Cardiometabolic risk in high–normal blood pressure state: mechanistic insights

Current guidelines on the diagnosis and management of arterial hypertension jointly issued by the European Society of Hypertension/European Society of Cardiology (ESH/ESC) highlight the relevance of the metabolic disarray, frequently detected in hypertensive patients, in determining the elevated cardiovascular risk profile of the high blood pressure state [1]. This statement is based on a large number of epidemiological findings, which throughout the years have shown that alterations in glucose and lipid metabolism frequently cluster with blood pressure alterations [2–16], making diabetes, prediabetes and hypercholesterolaemia of more frequent detection in the presence than in the absence of a blood pressure elevation; and that the ‘cardiometabolic clustering’ has an adverse impact on patients' prognosis [9,17,18]. Metabolic/high blood pressure interactions: the evidence The above-mentioned association does not represent a pathophysiological curiosity with no or few practical implications but rather a finding with important clinical outcomes. A number of studies have indeed shown that various combinations of abnormalities in glucose metabolism, lipid metabolism and blood pressure are frequently associated with subclinical organ damage, such as microalbuminuria, reduced glomerular filtration rate, arterial stiffening, carotid atherosclerosis and cardiac hypertrophy [18–25]; and display a risk of fatal and nonfatal cardiovascular events much higher than that of normotensive or even hypertensive states without the metabolic disarray [17,18,26–30]. However, the data collected on the clustering between blood pressure and metabolic alterations have been mainly based on clinic blood pressure, that is, a variable that retains some major intrinsic limitations, such as for example, the fact that this pressure is in clinical studies often based on a single evaluation; is affected by the so-called altering reaction; is highly variable within the same day and throughout different days; and its specific power to correlate with hypertension-related organ damage or to predict cardiovascular risk is much lower than that of ambulatory or home blood pressure [1]. In a recent substudy of the Pressioni Arteriose Monitorate E loro Associazioni (PAMELA) Research Project [15], the relationship between metabolic and blood pressure profile has been evaluated by assessing serum total cholesterol, high-density lipoprotein (HDL) cholesterol and fasting blood glucose and calculating the percentage of incidence of hypercholesterolaemia, impaired fasting glucose and diabetes mellitus. The cohort was then subdivided into four groups according to the presence of optimal, normal, high–normal and hypertensive blood pressure values, according to ESH/ESC Guidelines criteria. A similar subdivision was made taking into account home and 24-h blood pressure. The results show that all three blood pressure measurements have an independent and direct relationship with blood glucose and serum cholesterol. They also show that the progressively greater prevalence of diabetes, impaired fasting glucose and hypercholesterolaemia observed going from optimal to normal, high–normal and elevated office blood pressure also occurs when home and/or ambulatory blood pressure classification is taken into account. Interestingly, clinic (or sphygmomanometric) blood pressure displays some predictive value, but in this case the estimated power appears to be lower than that displayed by the other two already mentioned blood pressures [15]. The contribution of the PAMELA study to the investigation of the relationships between metabolic variables and blood pressure is not limited to the above-mentioned data, but it also includes information on the metabolic syndrome [18,25] as well. During the follow-up performed in the PAMELA study, lasting on average more than 12 years, we observed that metabolic syndrome markedly increases the risk of cardiovascular mortality, with a negative impact also on all-cause mortality [18]; the most important components of the metabolic syndrome with prognostic significance are the elevation in blood pressure and the impaired fasting glucose [18]; patients with metabolic syndrome in whom office, home and 24-h blood pressure are all abnormal display a cardiovascular risk greater than those in whom the elevation does not affect ‘in’ and ‘out-of’ office blood pressure [18]; and metabolic syndrome is associated with an increased long-term risk of developing new cases of diabetes, hypertension and cardiac hypertrophy as well [25]. High–normal blood pressure and metabolic risk In the present issue of the Journal, a study by Bo et al. [31] provides new insights into the complex interrelationships between high blood pressure and the metabolic disarray. In a cross-sectional study, the authors evaluated, in a large cohort of approximately 1700 participants representative of a general population of Asti, a town in the north western region of Italy, the prevalence of cardiometabolic risk factors and related the cardiometabolic risk to the blood pressure levels classified in different categories according to the ESH/ESC Guidelines [1]. The main study's findings can be summarized as follows. First, in the population as a whole, the prevalence of the metabolic abnormalities increased progressively from optimal to normal, high–normal and established hypertension. Second, the high–normal blood pressure state is already characterized by an increase in the metabolic risk, blood glucose, blood triglycerides, total cholesterol, glucose tolerance and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) index as compared with the true normotensive one. Finally, high–normal blood pressure is characterized by endothelial dysfunction, increased circulatory plasma levels of markers of oxidative stress and vascular inflammation as well as of biochemical predictors of the atherogenic process. Altogether the results of the present study, while confirming data collected in other population studies on the close relationship linking high–normal blood pressure to metabolic disarray, highlight the potential prognostic importance of some of the above-mentioned abnormalities (including the reduction in circulating plasma levels of the antiatherogenic adiponectin) in the development and progression of the metabolic abnormalities and of their cardiovascular sequelae. Balancing study's strengths and limitations The study by Bo et al. [31] has a number of strengths, which include the large size of the population sample studied and the consistency of the data with those collected in previous reports. A further important study strength refers to the assessment of the mechanistic insights, identifying the endothelial dysfunction, the oxidative stress as well as the adipokine abnormalities, the possible factors responsible for the development and the progression of the metabolic disarray. As the authors also recognize, however, the study has some limitations, which call upon further investigations. From a methodological view point, for example, a longitudinal study design would have allowed one to define whether and to what extent the alterations in endothelial function, oxidative process and adiponectin release represent the causes or rather the consequences of the metabolic disarray. Furthermore, blood pressure data were based only on clinic measurement of this haemodynamic variable, that is, a methodological approach that, as mentioned above, encompasses major limitations in reflecting the ‘true’ blood pressure load characterizing the 24-h period [1]. In this regard, it is worthy of mention that this limitation has been circumvented in the already quoted PAMELA study by the use of home and 24-h ambulatory blood pressures. These have been shown to be superior over sphygmomanometric blood pressure in predicting the long-term prognosis of the hypertensive or the cardiometabolic disease; the development and progression of left ventricular hypertrophy; and the occurrence of new diabetes mellitus [18,25,32]. Finally, in the database of the study, heart rate appears, somewhat surprisingly, not to be included. The information on this parameter would be of some interest, considering that this haemodynamic variable is regarded as a marker, although of indirect nature, of the adrenergic cardiovascular drive [5]. Thus, if an increase in resting heart rate were to be seen in people with high–normal blood pressure and metabolic disarray, the intriguing hypothesis that sympathetic activation might represent a hallmark of the cardiometabolic alteration could be advanced. It should be mentioned, however, that, as summarized in the Table 1, the behaviour of heart rate in a number of cardiovascular and noncardiovascular diseases does not invariably go hand in hand with that of direct indices of sympathetic drive, such as venous plasma norepinephrine and muscle sympathetic nerve traffic [33]. This is supported by the evidence that in different studies performed in people with metabolic syndrome, the increase in sympathetic nerve traffic is not paralleled by a concomitant increase in heart rate [34,35]. Further studies are thus needed to better clarify the complex relationships between endothelial dysfunction, oxidative stress, metabolic factors and adrenergic function.