aHypertension Center and Cardiovascular Research Laboratory, 1st Department of Propaedeutic Medicine, ‘Laiko’ Hospital Medical School, National and Kapodistrian University of Athens, Athens, Greece
bParis Descartes University; AP-HP; Diagnosis and Therapeutic Center, Hôtel-Dieu, Paris, France
Correspondence to Professor Michel Safar, Centre de Diagnostic et de Thérapeutique, Hôtel-Dieu 1, place du Parvis Notre-Dame, 75181 Paris Cedex 04, France. Tel: +33 1 42 34 80 25; fax: +33 1 42 34 86 32; e-mail: firstname.lastname@example.org
In an article in the current issue of the Journal of Hypertension O’Rourke and Adji  touch upon one of the most challenging issues of modern hypertension that will dominate the field in the decades to come. They stress the need to develop new treatment strategies for the reduction of the cardiovascular risk associated with elevated blood pressure (BP) based on two fundamental parameters: aging (and arterial aging) and sex. This is a necessary and long awaited advance in the field of arterial hypertension. It would remain, however, incomplete without the modern concept of central haemodynamics, which has been clarified over the past 30 years, thanks to the work of Michael O’Rourke and his associates . The phenotype of isolated systolic hypertension (ISH) is a classical paradigm, but not the only one. Recent data suggest that another equally important phenomenon, i.e. the interaction between insulin resistance and BP, cannot be dissected without considering age, gender and the role of central haemodynamics .
Isolated systolic hypertension is defined on the basis of brachial BP, as normal DBP with abnormal SBP. Data from epidemiological studies including the National Health and Nutrition Examination Survey (NHANES) show that both in the elderly (>60 years of age)  as well in the youth  (particularly in men around adulthood) ISH is the most prevalent hypertension phenotype. As pointed out by O’Rourke and Adji  the two assumingly identical hypertension phenotypes are indeed completely different in terms of central haemodynamics. When the two are compared, the ISH of the elderly (ISHe) is characterized by the triplet of: increased aortic stiffness, increased pressure wave reflections and low pulse pressure (PP) amplification  whereas the ISH of the youth (ISHy) is characterized by exactly the opposite pattern [7–11]. The analysis of the dominant pressure wave characteristics [propagation (arterial stiffening), reflection and amplification within the arterial tree] , have made this distinction possible and clear. Yet, there are still major difficulties in clinical practice and both subtypes of ISH constitute a challenge for the clinician. The reasons are multiple, but mainly depend on the lack of data from relevant clinical trials and of ‘gold-standard’ methods regarding the assessment of central haemodynamics.
Here we wish to comment on the unresolved issues regarding both types of ISH, focusing: on the still underestimated role of brachial pulse pressure, the emerging role of the PP amplification phenomenon, the future perspectives derived from recent innovations in biomedical engineering, and finally the role of guidelines and recommendations.
BRACHIAL PULSE PRESSURE IN CLINICAL PRACTICE
Both the ISHe and the ISHy are per se characterized by elevated brachial PP (>60 mmHg) [6–11]. A closer look to the data suggests the presence of higher SBP variability in ISHe, potentially as a result of a rigid aorta. Elevated brachial PP is a well established predictor of cardiovascular mortality above the age of 60, but this is not true for the youth . Moreover, a number of large clinical trials have demonstrated beyond any doubt that ISHe is associated with high absolute cardiovascular risk and that drug-induced systolic BP reduction is beneficial . The major difficulty in the management of ISHe derives from the fact that in the elderly there are no well defined optimal brachial SBP targets ; SBP is difficult to control due to increased aortic stiffness , and thus intensive drug treatment may lead to disproportionally excessive DBP reduction potentially responsible for adverse effects either via the often described J-curve phenomenon , and/or the unexpected PP increase which takes place particularly at the level of the aorta . Clinical trials in the past have commonly underestimated the role of brachial PP, and for this reason when and how ‘To Treat or Not To Treat’ ISHe remains a clinical challenge. On the basis of central haemodynamic concepts blockade of the renin–angiotensin system and/or of calcium channels seems the wisest choice in order to restore PP amplification by reducing wave reflections and aortic stiffness . This strategy is in line with data provided from the ACCOMPLISH study .
THE EMERGING ROLE OF PULSE PRESSURE AMPLIFICATION
During the past few years the well described phenomenon of PP amplification  has been recognized as a novel mechanical marker . In the ISHe the disparity (amplification) of the PP between the brachial artery and the aorta is, though present, small , suggesting that brachial PP is an acceptable surrogate of aortic PP, and explaining why brachial PP is a valid cardiovascular marker above 60 years of age. However, even in the elderly, PP amplification can still be used to improve calculation of cardiovascular risk .
In terms of physiology, PP amplification integrates and combines the effect of aging, arterial aging (both stiffening and wave reflections alterations) as well as the impact of sex . We have previously shown that in the elderly the combination of increased aortic stiffness (carotid to femoral pulse wave velocity) and increased pressure wave reflections (augmentation index) was associated with higher mortality, even though each biomarker individually was without predictive value . This suggests that a marker combining both parameters may be superior for the prediction of cardiovascular mortality. Furthermore, PP amplification incorporates the effect of autonomic nervous system (on heart rate) and can detect the differential effect of antihypertensive drug treatment on central and peripheral arteries [12,17]. In other words, PP amplification is an emerging marker that might provide the opportunity to develop new treatment strategies for reducing elevated mean BP, on the basis of two fundamental parameters: aging (and arterial aging) and sex, as previously discussed [22,23].
In ISHy, as initially described 30 years ago , there are underlying mechanisms that until now have remained only partly explained, and, are still under investigation. PP amplification tends to be higher and wave reflection tends to be lower  in young individuals with ISH when compared with age-matched normotensive individuals and systolic/diastolic hypertensive patients. Increased stroke volume (hyperdynamic circulation) and/or relatively increased aortic stiffness may be the underlying cause [9,12,24–26]. As discussed by O’Rourke and Adji , no evidence exists as to whether ‘To Treat or Not To Treat’ ISHy (i.e. to start drug treatment beyond the implementation of lifestyle modifications), and brachial PP is not a valid marker of cardiovascular risk in this age group due to high PP amplification . However, as we recently described in an experts’ opinion statement , the population carrying the ISHe phenotype should not be considered a ‘normal’ population since DBP and central SBP are higher in most cases [9,10] in comparison to matched normotensive individuals. Moreover, the terms ‘spurious hypertension’ or ‘pseudo-hypertension’ [7,8,10], initially proposed to describe young tall male individuals with elastic aortas who had ISH and normal central systolic BP, may be applicable only to special cases of extreme pulse pressure amplification, for example, above 30 mmHg. Currently there are no normal values for aortic BP (they are anticipated to be published in 2013); therefore, using these terms in most cases might be misleading .
Until the natural history of each potential subtype of ISHy is clarified, all patients with ISHy should be regarded as intermediate BP phenotypes and followed up to determine whether these individuals are going to develop essential hypertension and/or exhibit ‘abnormal’ progression in markers of target organ damage or regress to normotension . A further and closer look of the data derived from the 19–29 years of age subgroup in the NHANES  leads to the following conclusions: the prevalence of the ISHy was doubled within the last 10 years mostly as a result of the obesity epidemics; ISHy is the predominant phenotypic subtype of hypertension in males [i.e. it is more common than isolated diastolic hypertension (IDH) or the systolic–diastolic hypertension (SDH)] reaching 2.5% of the overall population; most importantly, although in males the prevalence of IDH and SDH increased substantially over the next decade (between 30 and 39 years of age), the prevalence of ISHy was reduced. Therefore, the NHANES findings suggest that ISHy in the third decade of life may regress during the subsequent decade. On the basis of these data and the lack of evidence on benefits of drug treatment, close monitoring of BP and target organ damage appears to be an acceptable choice, at least for this age group (<30 years of age), as long as the individuals are closely monitored. If a decision to treat is taken because, for example, the presence of target organ damage, the antihypertensive drug class of choice is not known: an agent reducing cardiac output was the ‘usual’ choice until recently, but the evidence β-blockers may be less effective on central haemodynamics [12,17] may lead to different decision. The most appropriate drug selection may be based on the type of target organ damage found.
BRACHIAL-CUFF BASED ASSESSMENT OF AORTIC BLOOD PRESSURE AND FUTURE PERSPECTIVES
Further studies should investigate the ability of central haemodynamics (stiffness, BP, wave reflections, amplification) to guide individualization of cardiovascular risk between sexes and within age groups. Lack of consensus on methods to be employed, cut-off values and ‘gold standards’ is the main drawback for a wider use of central haemodynamics in cardiovascular assessment [12,28]. During the past few years technical innovation has made the assessment of aortic BP feasible via operator-independent brachial-cuff based automated oscillometric devices. This technology is likely to take over radial applanation tonometry used until now. These new devices may allow an easier assessment of central haemodynamics in clinical research , even during 24-h ambulatory BP monitoring , and provide further opportunities to investigate the physiology of ISH.
The strongest recommendations in guidelines prepared by scientific societies must be based on solid evidence derived from well designed clinical trials. For this reason the ESH guidelines on hypertension in adults (the 2007 edition  and its reappraisal ) and those on children/adolescents  did not include any comments on the role of central haemodynamics assessment in ISH diagnosis. However, when evidence from trials is lacking guidelines can also be based on experts’ opinion  and wisdom. It is desirable that future recommendations alert clinicians that available methods for assessing central haemodynamics and target organ damage in patients with ISH may be helpful before drug treatment initiation.
It is now clear that the same brachial BP phenotypes should be interpreted differently on the basis of arterial age and gender, as discussed in this issue by O’Rourke and Adji  for ISH. Technological innovation may provide new opportunities to move forward (or rather backwards from the periphery towards the heart) and develop new hypertension treatment strategies in the decades to come. Central haemodynamics evaluation may help solving the dilemma ‘To Treat or Not To Treat’ brachial ISH.
Conflicts of interest
There are no conflicts of interest.
1. O’Rourke MF, Adji A. Guidelines on guidelines: focus on isolated systolic hypertension in youth. J Hypertens
2. Nichols WW, O’Rourke MF, Vlachopoulos C. McDonald's blood flow in arteries: theoretical, experimental and clinical principles. 6th ed.London:Edward Arnold; 2012.
3. Safar ME, Balkau B, Lange C, Protogerou AD, Czernichow S, Blacher J, et al. Hypertension and vascular dynamics in men and women with metabolic syndrome. J Am Coll Cardiol
4. Franklin SS, Jacobs MJ, Wong ND, L’ Italien GJ, Lapuerta P. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension
5. Grebla RC, Rodriguez CJ, Borrell LN, Pickering TG. Prevalence and determinants of isolated systolic hypertension among young adults: the 1999–2004 US National Health And Nutrition Examination Survey. J Hypertens
6. Wallace SM, Yasmin, McEniery CM, Mäki-Petäjä KM, Booth AD, Cockcroft JR, Wilkinson IB. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension
7. O’Rourke MF, Vlachopoulos C, Graham RM. Spurious systolic hypertension in youth. Vasc Med
8. Mahmud A, Feely J. Spurious systolic hypertension of youth: fit young men with elastic arteries. Am J Hypertens
9. McEniery CM, Yasmin, Wallace S, Maki-213 Petaja K, McDonnell B, Sharman JE, et al.
; ENIGMA Study Investigators. Increased stroke volume and aortic stiffness contribute to isolated systolic hypertension in young adults. Hypertension
10. Hulsen HT, Nijdam ME, Bos WJ, Uiterwaal CS, Oren A, Grobbee DE, Bots M. Spurious systolic hypertension in young adults; prevalence of high brachial systolic blood pressure and low central pressure and its determinants. J Hypertens
11. Saladini F, Santonastaso M, Mos L, Benetti E, Zanatta N, Maraglino G, Palatini P. HARVEST Study GroupIsolated systolic hypertension of young-to-middle-age individuals implies a relatively low risk of developing hypertension needing treatment when central blood pressure is low. J Hypertens
12. Avolio AP, Van Bortel LM, Boutouyrie P, Cockcroft JR, McEniery CM, Protogerou AD, et al. Role of pulse pressure amplification in arterial hypertension: experts’ opinion and review of the data. Hypertension
13. Blacher J, Protogerou AD, Safar ME. Safar ME. Cardiovascular risk and the macrocirculation. Macro- and microcirculation in hypertension
. London:Lippincott Williams & Wilkins; 2005. 83–97.
14. Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, et al. European Society of Hypertension. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens
15. Protogerou AD, Blacher J, Stergiou GS, Achimastos A, Safar ME. Blood pressure response under chronic antihypertensive drug treatment. The role of aortic stiffness in the REASON study. J Am Coll Cardiol
16. Protogerou AD, Safar ME, Iaria P, Safar H, Le DK, Filipovsky J, et al. Diastolic blood pressure and mortality in the elderly with cardiovascular disease. Hypertension
17. Protogerou AD, Stergiou GS, Vlachopoulos C, Blacher J, Achimastos A. The effect of antihypertensive drugs on central blood pressure beyond peripheral blood pressure. Part II: Evidence for specific class-effects of antihypertensive drugs on pressure amplification. Curr Pharm Des
18. Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, et al. ACCOMPLISH Trial InvestigatorsBenazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med
19. Benetos A, Thomas F, Joly L, Blacher J, Pannier B, Labat C, et al. Pulse pressure amplification a mechanical biomarker of cardiovascular risk. J Am Coll Cardiol
20. Benetos A, Gautier S, Labat C, Salvi P, Valbusa F, Marino F, et al. Mortality and cardiovascular events are best predicted by low central/peripheral pulse pressure amplification but not by high blood pressure levels in elderly nursing home subjects: the PARTAGE (Predictive Values of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population) study. J Am Coll Cardiol
21. Protogerou AD, Safar ME, Papaioannou TG, Zhang Y, Agnoletti D, Papadogiannis D, Blacher J. The combined effect of aortic stiffness and pressure wave reflections on mortality in the very old with cardiovascular disease: the PROTEGER Study. Hypertens Res
22. Protogerou AD, Smulyan H, Safar ME. Closer to noninvasive out-of-office aortic blood pressure assessment: a time to think and act. Hypertension
23. Papaioannou TG, Protogerou AD, Stefanadis C. What to anticipate from pulse pressure amplification. J Am Coll Cardiol
24. Simon AC, Safar ME, Levenson JA, Kheder AM, Levy BI. Systolic hypertension: hemodynamic mechanism and choice of antihypertensive treatment. Am J Cardiol
25. Sorof JM, Poffenbarger T, Franco K, Bernard L, Portman RJ. Isolated systolic hypertension, obesity, and hyperkinetic hemodynamic states in children. J Pediatr
26. Eich RH, Peters RJ, Cuddy RP, Smulyan H, Lyons RH. The hemodynamics in labile hypertension. Am Heart J
27. Wilkinson IB, Franklin SS, Hall IR, Tyrrell S, Cockcroft JR. Pressure amplification explains why pulse pressure is unrelated to risk in young subjects. Hypertension
28. Papaioannou TG, Protogerou AD, Stamatelopoulos KS, Vavuranakis M, Stefanadis C. Noninvasive methods and techniques for central blood pressure estimation: procedures, validation, reproducibility and limitations. Curr Pharm Des
29. Wilkinson IB, McEniery CM, Cockcroft JR. Central blood pressure estimation for the masses moves a step closer. J Hum Hypertens
30. Protogerou AD, Argyris A, Nasothimiou E, Vrachatis D, Papaioannou TG, Tzamouranis D, et al. Feasibility and reproducibility of noninvasive 24-h ambulatory aortic blood pressure monitoring with a brachial cuff-based oscillometric device. Am J Hypertens
31. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens
32. Lurbe E, Cifkova R, Cruickshank JK, Dillon MJ, Ferreira I, Invitti C, et al. European Society of Hypertension. Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. J Hypertens