Overweight, hypertension and cardiovascular disease: focus on adipocytokines, insulin, weight changes and natriuretic peptides.

BACKGROUND: Hypertension is one of the leading causes of cardiovascular disease (CVD) worldwide. Overweight and obesity are major risk factors for hypertension. The mechanisms linking these two diseases are incompletely understood, but abnormalities in several different pathways including insulin and glucose metabolism, inflammation, the sympathetic nervous system and the renin-angiotensin-aldosterone system have been known for decades. Lately, the attention has shifted toward the endocrine function of adipose tissue, which among others secrete adiponectin, leptin and interleukin-6 (IL-6), which stimulates liver CRP production. These substances have all been regarded as candidate intermediates between adiposity and the development of hypertension. Furthermore, the so-called "natriuretic handicap" which characterizes obesity, has also attracted a great deal of attention as a possible pathway.   Primary hypotheses: • The adipocytokines, adiponectin, leptin and CRP (used as a surrogate marker of IL-6) are independently associated with prevalent and incident hypertension.   • Five-year weight changes associate with BP alterations, even after adjustment for changes in lifestyle risk factors and serum insulin.   • NT-proBNP (used as a surrogate marker of active BNP) is positively associated with prevalent hypertension, but negatively associated with incident hypertension.   • The adipocytokines, adiponectin, leptin and CRP (used as a surrogate marker of IL-6), are independently associated with incident CVD.  

METHODS: The Inter99 study provided data for this thesis. In brief, Inter99 is a randomized, non-pharmacological intervention study for the prevention of ischemic heart disease. The study included approximately 6,700 participants from the background population, who were thoroughly examined at baseline. Various measurements, including blood samples, were done at baseline and five-year follow-up. Data about cardiovascular events were gathered from national registers.  

RESULTS: Paper I: In the prevalent model including leptin, CRP, adiponectin, sex, age, lifestyle risk factors, lipids, insulin, haemoglobin A1c, and in the incident model which also included baseline heart rate and blood pressure, only leptin of the three candidate intermediates was significantly associated with both prevalent and incident hypertension. Paper II: Five-year weight changes were associated with blood pressure alterations and had a substantial impact on both fasting and two-hour post-glucose serum insulin levels. However, in multivariable regression analyses, additional adjustments for insulin values only attenuated the associations between weight changes and blood pressure minimally. Paper III: Higher serum concentrations of NT-proBNP associated with prevalent hypertension whereas lower concentrations associated with incident hypertension. Paper IV: Among 6,502 participants with a mean follow-up time of 11.4 years, 527 participants experienced one or multiple cardio-vascular events. Among adiponectin, leptin and CRP, only CRP were significantly positive associated with CVD in all models.  

CONCLUSIONS: Regarding the pathophysiology of overweight-related hypertension and CVD, our results indicate that:   • Leptin is possibly an independent risk factor for the development of hypertension.   • Albeit weight loss improves insulin-profile, the effect of insulin on blood pressure changes seems minimal, indicating that insulin does not play a major direct role in the early development of hypertension.   • A deficiency of the natriuretic peptides, resulting in reduced vasodilation and natriuresis, could be involved in the pathogenesis of hypertension in its early stages.   • Since adjustment for CRP decreased the BMI-associated CVD risk markedly, our data indirectly suggest that IL-6 originating from fat tissue could play a role in overweight and obesity-related cardiovascular disease.