Background: Men account for over 85% of Sudden Cardiac Arrest (SCA) occurring during sport activities. This over-representation persists even after adjusting for sports participation and cannot be fully explained by biological or physiological factors. We hypothesized that male psychology and related behavioral responses might play a role in this over-representation. Method: We integrated data from two independent sources. The first was a cardiac arrest registry that prospectively and extensively collected data on 55,000 out-of-hospital cardiac arrest in individuals over 18 years old within a given area between October 2011 and April 2024. The second source contained race participation records for half-marathon (HM) and 20 km race from 2011 to 2024. Data were collected annually (excluding 2020 due to the pandemic) before being aggregated. This study focused exclusively on race finishers and SCA cases. Acceleration was calculated by comparing the speed over the last kilometer with the average speed over the previous five kilometers, with each runner serving as their own control. Acceleration was categorized into 0.2 km/h intervals, and we analyzed the distribution of male and female runners within these categories. To estimate the 95% confidence interval (CI) for the male-to-female ratio in each acceleration category, we used the log-ratio method. Results: Over the past 10 years, among 714,856 participants (68.2% of males), 12 cases of SCA were recorded. Of these, 83.3% (10/12) were men, with a mean age of 39.7 ± 10.7 years. Notably, 9 out of 12 SCAs occurred in the final kilometer of the race. An acceleration in speed was observed in 87% of finishers during this last kilometer. The proportion of men who accelerated within 0 and 1 km/h (mild) was lower than that of women (0.87 [95%CI 0.86-0.87], p<0.001). Conversely, the proportion of men who accelerated by more than 2 km/h (strong) was nearly twice that of women (1.96 [95%CI 1.86-2.06], p < 0.001) (Figure 1). Conclusion: While direct causality cannot be established, men’s competitive attitudes and behavioral responses may partially explain their over-representation in sport-related SCA.

HomeHypertensionVol. 81, No. 5Michel Emile Safar 1937 to 2024 Free AccessObituaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessObituaryPDF/EPUBMichel Emile Safar 1937 to 2024 Jacques Blacher, Athanase Benetos, Athanase D. Protogerou, Harry Struijker-Boudier, Bernard I. Levy and for Michel Safar's students, colleagues and friends of the Paris Vascular School Jacques BlacherJacques Blacher Correspondence to: Jacques Blacher, Unité hypertension artérielle, prévention et thérapeutiques cardiovasculaires, Centre de diagnostic et de thérapeutique, Hôtel-Dieu; Assistance Publique Hôpitaux de Paris; Université Paris Cité, Paris, France. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4860-4279 Université Paris Cité; Unité hypertension artérielle, prévention et thérapeutiques cardiovasculaires, Centre de diagnostic et de thérapeutique, Hôtel-Dieu, Assistance Publique Hôpitaux de Paris, Paris, France (J.B.). , Athanase BenetosAthanase Benetos https://orcid.org/0000-0002-5197-1515 CHRU Nancy, University Hospital of Nancy, France (A.B.). , Athanase D. ProtogerouAthanase D. Protogerou https://orcid.org/0000-0002-3825-532X Cardiovascular Prevention & Research Unit, Clinic/Laboratory of Pathophysiology, Laiko Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece (A.D.P). , Harry Struijker-BoudierHarry Struijker-Boudier https://orcid.org/0000-0003-2350-7675 Cardiovascular Research Institute, Maastricht, the Netherlands (H.S.-B.). , Bernard I. LevyBernard I. Levy https://orcid.org/0000-0001-9596-5347 Inserm U970, PARRC, Hôpital Européen Georges Pompidou, Paris, France (B.I.L). and for Michel Safar's students, colleagues and friends of the Paris Vascular School Originally published17 Apr 2024https://doi.org/10.1161/HYPERTENSIONAHA.124.22893Hypertension. 2024;81:e49–e50Michel Safar died on January 28, 2024. He was 86 years old. Michel Safar was born in Algiers in 1937. He began his medical studies in early 50s in Paris, was an extern, a fellow, and then clinical head before graduating in nephrology and being appointed as associate professor in 1972. He was appointed professor of internal medicine in 1980, then professor of therapeutics in 1990. He was the Director of the Clinical Diagnosis Center of the Broussais Hospital (Paris) from 1980, and the Director of the Internal Medicine Department of the same hospital from 1989. In 2002, he moved to another major hospital of Paris, Hôtel-Dieu and became the Director of the Diagnosis Center of this hospital until his retirement. From 1991 to 1999, he was also director of the research unit u337 of the Inserm (National Institutes of Health and Medical Research).Since the late 60s, Michel Safar was the specialist in arterial hemodynamics within the team of his mentor, Paul Milliez. Since the publication of his first scientific article in 1970,1 arterial hemodynamics has been the main subject of his 1300 publications, which appeared in high-quality peer-reviewed journals in French and English.2–4Throughout Dr Safar's career, he worked with multiple colleagues to define and implement innovative approaches to understand factors that regulate arterial pressure. He managed to have a global, holistic vision, ranging from physics and engineering to physiology and pharmacology, from fundamental sciences to clinical applications.5–7 He juggled between the concepts of vascular impedance, arterial compliance, elastic modulus, and propagation of the pulsatile wave; he evaluated arterial stiffness and studied the determinants of the incident and the reflected pulse waves. Michel allowed us to better understand the impact of the systolic component of blood pressure, at a time when only diastolic pressure focused the attention of experts.8Through tenacity, his work allowed him to hypothesize, before confirming in large clinical studies, that the pulsatile component of blood pressure, namely the pulse pressure, was the most closely parameter associated with the prognosis of hypertensive patients especially in the older ones.9,10The qualities of the man were just as exceptional as the qualities of the scientist. His secretary received, during the last weeks, dozens and dozens of messages, of sadness, pain, friendship but also poignant tributes to the man he was.Here are a few of these messages:I loved seeking his advice, as discreet as it was luminous, full of common sense and subtle intelligence. So many exceptional hours spent together.His speeches combined rigor, elegance, and clarity.I really liked Michel, a loyal and warm friend, always available during difficult times, including my personal worries.Michel was for us a support and a faithful, unforgettable advisor, to my memory and to my heart.The disappearance of Michel leaves us all a little orphaned.His inimitable style will remain in our memories: elegance and conciseness, making people understand, kindness, humor, generosity.Through his research work, Michel had created a real scientific dynamic, while being a fair and discreet man, rigorous, caring, and respected by all.Michel very clearly guided my career and I still think of him very often.A man of very high quality, the community of clinicians owes him a lot.Michel Safar was much more than a leader. He was a guide, a model, a mentor for a very large number of physicians and researchers who spent from a few months to several years working with him. He had this positive and caring requirement that pulls you up. Michel Safar was a very hard worker and at the same time, he was very demanding regarding the quality of his team's work and could hardly tolerate those who did not respect their commitments. He wanted the best for his team members; he had this ability, so rare, to guide without imposing, at each people's pace to help them evolve as best as possible. Dr Safar was keen on history and arts, having been raised and educated in a cultivated and philosophical environment. He had a particular taste and talent for transmission. Many physicians and researchers from all over the world knocked on his door; he welcomed them all and did his best to find a place for everyone. Michel Safar had this generosity. He was committed to his colleagues, students, friends, and even sometimes to people he barely knew. His loyalty was unwavering. He has set up numerous collaborations with dozens of teams around the world. He was the founder and chairman of the Paris workshops on structure and function of large arteries (mainly known as the Safar's workshops) from 1992 to 2020, involving every 2 years 100 of scientists and physicians throughout the world. He was at the origin of the Paris Vascular School.We will miss Michel Safar terribly.Our warm thoughts go to Anne, his wife and Marie-Claude, Hélène, and Pierre, his children.Download figureDownload PowerPointFigure. Photograph of Michel Safar.ARTICLE INFORMATIONSources of FundingNone.Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page e50.Correspondence to: Jacques Blacher, Unité hypertension artérielle, prévention et thérapeutiques cardiovasculaires, Centre de diagnostic et de thérapeutique, Hôtel-Dieu; Assistance Publique Hôpitaux de Paris; Université Paris Cité, Paris, France. Email jacques.blacher@aphp.frREFERENCES1. Safar M, Weil B. Hemodynamic study in arterial hypertension.Bull Acad Natl Med. 1970; 154:252–255MedlineGoogle Scholar2. O'Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy.Hypertension. 2005; 46:200–204. doi: 10.1161/01.HYP.0000168052.00426.65LinkGoogle Scholar3. Safar ME, Frohlich ED. The arterial system in hypertension. A prospective view.Hypertension. 1995; 26:10–14. doi: 10.1161/01.hyp.26.1.10LinkGoogle Scholar4. Mourad JJ, Pannier B, Blacher J, Rudnichi A, Benetos A, London GM, Safar ME. Creatinine clearance, pulse wave velocity, carotid compliance and essential hypertension.Kidney Int. 2001; 59:1834–1841. doi: 10.1046/j.1523-1755.2001.0590051834.xCrossrefMedlineGoogle Scholar5. Benetos A, Levy BI, Lacolley P, Taillard F, Duriez M, Safar ME. Role of angiotensin II and bradykinin on aortic collagen following converting enzyme inhibition in spontaneously hypertensive rats.Arterioscler Thromb Vasc Biol. 1997; 17:3196–3201. doi: 10.1161/01.atv.17.11.3196LinkGoogle Scholar6. Safar ME, Asmar R, Benetos A, Blacher J, Boutouyrie P, Lacolley P, Laurent S, London G, Pannier B, Protogerou A, et al; French Study Group on Arterial Stiffness. Interaction between hypertension and arterial stiffness.Hypertension. 2018; 72:796–805. doi: 10.1161/HYPERTENSIONAHA.118.11212LinkGoogle Scholar7. Benetos A, Laurent S, Hoeks AP, Boutouyrie PH, Safar ME. Arterial alterations with aging and high blood pressure. A noninvasive study of carotid and femoral arteries.Arterioscler Thromb. 1993; 13:90–97. doi: 10.1161/01.atv.13.1.90LinkGoogle Scholar8. Safar ME, Levenson JA, Kheder AM, Simon AC. Arterial compliance and systolic hypertension in men.Arch Int Pharmacodyn Ther. 1980; Suppl:233–240MedlineGoogle Scholar9. Safar ME, St Laurent S, Safavian AL, Pannier BM, London GM. Pulse pressure in sustained essential hypertension: a haemodynamic study.J Hypertens. 1987; 5:213–218. doi: 10.1097/00004872-198704000-00013CrossrefMedlineGoogle Scholar10. Benetos A, Thomas F, Joly L, Blacher J, Pannier B, Labat C, Salvi P, Smulyan H, Safar ME. Pulse pressure amplification a mechanical biomarker of cardiovascular risk.J Am Coll Cardiol. 2010; 55:1032–1037. doi: 10.1016/j.jacc.2009.09.061CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails May 2024Vol 81, Issue 5 Advertisement Article InformationMetrics © 2024 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.124.22893PMID: 38630795 Originally publishedApril 17, 2024 PDF download Advertisement SubjectsHigh Blood PressureHypertension

Introduction: Cerebral blood flow (CBF) is reduced in patients with Alzheimer's disease (AD). Flow-mediated dilation (FMD), which plays a key role in the regulation of blood flow, is attenuated by endothelin-1. We hypothesized that endothelin receptor blockade may improve CBF in AD.Methods: We investigated cerebrovascular reactivity in a mouse model of AD (APP-PS1; 5-6-month-old male subjects). We assessed the in vivo response to normoxic hypercapnia and in vitro FMD in isolated cerebral and mesenteric resistance arteries before and after endothelin receptor blockade (bosentan).Results: Normoxic hypercapnia increased basilar trunk blood flow velocity (+12.3 +/- 2.4%; p = 0.006, n = 6) in wild-type (WT) mice but reduced blood flow in APP-PS1 mice (-11.4 +/- 1.2%; p < 0.0001, n = 8). Bosentan (50 mg/kg, acute intraperitoneal injection) restored cerebrovascular reactivity in APP-PS1 mice (+10.2 +/- 2.2%; p < 0.0001, n = 8) but had no effect in WT. FMD was reduced in the posterior cerebral artery of APP-PS1 compared to WT and was normalized by bosentan (1 mu mol/L, 30 min, or 50 mg/kg/day for 28 days). FMD was similar in the mesenteric artery of APPS-PS1 and WT.Conclusion: APP-PS1 mice exhibited cerebrovascular endothelial dysfunction. Acute and chronic blockade of endothelin receptors restored endothelial vasomotor function, suggesting a promising therapeutic approach to restoring cerebral vasoreactivity in AD.

Drugs acting by inhibition of the angiogenic action of VEGF (vascular endothelial growth factor) have become major instruments in the treatment of cancer. The downside of their favorable effects in cancer treatment is their frequent cardiovascular side effects. The most consistent finding thus far on the cardiovascular side effects of VEGF inhibitors is the high incidence of hypertension. In this short review, we discuss the evidence that hypertension occurring during VEGF inhibitor treatment is caused by microvascular rarefaction. After a review of the role of VEGF in microvascular growth and differentiation, we present evidence from studies in experimental models of hypertension as well as clinical studies on the microvascular network changes during and after VEGF inhibitor treatment.

Objective: Myogenic tone, which has a major role in the regulation of local blood flow, refers to the ability of vascular smooth muscle to adapt its contractility to changes in transmural pressure. Although Rho-kinase is involved in myogenic tone, the pathway involved remains unclear, especially concerning translocation to the plasma membrane and activation of RhoA. As caveolae have a key role in the signal transduction of membrane-bound proteins, we tested the hypothesis that RhoA might be activated by pressure and that its activation might involve caveolin-1, which has been shown to be involved in vascular functions. Methods: Myogenic tone was studied in isolated rat mesenteric resistance arteries (118 +/- 15 mu m internal diameter with a pressure of 75 mmHg) submitted to pressure steps (25, 75, and 150 mmHg). Pharmacological blockade of caveolae or RhoA-Rho-kinase pathway was assessed by confocal microscopy in pressurized arteries to analyze protein co-localization and by co-immunoprecipitation in order to confirm protein interactions. Caveolin-1-deficient mice were used to confirm the role of the protein in myogenic tone. Results: Pressure-induced myogenic tone was significantly reduced by RhoA inactivation with TAT-C3 (90.5% inhibition at 150 mmHg) and by the Rho-kinase inhibitor Y27632 (91.8% inhibition at 150 mmHg). In arteries pressurized at 150 mmHg, RhoA was localized to the plasma membrane (localization by confocal microscopy and increased quantity of RhoA in the membrane fraction after protein extraction). Thus, translocation of RhoA to the plasma membrane was associated with pressure-induced tone. In addition, caveolae disruption with methyl-beta-cyclodextrin reduced myogenic tone by 66% at 150 mmHg. Further, myogenic tone was significantly reduced to 24% of control in caveolin-1-deficient mice (active tone was 32.3 +/- 2.8 mu m and 9.1 +/- 3.7 mu m in +/+ and -/- mice, respectively, n=5 per group), suggesting a key role of caveolin-1 in myogenic tone. Finally, RhoA and caveolin-1 co-immunoprecipitation and co-localization significantly increased when myogenic tone developed at 150 mmHg (co-localization showed 26 +/- 13% merging at 25 mmHg versus 97 +/- 21% at 150 mmHg, n=5). Co-immunoprecipitation was prevented by TAT-C3 and by methyl beta-cyclodextrin. Conclusion: RhoA activation is critical for the development of myogenic tone in resistance arteries. This activation induced translocation of RhoA to the plasma membrane within caveolae, where the interaction of RhoA with caveolin-1 leads selectively to the activation of a Rho-kinase-dependent force development. (c) 2006 European Society of Cardiology. Published by Elsevier B.V.

AIMS:Hypertension and hypercholesterolemia are independent risk factors for atherosclerotic cardiovascular disease (ASCVD) by acting directly on the endothelium and activating the renin-angiotensin aldosterone system (RAAS) and mevalonate pathways. This review examines how the severity and duration of these risk factors may influence the cardiovascular risk through a reciprocal interplay leading to oxidative stress and pro-inflammatory response.DATA SYNTHESIS:The review highlights the clinical evidence supporting the benefits of statins and angiotensin-converting enzyme (ACE) inhibitors for hypertension, lipid disorders and ASCVD management, both individually and combined, at all stages of the cardiovascular continuum.CONCLUSION:Drug strategies incorporating an ACE-inhibitor and a statin, and in particular perindopril and atorvastatin, have consistently demonstrated reductions in the rate of ASCVD events in patients with hypertension and lipid disorders, cementing their position as first-line therapies for the management of atherosclerosis complications.

Despite a similar beneficial effect on blood pressure lowering observed with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor (AT1R) blocker (ARBs), several clinical trials and meta-analyses have reported higher cardiovascular mortality and lower protection against myocardial infarction with ARBs when compared with ACEIs. The European guidelines for the management of coronary syndromes and European guidelines on diabetes recommend using ARBs in patients who are intolerant to ACEIs. We reviewed the main pharmacological differences between ACEIs and ARBs, which could provide insights into the differences in the cardiac protection offered by these 2 drug classes. The effect of ACEIs on the tissue and plasma levels of bradykinin and on nitric oxide production and bioavailability is specific to the mechanism of action of ACEIs; it could account for the different effects of ACEIs and ARBs on endothelial function, atherogenesis, and fibrinolysis. Moreover, chronic blockade of AT1 receptors by ARBs induces a significant and permanent increase in plasma angiotensin II and an overstimulation of its still available receptors. In animal models, AT4 receptors have vasoconstrictive, proliferative, and inflammatory effects. Moreover, in models with kidney damage, atherosclerosis, and/or senescence, activation of AT2 receptors could have deleterious fibrotic, vasoconstrictive, and hypertrophic effects and seems prudent and reasonable to reserve the use of ARBs for patients who have presented intolerance to ACE inhibitors.

Since December 2019, the coronavirus 2019 (COVID-19) pandemic has rapidly spread and overwhelmed healthcare systems worldwide, urging physicians to understand how to manage this novel infection. Early in the pandemic, more severe forms of COVID-19 have been observed in patients with cardiovascular comorbidities, who are often treated with renin-angiotensin aldosterone system (RAAS)-blockers, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), but whether these are indeed independent risk factors is unknown. The cellular receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the membrane-bound angiotensin converting enzyme 2 (ACE2), as for SARS-CoV(-1). Experimental data suggest that expression of ACE2 may be increased by RAAS-blockers, raising concerns that these drugs may facilitate viral cell entry. On the other hand, ACE2 is a key counter-regulator of the RAAS, by degrading angiotensin II into angiotensin (1-7), and may thereby mediate beneficial effects in COVID-19. These considerations have raised concerns about the management of these drugs, and early comments shed vivid controversy among physicians. This review will describe the homeostatic balance between ACE-angiotensin II and ACE2-angiotensin (1-7) and summarize the pathophysiological rationale underlying the debated role of the RAAS and its modulators in the context of the pandemic. In addition, we will review available evidence investigating the impact of RAAS blockers on the course and prognosis of COVID-19 and discuss why retrospective observational studies should be interpreted with caution. These considerations highlight the importance of solid evidence-based data in order to guide physicians in the management of RAAS-interfering drugs in the general population as well as in patients with more or less severe forms of SARS-CoV-2 infection.