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Journal of Hypertension:
doi: 10.1097/HJH.0000000000000166
Editorial Commentaries

Blood pressure and mortality risk, need to revise current risk stratification?

Van Bortel, Luc M.

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Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium

Correspondence to Luc M. Van Bortel, MD, PhD, Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. E-mail: luc.vanbortel@ugent.be

The recent 2013 European Society of Hypertension (ESH) and European Society of Cardiology (ESC) guidelines discussed the methods used for total cardiovascular risk assessment. This assessment is easy in groups of patients with known high to very high cardiovascular risk like those with antecedents of established cardiovascular disease and diabetes. But in a large number of hypertensive patients, cardiovascular risk assessment is far from easy, requiring models to estimate total cardiovascular risk to identify those at low, moderate, high, or very high risk [1]. The Systematic COronary Risk Evaluation (SCORE) model and the Framingham Risk Score are frequently used models. Both are based on similar risk factors: age, sex, smoking, cholesterol, and SBP. Risk stratification using these charts has its limitations. For example, the risk for a first coronary heart disease (CHD) event within 6 years was in hypertensive patients with high aortic stiffness higher than predicted by the Framingham Risk Score, although the opposite was also found: patients with a low aortic stiffness had a lower risk than predicted by the Framingham Risk Score [2]. This study clearly showed the added value of aortic stiffness to this classical risk score. Most importantly, the risk for a first CHD event was in patients with high aortic stiffness and a low Framingham risk score nearly as high as in patients with a high Framingham risk score, but with low aortic stiffness. Other examples of conditions in which risk may be higher than indicated in the charts are sedentary individuals, central obesity, socially deprived individuals, ethnic minorities, insulin resistance, increased triglycerides, increased levels of high-sensitivity C-reactive proteins, and family history of premature CVD [1]. In addition, in young individuals, risk for an event within the next 10 years may be low, and the use of the risk score may be of little value for the management of these patients, because, if insufficiently treated, the high blood pressures and other risk factors may lead to irreversible risk conditions in later years [1]. Therefore, interest in the prevention of early vascular aging is increasing [3].

The current charts make use of SBP at all ages. In this issue of the Journal, Vishram et al.[4] report their analysis of the MORGAM project, which challenges the use of SBP above the diastolic pressure at all ages. In this apparently healthy population of Europeans and Australians, SBP was superior to DBP at all ages to predict CHD mortality. But for stroke and all-cause mortality, there was a gradual age-related shift from DBP to SBP in importance of risk factor: DBP was superior in young adults (up to 26 years), from 27 to 62 years both SBP and DBP were important, whereas between 63 and 78 years, SBP was superior. This study confirms the findings of previous studies [5–7] that the prognostic value of DBP was superior in individuals younger than 50.

We have to keep in mind that SBP and DBP are the extremes of the blood pressure. From a more physiological viewpoint, these extremes are the result of a mean arterial pressure (MAP) and the pulse pressure (PP) oscillating around this MAP. MAP is determined by the pump function of the heart (cardiac output; CO) and by the peripheral resistance (TPR), mainly determined by the microcirculation (arterioles and capillaries).

In contrast, the PP is largely determined by the pump function of the heart (stroke volume) and the buffering capacity (compliance; C) of the vascular system.

This buffering capacity depends on the arterial stiffness (S) and arterial volume (V; related to the diameter of the artery)

The buffering capacity of the vascular system is mainly determined by the large elastic arteries. With aging, elastic arteries like the aorta and carotid arteries gradually stiffen. But large and middle-sized more muscular arteries do not stiffen until the sixth to seventh age decade, while their buffering capacity increases through a gradual enlargement of the arterial diameter [8]. It, therefore, has been hypothesized that large and middle-sized muscular arteries can at least in part compensate for the decrease in buffering capacity of the large arteries with aging.

An increased resistance in the microcirculation will boost MAP, SBP, and DBP, whereas an increased stiffness of the large arteries will increase PP and SBP, but decrease DBP.

In this issue of the Journal, Vishram et al. found the transition to superiority of the SBP at earlier age when other cardiovascular risk factors were present. This observation is compatible with an earlier onset of aortic stiffening in the presence of more cardiovascular risk factors [9]. This earlier arterial stiffening will boost SBP, while by decreasing DBP, it decreases its predictive value.

At young vascular age, as long as arterial stiffness is normal, changes in DBP predominantly reflect changes in MAP. With exception of a particular group of young hypertensive patients with hyperkinetic circulatory state, changes in MAP mainly reflect alterations in the microcirculation. The MORGAM study and other studies [4–7] suggest that in young individuals, alterations in the microcirculation are more important than alterations in the macrocirculation. But from the fifth age decade on, arterial stiffening becomes more prominent, decreasing DBP through widening of the PP and decreasing the association between changes in MAP and DBP. With increasing arterial stiffness, the predictive value of MAP is expected to become superior to DBP. Authors of the MORGAM study found an important contribution of DBP to cardiovascular risk until the age of 62. This suggests that the contribution of MAP and the microcirculation to cardiovascular risk is still important at older age and may even remain important beyond the age of 62. The study results suggest that risk stratification might be improved by using MAP instead of DBP. But validated methods to measure MAP noninvasively are scarce or lacking. Alternatively, risk stratification might be improved by correcting the predictive value of DBP for PP.

The MORGAM study showed DBP at young age being a better predictor than SBP for stroke and all-cause mortality and not for CHD. It could be hypothesized that in young individuals, the proportion of hemorrhagic versus ischemic strokes might be much higher than in elderly individuals due to vascular malformations like aneurysms, from which events could be more related to the MAP than the SBP. The fact that CHD risk was at all ages more determined by systolic than by diastolic pressure suggests that (peak) afterload and increased oxygen demand may play an important role in CHD risk.

Like other studies, the MORGAM study found a J-shaped relationship between blood pressure and mortality. The relation of DBP to mortality risk was J-shaped with the lowest mortality risk at a DBP of about 75 mmHg for stroke, 78 mmHg for CHD, and 82 mmHg for all-cause mortality. For the SBP, the relation to stroke mortality was linear, whereas the relation was J-shaped for CHD and all-cause mortality with the lowest mortality at a SBP of about 116 and 120 mmHg [4]. Interestingly, the J-shaped relation between SBP and mortality from CHD was age-dependent. For those younger than 40 years, there was no J-shaped relation between SBP and CHD mortality. From 40 years on, there was a J-shaped relation, but the lowest threshold value was age-dependent: being at 116 mmHg in the 40–60 years group, which increased to 125 mmHg in the 60–78 years group. This study showed that the optimal SBP is already age-dependent from 40 years on, with increasing optimal values with aging. Whether a treatment striving to reach the optimal value will decrease mortality risk has to be further demonstrated.

Although studies have demonstrated the importance of treating isolated systolic hypertension even with low DBP [10,11], the observation by Vishram et al. that a low DBP (<82 mmHg) was significantly associated with increased all-cause mortality from the age of 59 years raises the question whether treatment of isolated systolic hypertension could be improved by antihypertensive drugs that decrease systolic hypertension without further decreasing DBP. These drugs should decrease arterial stiffness with no or very limited effect on resistance vessels. Although all currently available first-line antihypertensive drugs decrease stiffness in the long term [12], angiotensin-converting enzyme inhibitors may have the most pronounced effect on arterial stiffness. But all these first-line antihypertensive drugs also have a major effect on resistance vessels, thereby further decreasing DBP, which may be harmful and decrease the beneficial effect of lowering the SBP. Development of new drugs with a high selectivity to large arteries compared to resistance vessels appears possible and might be an asset in the treatment of the rapidly growing number of patients with isolated systolic hypertension [13].

Finally, the study by Vishram et al. was limited to the analysis of cardiovascular risk factors without taking into account target organ damage. There is ample evidence that the use of target organ damage like arterial stiffness improves cardiovascular risk stratification by identifying those hypertensive patients in whom the presence of risk factors leads to damage. The use of blood pressure for cardiovascular risk stratification, and adding DBP in particular is less expensive than measuring target organ damage like aortic stiffness. But because of loss of predictive value when arteries stiffen, it is doubtful that DBP becomes more cost-effective than measuring aortic stiffness. Nowadays, reference values for aortic stiffness are available [14] and its method has been standardized [15,16]. It is now ready for use in clinical practice to improve cardiovascular risk stratification. The ongoing ‘Stratégie de Prévention Cardiovasculaire Basée sur la Rigidité Artérielle’ (SPARTE) study led by the Paris group will tell us whether a stiffness-guided treatment will also improve outcome [17].

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ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest related to this editorial comment.

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