010
    • Victor Chang Cardiac Research Institute
      Darlinghurst, New South Wales, Australia
    • Private geriatrics hospital “les Magnolias”
      Île-de-France, France
    • Conservatoire National des Arts et Métiers
      Lutetia Parisorum, Île-de-France, France
  • 2007–2009
    • National and Kapodistrian University of Athens
      • • Department of Medicine
      • • Division of Clinical Therapeutics
      Athens, Attiki, Greece
    • Hôpital "Sainte-Périne - Rossini - Chardon-Lagache" – Hôpitaux universitaires Paris Ile-de-France Ouest
      Lutetia Parisorum, Île-de-France, France
    • Charles University in Prague
      • Department of Internal Medicine (2. LF)
      Praha, Praha, Czech Republic
  • 1989–2009
    • French Institute of Health and Medical Research
      • Paris-Cardiovascular Research Center PARCC
      Lutetia Parisorum, Île-de-France, France
  • 2004–2007
    • Centre Hospitalier Universitaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
    • University of Naples Federico II
      Napoli, Campania, Italy
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
    • Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)
      Lutetia Parisorum, Île-de-France, France
    • Hotel Dieu Hospital
      Kingston, Ontario, Canada
  • 2003–2007
    • Maastricht University
      • Farmacologie
      Maestricht, Limburg, Netherlands
  • 2004–2006
    • University Medical Center – Rizk Hospital
      Beyrouth, Beyrouth, Lebanon
  • 2002–2004
    • Centre Chirurgical Marie Lannelongue
      Plessis-Robinson, Île-de-France, France
  • 2001
    • ICPS - Institut Cardiovasculaire Paris Sud
      Масси, Île-de-France, France
    • Ghent University
      Gand, Flanders, Belgium
  • 1989–2001
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2000
    • University of Ottawa
      Ottawa, Ontario, Canada
    • Catholic University of Louvain
      Лувен-ла-Нев, Walloon, Belgium
  • 1989–2000
    • American Hospital of Paris
      Lutetia Parisorum, Île-de-France, France
  • 1979–1999
    • University of Lyon
      Lyons, Rhône-Alpes, France
    • Université de Picardie Jules Verne
      Amiens, Picardie, France
  • 1998
    • University of Leuven
      • Division of Hypertension and Cardiovascular
      Louvain, Flemish, Belgium
  • 1994
    • Hôpital Foch
      Lutetia Parisorum, Île-de-France, France
  • 1991
    • Institut de France
      Lutetia Parisorum, Île-de-France, France
    • Innovació i Recerca Industrial i Sostenible
      Castelldefels, Catalonia, Spain
  • 1987
    • University of Vienna
      Wien, Vienna, Austria