Obesity-related cardiac and vascular structural alterations: beyond blood pressure overload

Studies performed in the past few years have convincingly documented the adverse impact the obese state carries on cardiovascular morbidity and mortality with particular reference to congestive heart failure, myocardial infarction and renal failure as well [1–3]. Data recently collected in the context of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study have reinforced the results of the above-mentioned studies, by showing, for example, that the occurrence of an obese state is an important predictor of cardiovascular events in the general population living in northern Italy, Brianza area, even when data are adjusted for confounders such as age and clinic blood pressure values (Mancia G, Grassi G, et al., unpublished observations). Interestingly, similar conclusions can be achieved when the data are adjusted for 24-h ambulatory blood pressure values, suggesting that extrahaemodynamic factors participate at the obesity-related increase in cardiac mass. Despite the large amount of data collected in the past years, several aspects related to this issue still remain far from being fully elucidated. These include, for example, the pathophysiology of obesity-related left ventricular hypertrophy. They also include, however, other aspects such as the relative weight of haemodynamic vs. nonhaemodynamic factors in the development and progression of the cardiac structural changes; the role of neurohumoral factors in the pathophysiology of this complication; and the clinical impact of different types of cardiac structural alterations reported in the obese state. In the present issue of the Journal, Norton et al. [4] report the results of a study designed at determining whether and to what extent the impact of hypertension on left ventricular mass can be in some way affected by the presence of an obese state. To this aim, about 400 individuals belonging to the general population living in the outskirts of Johannesburg, South Africa, were cross-sectionally examined by performing a number of clinical and instrumental evaluations. These included clinic and 24-h ambulatory blood pressure, demographic and anthropometric variables, humoral data (e.g. leptin), carotid pulse pressure wave analysis and echocardiographically determined left ventricular mass as well. Three are the main study findings. First, confirming data collected in a previous study [5], the authors found a direct and highly significant relationship between BMI, waist circumference or mean skin-fold thickness and various haemodynamic variables, such as clinic blood pressure, 24-h blood pressure as well as pulse pressure. Second, different indices of adipose tissue depot appear to play a major role in determining cardiac and vascular structural alterations, by potentiating and amplifying the prohypertrophic effects a stable blood pressure elevation has on cardiac wall thickness and pulse wave velocity. Finally, leptin is suggested to represent one of the major pathophysiological links between the abnormal adipose tissue depot and the development and progression of the cardiac structural changes. Cardiac structural changes and obesity: an evolving concept The complex chain of events leading from obesity (without and with hypertension) to an increased cardiac mass has been originally described about 30 years ago [6,7]. These alterations can be schematically summarized as follows. The obese normotensive state is characterized, from a haemodynamic point of view, by an increase in cardiac output, an augmented circulating blood volume and a parallel decrease in vascular resistance. When hypertension develops, vascular resistance undergoes a marked increase in proportion to the blood pressure rise associated with a further volume overload. The latter alteration represents an additional cardiac stimulus for development of left ventricular structural abnormalities, including concentric remodelling and concentric or eccentric hypertrophy. The above-mentioned pathophysiological picture, although receiving a number of experimental and clinical supports, underwent remarkable changes throughout the years, with the evidence that metabolic (insulin resistance) as well as sympathetic (adrenergic activation) factors may represent the driving forces for development of cardiac organ damage in conjunction with haemodynamic factors [8]. The results of the study by Norton et al. [4] reinforce this latter pathophysiological picture, by showing that the presence of an obese state exponentially potentiates the prohypertrophic effects of blood pressure elevation. This finding has two major implications. First, it provides further confirmation to the hypothesis prompted some years ago that even from a pathophysiological point of view, not all forms of cardiac hypertrophy have a similar background [9]. Second, it suggests that frequently extrahaemodynamic factors play a major role in the development and progression of this target organ damage. This latter conclusion can be also applied to pulse wave velocity, taken as an index of a large artery dysfunction. Norton et al. [4] also provide some insights into the pathophysiological mechanisms linking an excess adiposity to an abnormal left ventricular mass. Indeed in their study, the authors emphasize the potential prohypertrophic role exerted by leptin, as indicated by the results of the multivariate analysis, which included a number of haemodynamic as well as nonhaemodynamic variables. It should be mentioned, however, that leptin cannot be regarded as the only extrahaemodynamic factor responsible for the structural alteration of the left ventricle. Indeed, evidence exists that several other mechanisms may play a role, including the insulin-resistance state, the insulin-like growth factor, the sympathetic overdrive, the renin–angiotensin system activation and the sleep apnoea syndrome [10,11]. Recently, it has been shown that human adipose tissue expresses and secretes cardiotrophin-1, a cytokine that induces cardiomyocyte hypertrophy, and that circulating levels of this molecule are abnormally elevated in obese individuals [12]. As an association has been reported between an excess of circulating cardiotrophin-1 and exaggerated left ventricular mass in hypertensive patients [13,14], the possibility exists that this cytokine may be an additional link between obesity and left ventricular hypertrophy. It should, thus, appear that, as schematically depicted in Fig. 1, the pathophysiological profile of the structural cardiac alterations described in obesity and more so in obesity-related hypertension should be regarded as multifactorial.Fig. 1Clinic vs. 24-h blood pressure overload A rather surprising finding of the investigation carried out by Norton et al. [4] refers to the evidence that in the whole study population, assessment of 24-h ambulatory blood pressure profile does not seem to add so much, in terms of correlation coefficient, to the relationships between clinic blood pressure and left ventricular mass. On the opposite, the results of the study seem to indicate a better correlation between clinic rather than ambulatory blood pressure and left ventricular mass. This finding is not in line with the results of several other studies, including those carried out by the Milan/Monza group in the context of the already mentioned PAMELA Research Project [15], showing the superiority of 24-h blood pressure in detecting alterations in left ventricular mass as compared with the clinic blood pressure. Once again, however, it should be noted that the main features of the two study populations were considerably different and that not necessarily what is found in normoweight individuals can be safely extrapolated to the obese ones. In addition, the relationship may be affected by antihypertensive drug treatment, which in the study by Norton et al. [4] was not withdrawn at the time of the blood pressure and echocardiographic evaluation. Finally, no data are available in the present study on the relative weight of daytime vs. night-time blood pressure values in determining the development and progression of the cardiac and vascular alterations described in the population of the study. Study limitations As above mentioned and as properly emphasized by the authors, inclusion of untreated hypertensive patients in the study may have weakened in some way the strength of the relationships between haemodynamic, cardiovascular and anthropometric variables. A further potential limitation consists in the lack of measures of adipose tissue depot more sensitive and sophisticated than the ones employed in the present study. Finally, and quite surprisingly, no mention in the study was made on the behaviour of clinic and 24-h heart rate values. Information on this issue would have been of great help for data interpretation. Indeed, heart rate data would allow to more completely define the haemodynamic profile of the patients studied. They would also have allowed to provide some insights into the role of adrenergic neural factors in the adipose tissue/left ventricular mass interactions. This because heart rate, although representing the result of the sympathovagal balance, has been shown to bear a satisfactory relationship with indices of sympathetic function, such as plasma norepinephrine and efferent postganglionic sympathetic nerve traffic [16,17]. Heart rate values would, thus, have been of help in defining a possible adrenergic involvement.