Pulse pressure and arterial stiffness in type 1 diabetic patients

During the 1990s, evidence was beginning to accumulate in support of a significant role of pulse pressure in cardiovascular (CVD) morbidity and mortality [1–3]. There are now several studies showing such a relationship in different populations of patients (hypertensives, heart failure patients and in the general population). More recently, a number of studies have shown that in subjects aged over 55 years, systolic blood pressure (SBP) and pulse pressure were stronger determinants of CVD morbidity and mortality than diastolic (DBP) and mean arterial pressure (MAP) [4,5]. In this issue of the journal, Schram et al. [6] investigated the determinants of increased pulse pressure and the impact of pulse pressure on cardiovascular complications in a large population of type 1 diabetic patients. Several results of the present study contribute to clarify the role of pulse pressure and large artery stiffness in a group of high-risk patients. It is interesting to note that, in this young population (mean age 33 years), pulse pressure is, in addition to MAP, a significant determinant of cardiovascular complications. This is contrary to what has previously been reported in a general population, which is that DBP better reflects the CVD risk in younger subjects, whereas SBP and pulse pressure better reflect the risk in older subjects [5]. This age-dependent change in the prognostic value of blood pressure levels is due to various factors. DBP in young patients is mainly dependent on peripheral resistance: low DBP reflects low peripheral resistance. However, in older subjects, a low DBP may reflect high arterial stiffness which is a major manifestation of arterial ageing, rather than low peripheral resistance [7]. In this case, low DBP is associated with high SBP (the other manifestation of arterial stiffness) and high pulse pressure and increased cardiovascular risk. Therefore, low/normal DBP values in older subjects may be either the result of low peripheral resistance and normal arterial stiffness or, most commonly, the result of an enhanced aortic stiffness. These considerations may explain why DBP levels better reflect CVD risk in younger subjects than in older ones. Two supplementary reasons may also explain the better ‘predictivity’ of DBP in younger patients in terms of CVD risk. First, DBP is less variable than is SBP, especially in younger subjects with hyperkinetic circulation. Second, in younger subjects (i.e. in the absence of arterial ageing), SBP and pulse pressure increase significantly from the central to the peripheral arteries, due principally to lower central artery stiffness and lower velocity in the propagation of reflection waves [7,8]. However, central and peripheral DBP values are not significantly different. The clinical consequence is that SBP and pulse pressure measured at the peripheral arteries overestimate the central aortic values. After the age of 55–60 years, SBP and pulse pressure tend to be quite similar in all parts of the arterial tree [8]. Again, this is a consequence of arterial ageing which is more pronounced at the site of the central arteries. This ‘equalization’ of SBP and pulse pressure values along the arterial system leads to the fact that in older subjects, values recorded at the site of the brachial artery correspond to the central aortic values (which greatly determines the level of left ventricle post charge). The fact that, in young type 1 diabetics, pulse pressure is a major determinant of cardiovascular complications, strongly suggests that these patients have a more advanced arterial age than their chronological age. This could explain why what is found only for older subjects in the general population is observed even in much younger subjects with type 1 diabetes. The following result of this study is also in favour of an advanced arterial age in this cohort of young diabetics: the significant increase in pulse pressure with age. Interestingly, in non-diabetics the increase in pulse pressure usually starts after the age of 50 years. This is due to a more pronounced increase in arterial stiffness with age, after that age [9,10]. It is therefore possible that, in this young population, increase in pulse pressure could be due to an increase in cardiac output or to an increase in peripheral resistance. However, the fact that the increase in pulse pressure was due to both an increase in SBP and a decrease in DBP, which is the classic pattern of large artery stiffening that is frequently associated with ageing, goes against this hypothesis [9,11]. We previously reported in a prospective study that subjects who presented an increase in SBP combined with a decrease in DBP over an extended period of time (i.e. patients with the more pronounced progression in pulse pressure and arterial stiffness) were at higher cardiovascular risk compared to subjects with a different pattern of blood pressure evolution [12]. The present study shows that, in diabetics without initial cardiovascular complications, increase in pulse pressure over the follow-up period was a significant determinant of an initial manifestation of cardiovascular disease. In the present study, the authors report that the increase in pulse pressure with age was more pronounced in diabetics with initial micro-, macro-albuminuria and retinopathy, suggesting that the progression in arterial ageing is more pronounced in the presence of target organ damage. All these data suggest that large artery stiffness and its clinical expressions (i.e. high SBP and pulse pressure) are prematurely developed in type 1 diabetics and are key factors in the evolution of diabetes. Arterial stiffness develops as a consequence of several structural and functional changes of the large arteries. Wall hypertrophy, calcium deposits and changes in the extracellular matrix, such as an increase in collagen and in fibronectin, fragmentation and disorganization of the elastin network, enzymatic and non-enzymatic crosslinks and cell–matrix interactions, are the main structural determinants of the decrease in the elastic properties and development of large artery stiffness [13]. Loss of vascular endothelium function (decrease in the release of vasodilators and increased synthesis of vasoconstrictors), and modification of smooth muscle reactivity could be the main functional changes leading to decreased elasticity and increased stiffness. Diabetes induces several functional and structural changes of the arterial wall which could explain the development of arterial stiffness. Endothelial dysfunction has been described in several studies. However, the most important mechanism of accelerated stiffening in diabetics appears to be the reaction between glucose and the proteins of the extracellular matrix called non-enzymatic glycation. This leads to the formation of advanced glycation end products (AGEs) on the extracellular matrix, responsible for the increase in collagen crosslinks [13,14]. These reactions that are observed during ageing are greatly accelerated in the presence of diabetes. They are the main structural alterations at the site of the large artery media, and account for arterial stiffness and increase in SBP and pulse pressure in diabetics. These structural alterations can also explain the failure of classical antihypertensive drugs to control SBP in diabetics. Thus, despite the use even of combination therapies, SBP in most patients remains well above the goals determined by international guidelines (< 130 mmHg). A new class of ‘AGE breakers’ is able to react with the AGE-derived protein crosslinks. Recent experimental data in diabetic rats showed that an AGE breaker, ALT-711, was able to decrease the collagen crosslinks [14] and improve carotid artery distensibility and compliance. Similar results have been shown with this drug in reducing arterial stiffness in older animals. Clinical development of these drugs could contribute to major progress in the treatment of age-related arterial alterations, especially in those patients with an accelerated ageing, such as diabetics. The predominant role of SBP and pulse pressure in the evolution and complications of diabetes has also been suggested by the results of several large clinical trials showing that SBP control is by far the most important therapeutic goal in order to protect type 2 diabetics [15]. As for type 1 diabetics, presently, we do not know of any large therapeutic trial comparing the effects of the different class drugs on cardiovascular morbidity and mortality. However, since the role of arterial stiffness appears to be major in these patients, we can suggest that drugs which are able to reduce arterial stiffness could have more beneficial effects in this case. Recent data from another population that also presents a very accelerated arterial ageing and stiffness (i.e. end-stage renal disease patients in dialysis) show that drug-induced reduction in cardiovascular morbidity and mortality was directly related to the decrease in arterial stiffness by treatment [16]. In conclusion, the study by Schram et al. [6] points out the importance of the evaluation of large artery stiffness and the need to develop new therapeutic approaches to slow down its progression in young patients at high cardiovascular risk. A limitation of this study is that arterial stiffness was evaluated only with blood pressure measurements. During the last decade, the development of several non-invasive, valid methods has allowed us to measure large artery distensibility and compliance, and wave reflections, directly. The use of these methods in epidemiological and pharmacological clinical studies could lead to an even more comprehensive estimation of arterial stiffness and its possible reversal with drugs.