R. Dell’Oro

Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome

Aims/hypothesisPrevious studies have shown that alterations in vascular, metabolic, inflammatory and haemocoagulative functions characterise the metabolic syndrome. Whether this is also the case for sympathetic function is not clear. We therefore aimed to clarify this issue and to determine whether metabolic or reflex mechanisms might be responsible for the possible adrenergic dysfunction.MethodsIn 43 healthy control subjects (age 48.2±1.0 years, mean±SEM) and in 48 untreated age-matched subjects with metabolic syndrome (National Cholesterol Education Program’s Adult Treatment Panel III Report criteria) we measured, along with anthropometric and metabolic variables, blood pressure (Finapres), heart rate (ECG) and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during baroreceptor manipulation (vasoactive drug infusion technique).ResultsCompared with control subjects, subjects with metabolic syndrome had higher BMI, waist circumference, blood pressure, cholesterol, triglycerides, insulin and homeostasis model assessment (HOMA) index values but lower HDL cholesterol values. Sympathetic nerve traffic was significantly greater in subjects with metabolic syndrome than in control subjects (61.1±2.6 vs 43.8±2.8 bursts/100 heartbeats, p<0.01), the presence of sympathetic activation also being detectable when the metabolic syndrome did not include hypertension as a component. Muscle sympathetic nerve traffic correlated directly and significantly with waist circumference (r=0.46, p<0.001) and HOMA index (r=0.49, p<0.001) and was inversely related to baroreflex sensitivity (r=−0.44, p<0.001), which was impaired in the metabolic syndrome.Conclusions/interpretationThese data provide evidence that the metabolic syndrome is characterised by sympathetic activation and that this abnormality (1) is also detectable when blood pressure is normal and (2) depends on insulin resistance as well as on reflex alterations.

[OP.1C.12] VISIT-TO-VISIT BLOOD PRESSURE VARIABILITY IS RELATED TO SYMPATHETIC NEURAL DRIVE AND BAROREFLEX SENSITIVITY IN HYPERTENSIVE PATIENTS

Objective: Neurogenic mechanims have been shown to regulate not only absolute blood pressure levels but also blood pressure variability during the short-term 24 hour period. No information are available on whether visit-to-visit blood pressure variability is related to sympathetic and baroreflex function. Design and method: 61 untreated essential hypertensive patients aged 56.1 ± 2.5 years (mean ± SEM) underwent 3 clinic BP measurements on 3 occasions during a 6 weeks period. In each patient we assessed muscle sympathetic nerve traffic (MSNA, microneurography), spontaneous MSNA-baroreflex sensitivity according to Kienbaum method, and blood pressure variability of systolic and diastolic BP, quantified as coefficient of variation (CV) and as standard deviation (SD) of the BP values. Results: Patients were subdivided into CV and SD quartiles. Quartiles were matched for age and gender. For each quartile a relationship was sought with MSNA and baroreflex sensitivity. Compared with the patients in the lowest systolic BP CV quartile, patients in the highest quartile showed significantly greater MSNA (62.5 ± 4 vs 48.2 ± 3 bursts/100 heart beats, P < 0.02) and significantly lower baroreflex sensitivity values (1.23 ± 0.2 vs 2.09 ± 0.2 a.u., P < 0.03). This was the case also when BP variability was expressed as SD. When diastolic BP data were analyzed no significant difference between quartiles was found. Conclusions: These data provide the first demonstration that in hypertension a greater visit-to-visit blood pressure variability is associated with greater levels of sympathetic activation and more pronounced baroreflex dysfunction. The relationship appears to be valid particularly for the systolic BP component. Thus sympathetic and reflex mechanisms contribute not only to the short-term but also to the long-term BP variability phenomenon.

[PP.23.16] TIME INTEGRATED SYMPATHETIC ACTIVITY CHANGES PARALLEL SIMULTANEOUS BP CHANGES AFTER RENAL DENERVATION

Objective: Renal denervation (RDN) reduces BP levels in treatment-resistant essential hypertension but there is apparently no relationship between sympathetic activity and BP changes after this intervention. We reassessed the problem in an incident series of 29 patients with ABPM documented resistant hypertension by measuring repeatedly (from 2 to 5 times) MNSAC and simultaneous (in lab) standardized BP and analyzed data by a novel statistical approach. Design and method: In all patients ABPM was performed the day before the MNSAC recording session. Since MNSAC is highly repeatable and stable over-time, the novel analytical approach calculates the proportional (%) difference between the expected area under the curve of repeated MSNAC measurements assuming that renal denervation has no effect on this variable (i.e., a rectangular area formed by individual baseline value [short side] and the individual time of observation [long side]) and the actual area under the MSNAC curve. The same calculation is applied to simultaneous BP and heart rate data Results: Overall RDN reduced BP over-time (SBP: from 175 ± 14 to 160 ± 19 mmHg; DBP: from 96 ± 11 to 88 ± 9 mmHg). MNSAC showed a parallel trend (from 67 ± 13 to 53 ± 17 burst/100 HR). HR did not change over-time (from 65 ± 12 to 64 ± 11 beats/min, In Mixed Linear Modelling (MLM) analyses, there was no relationship between SBP (r = 0.03, p = 0.72) and DBP (r = 0.03, p = 0.67) values over time and concomitant values of MSNA after RDN. The re-analyzing by MLM showed a strong relationship between proportional changes in MNSAC over time and simultaneous proportional changes in BP but not with HR (r = 0.28, p = 0.13). Likely due to the non-simultaneous nature of measurements and the influence of daily living environment, no relationship was found between MNSAC and ABPM. Conclusions: The proportional time-integrated BP-lowering effects of RDN are strongly associated with simultaneous time-integrated changes in MNSAC while no such time trend emerges in analyses of in-lab or ABPM data by the conventional MLM. These findings indicate that integrated sympathetic activity changes in the short and medium term rather than single measurements capture the pathophysiological relevance of the sympathetic system in the BP response to renal denervation.

[OP.4C.01] ANTIHYPERTENSIVE DRUG TREATMENT FAILS TO NORMALIZE SYMPATHETIC ACTIVITY: MICRONEUROGRAPHIC EVIDENCE AND CLINICAL IMPLICATIONS

Objective: It is unknown whether and to what extent antihypertensive drug treatment capable to reduce adrenergic overactivity normalizes cardiovascular sympathetic drive. Design and method: Results of three studies carried out by our group assessing muscle sympathetic nerve traffic (MSNA) via the microneurographic technique were analyzed, comparing the data obtained after long-term combination drug treatment with ACE-inhibitors, diuretics and calcium channel blockers with those detected in 30 age-matched untreated healthy normotensive controls (C). A total of 78 middle-age treated hypertensive patients (HTs) were analyzed. Average follow-up amounted to 10 weeks. Results: At baseline, before treatment, clinic and ambulatory blood pressure (BP) values were as expected significantly greater in HTs than in C. This was the case also for MSNA (62.4 ± 1.4 vs 35.1 ± 1.8 bursts/100 heart beats, p < 0.01). Drug treatment significantly reduced BP to values <140/90 mmHg and <125/79 mmHg for clinic and ambulatory data respectively. MSNA values were also significantly reduced. In no study,however treatment was capable to bring back to normal MSNA values, which remained significantly greater than controls both when ACEI-diuretic, ACEI/calcium antagonists and angiotensin II receptor blockers/diuretic combination treatment was used (51.3 ± 2.7, 49.4 ± 2.3 and 44.5 ± 2.4 bursts/100 heart beats, p < 0.05 at least vs C). Conclusions: Our study provides the first evidence that antihypertensive combination drug treatment, although allowing to achieve normal BP values, fails to normalize sympathetic activity, independently on the type of drugs used. This lack of normalization might contribute to determine the so-called residual risk of treated hypertensive patients.