Impact of the metabolic syndrome on subcutaneous microcirculation in obese patients.

OBJECTIVES: Patients with the metabolic syndrome are at increased cardiovascular risk and display an augmented wall stiffness of the large-sized and medium-sized arteries, coupled with an endothelial dysfunction. Whether this is the case also for the small resistance arteries is unknown, however. It is also unknown whether and to what extent the hypothesized microvascular alterations are greater for magnitude than the ones characterizing obesity, that is the most common component of the metabolic syndrome. METHODS: In 14 lean healthy controls (age 48.7 +/- 2.4 years, mean +/- SEM), 13 obese participants and 12 individuals with the metabolic syndrome (Adult Treatment Panel III criteria), all age-matched with healthy controls, we assessed the small resistance arteries dissected from the abdominal subcutaneous tissue on a pressurized myograph. RESULTS: The media thickness, media cross-sectional area (CSA) and media-to-lumen ratio (M/L) of the small resistance arteries were markedly and significantly greater in metabolic syndrome than in controls (media thickness: 28.3 +/- 0.7 vs. 17.5 +/- 0.3 microm; CSA: 24 760.8 +/- 1459 vs. 16 170.7 +/- 843.6 microm and M/L: 0.12 +/- 0.01 vs. 0.064 +/- 0.002 a.u., respectively, P < 0.01 for all). Acetylcholine-induced relaxation was impaired in the vessels from metabolic syndrome participants compared with the lean healthy individuals (-48.8%, P < 0.01), whereas endothelium-independent vasorelaxation was similar in the two groups. The structural and functional microvascular alterations seen in metabolic syndrome were slightly, although not significantly, greater than the ones seen in uncomplicated obese participants. Stiffness of small arteries, as assessed by the stress/strain relationship, was also similar in the three groups of participants. CONCLUSION: Thus, metabolic syndrome is characterized by marked alterations in the structural and functional patterns of the small resistance arteries. These alterations, which are only slightly greater than the ones seen in obesity, may be responsible for the increased incidence of coronary and cerebrovascular events reported in metabolic syndrome.

Behaviour of regional adrenergic outflow in mild-to-moderate renal failure.

OBJECTIVES: Chronic renal failure is characterized by a marked sympathetic activation. No information exists, however, as to whether the adrenergic overdrive is confined to selected vascular districts or is rather generalized to the whole cardiovascular system. METHODS: In 15 patients aged 60.5 +/- 2.0 years (mean +/- SEM) with stable chronic renal failure belonging to stage 2-3 of the Kidney Foundation classification and in 12 age-matched healthy controls, we measured arterial blood pressure (Finapres), heart rate (ECG), venous plasma norepinephrine (high-performance liquid chromatography) and postganglionic sympathetic nerve traffic in skeletal muscle and skin areas (microneurography). Muscle and skin nerve traffic measurements were made in a randomized sequence over two periods of 30 min each, spaced by a 20-30-min interval. Measurements also included evaluation of skin sympathetic responses to emotional stimuli. RESULTS: Muscle sympathetic nerve traffic was markedly and significantly greater in renal failure patients compared with controls (58.2 +/- 3.6 vs. 36.8 +/- 5.7 bursts/100 heart beats, P < 0.01), with this also being the case for plasma norepinephrine (380.6 +/- 63 vs. 210.8 +/- 29 pg/ml, P < 0.05). By contrast, skin sympathetic nerve traffic was superimposable in the two groups (11.5 +/- 0.8 vs. 12.7 +/- 1.7 bursts/minute, P = not significant), this being the case also for the responses to emotional arousal. CONCLUSION: These data provide the first evidence that the sympathetic activation characterizing renal failure is not generalized to the entire cardiovascular system. This may depend on the fact that the two sympathetic districts are governed by mechanisms that are differently affected by the chronic uraemic state.

Sympathetic activation in congestive heart failure: reproducibility of neuroadrenergic markers.

OBJECTIVE: To assess the reproducibility of the two markers of adrenergic drive, venous plasma norepinephrine (NE) and efferent postganglionic muscle sympathetic nerve activity (MSNA), in reflecting the sympathetic activation characterizing congestive heart failure (CHF). METHODS AND MEASUREMENTS: In 19 CHF male normotensive patients (mean age: 53.0+/-2.1 years, NYHA classes II and III, left ventricular ejection fraction 35.9+/-2.9%), blood pressure (BP, Finapres), heart rate (EKG), plasma NE (HPLC assay) and MSNA (microneurography, peroneal nerve) were measured in two experimental sessions separated by a week interval. At each session, three NE samples were obtained and NE reproducibility between sessions was assessed by considering single NE samples or averaging 2-3 samples. RESULTS: While MSNA values showed a highly significant correlation between sessions (r=0.85, P<0.001), NE values based on a single blood sample evaluation did not correlate with each other (r=0.41, P=NS). NE correlation coefficients improved and achieved statistical significance when average data from 2 and 3 blood samples were examined (r=0.54 and r=0.57, P<0.02 for both). CONCLUSIONS: In CHF, MSNA displays a better reproducibility pattern than plasma NE. The reproducibility of the NE approach, however, can be improved by performing the assay on multiple blood samples.

Adrenergic, metabolic, and reflex abnormalities in reverse and extreme dipper hypertensives.

Limited information is available on whether and to what extent the different patterns of the nocturnal blood pressure profile reported in hypertension are characterized by differences in sympathetic drive that may relate to, and account for, the different day-night blood pressure changes. In 34 untreated middle-aged essential hypertensive dippers, 17 extreme dippers, 18 nondippers, and 10 reverse dippers, we assessed muscle sympathetic nerve traffic, heart rate, and beat-to-beat arterial blood pressure at rest and during baroreceptor deactivation and stimulation. Measurements were also performed in 17 age-matched dipper normotensives. All patients displayed reproducible blood pressure patterns at 2 different monitoring sessions. The 4 hypertensive groups did not differ by gender or 24-hour or daytime blood pressure. Muscle sympathetic nerve traffic was significantly higher in nondipper, dipper, and extreme dipper hypertensives than in normotensive controls (58.6+/-1.8, 55.6+/-0.9, and 53.3+/-0.8 versus 43.5+/-1.4 bursts/100 heartbeats, respectively; P<0.01 for all), a further significant increase being detected in reverse dippers (76.8+/-3.1 bursts/100 heartbeats; P<0.05). Compared with normotensives, baroreflex-heart rate control was similarly impaired in all the 4 hypertensive states, whereas baroreflex-sympathetic control was preserved. The day-night blood pressure difference correlated inversely with sympathetic nerve traffic (r=-0.76; P<0.0001) and homeostasis model assessment index (r=-0.32; P<0.005). Thus, the reverse dipping state is characterized by a sympathetic activation greater for magnitude than that seen in the other conditions displaying abnormalities in nighttime blood pressure pattern. The present data suggest that in hypertension, sympathetic activation represents a mechanism potentially responsible for the day-night blood pressure difference.

Heart rate as a sympathetic marker during acute adrenergic challenge.

OBJECTIVE: Previous studies have shown that heart rate has a limited value in reflecting the chronic state of adrenergic overdrive characterizing several cardiovascular diseases. Whether this also applies to the ability of heart rate to reflect acute and generalized changes in sympathetic activity is unknown. METHODS: In 20 healthy young subjects (age: 25.2 +/- 1.2 years, mean +/- SEM) we measured beat-to-beat blood pressure (Finapres), heart rate (HR, ECG), venous plasma norepinephrine (NE, high-performance liquid chromatography) and efferent postganglionic muscle sympathetic nerve traffic (MSNA, microneurography) at rest and during a cold pressor test and two intravenous infusions of nitroprusside at increasing doses. RESULTS: Both cold pressor test and nitroprusside infusions triggered marked and significant increases in HR, plasma NE and MSNA; blood pressure showing an increase with cold pressor test and a reduction with nitroprusside. The magnitude of the responses was greater with the higher than with the lower dose of nitroprusside. The HR changes induced by cold pressor test were not significantly related to the concomitant NE and MSNA changes (r = -0.08 and r = -0.18, P = NS). This was also the case for the lower and the higher dose of nitroprusside (NE: r = -0.11 and r = 0.08; MSNA: r = 0.01 and r = -0.11, P = NS for all). In contrast NE and MSNA changes induced by cold pressor test and by the lower and the higher dose of nitroprusside were significantly related to each other (r = 0.70, r = 0.89 and r = 0.79 respectively, P < 0.01 for all). CONCLUSIONS: In a given individual, HR responses to sympathetic challenge do not quantitatively reflect the degree of acute and generalized adrenergic activation. Qualitative information on the acute adrenergic effects of given stimuli should thus be based on the assessment of NE and MSNA rather than on HR changes.

Neurogenic abnormalities in masked hypertension.

Patients with hypertension exhibit an increased sympathetic activity. No information exists as to whether this is the case in normotensive individuals in whom there is an increased ambulatory blood pressure, a condition termed "masked" hypertension. We studied 18 middle-aged subjects with masked hypertension in whom we measured muscle sympathetic nerve traffic (peroneal nerve and microneurography) and beat-to-beat arterial blood pressure at rest and during baroreceptor deactivation and activation. Measurements also included anthropometric values and insulin sensitivity (homeostasis model assessment index). Data were compared with those of 20 normotensive subjects, 18 subjects with white-coat hypertension, and 20 patients with "in-office" and "out-of-office" hypertension. All of the individuals were pharmacologically untreated and age-matched with subjects with masked hypertension. Patients with in- and out-of-office and white-coat hypertension displayed resting sympathetic nerve activity values significantly greater than normotensive subjects (75.8+/-2.5 and 70.8+/-2.2 versus 45.5+/-2.0 bursts per 100 heartbeats respectively; P<0.01). This was the case also for masked hypertension (73.5+/-2.4 bursts per 100 heartbeats; P<0.01), the degree of the sympathetic activation being similar for magnitude to that seen in the other 2 hypertensive conditions. Compared with normotensive subjects, baroreflex-heart rate control was significantly attenuated in all of the hypertensive states, whereas baroreflex-sympathetic control was unaffected. Homeostasis model assessment index was increased in patients with in- and out-of-office and white-coat hypertension, with a further increase in masked hypertension and a direct relation with resting sympathetic nerve traffic (r=0.46; P<0.01). These data provide the first evidence that masked hypertension is characterized by a marked sympathetic overdrive. They further show that the neurogenic alterations are coupled with metabolic and baroreflex abnormalities.

Excessive sympathetic activation in heart failure with obesity and metabolic syndrome: characteristics and mechanisms.

Congestive heart failure is characterized by sympathetic activation, which has also been described in the metabolic syndrome. No information exists, however, as to whether the sympathostimulating effects of these 2 conditions summate when heart failure is complicated by the metabolic syndrome, leading to an exceedingly high adrenergic drive. This is clinically relevant, because in heart failure sympathetic activation is closely related to mortality. We studied 48 control subjects (age: 58.4+/-1.6 years, mean+/-SEM) and 89 age-matched heart failure patients (New York Heart Association class II), of whom 47 were without and 42 were with metabolic syndrome. Measurements included blood pressure (Finapres), heart rate (ECG), and sympathetic nerve traffic (microneurography) at rest and during baroreceptor manipulation. Waist circumference, blood pressure, and metabolic variables were greater in heart failure with metabolic syndrome than in heart failure without metabolic syndrome and in control subjects. Left ventricular ejection fraction and end-diastolic diameter were similarly altered in the 2 heart failure groups. Compared with control subjects, sympathetic nerve activity was greater in heart failure patients without metabolic syndrome (64.7+/-3.2 versus 45.8+/-2.9 bursts/100 heartbeats; P<0.01), a further pronounced increase being detected in those with metabolic syndrome (80.9+/-3.2 bursts/100 heartbeats; P<0.01). In the multivariate analysis, waist circumference and body mass index were the variables most closely related to sympathetic activation. Compared with control subjects, baroreflex responses were significantly attenuated in the 2 heart failure groups, the impairment being more marked in the group with than without metabolic syndrome. Thus, obesity and metabolic syndrome potentiate the sympathetic activation characterizing heart failure. This potentiation is likely to mainly depend on metabolic and baroreflex mechanisms.

Obstructive sleep apnea-dependent and -independent adrenergic activation in obesity.

No agreement exists as to the mechanisms responsible for the sympathetic hyperactivity characterizing human obesity, which has been ascribed recently to a chemoreflex stimulation brought about by obstructive sleep apnea rather than to an increase in body weight, per se. In 86 middle-age normotensive subjects classified according to body mass index, waist-to-hip ratio, and apnea/hypopnea index (overnight polysomnographic evaluation) as lean and obese subjects without or with obstructive sleep apnea, we assessed via microneurography muscle sympathetic nerve traffic. The 4 groups were matched for age, gender, and blood pressure values, the 2 obese groups with and without obstructive sleep apnea showing a similar increase in body mass index (32.4 versus 32.0 kg/m2, respectively) and waist-to-hip ratio (0.96 versus 0.95, respectively) compared with the 2 lean groups with or without obstructive sleep apnea (body mass index 24.3 versus 23.8 kg/m2 and waist-to-hip ratio 0.77 versus 0.76, respectively; P<0.01). Compared with the nonobstructive sleep apnea lean group, muscle sympathetic nerve activity showed a similar increase in the obstructive sleep apnea lean group and in the nonobstructive sleep apnea obese group (60.4+/-2.3 and 59.3+/-2.0 versus 40.9+/-1.8 bs/100 hb, respectively; P<0.01), a further increase being detected in obstructive sleep apnea subjects (73.1+/-2.5 bursts/100 heart beats; P<0.01). Our data demonstrate that the sympathetic activation of obesity occurs independently in obstructive sleep apnea. They also show that this condition exerts sympathostimulating effects independent of body weight, and that the obstructive sleep apnea-dependent and -independent sympathostimulation contribute to the overall adrenergic activation of the obese state.

Effects of hypertension and obesity on the sympathetic activation of heart failure patients.

Previous studies have shown that congestive heart failure is characterized by sympathetic and reflex dysfunctions. Whether these alterations are potentiated in the presence of obesity and hypertension, two conditions that also display neuroadrenergic abnormalities and markedly increase the risk of heart failure, is unknown. In 14 healthy control subjects (C; age, 55.1+/-3.0 years; mean+/-SEM), 13 lean hypertensive subjects (H), 15 obese normotensive subjects (O), 14 lean normotensive subjects with congestive heart failure (CHF, New York Heart Association class II), 14 lean hypertensive subjects with CHF (CHFH), 14 obese normotensive subjects with CHF (CHFO), and 13 obese hypertensive subjects with CHF (CHFOH), all age-matched with C, we measured mean blood pressure (Finapres), heart rate (ECG), and muscle sympathetic nerve traffic (MSNA, microneurography) at rest and during baroreflex testing. Compared with C, body mass index was similarly increased in O, CHFO, and CHFOH, whereas mean blood pressure was similarly increased in HF, CHFH, and CHFOH, and left ventricular ejection fraction (echocardiography) was similarly reduced in CHF, CHFH, CHFO and CHFOH. Compared with C, MSNA was significantly increased in O, H, and CHF (43.0+/-2.2 versus 54.1+/-2.8, 53.1+/-2.5, and 57.4+/-2.8 bursts/100 heart beats, P<0.01). When O or H was combined with CHF, the MSNA increase was significantly more pronounced and maximal when O and H were concomitantly associated with CHF. Baroreflex sensitivity was reduced in O and H, with a further reduction in CHF and a minimal value in CHFOH. These data show that the sympathetic activation characterizing CHF is markedly potentiated when O and H alone or combined together are associated with a low cardiac output state and that this may depend on an arterial baroreflex impairment.

Short-versus long-term effects of different dihydropyridines on sympathetic and baroreflex function in hypertension.

Antihypertensive treatment with dihydropyridines may be accompanied by sympathetic activation. Data on whether this is common to all compounds and similar in the various phases of treatment are not univocal, however. In 28 untreated essential hypertensives (age, 56.4+/-1.8 years; mean+/-SEM) finger blood pressure (BP, Finapres), heart rate (HR, ECG), plasma norepinephrine (NE, high-performance liquid chromatography), and muscle sympathetic nerve traffic (MSNA, microneurography) were measured at rest and during baroreceptor manipulation (vasoactive drugs) in the placebo run-in period and after randomization to double-blind acute and chronic (8 weeks) felodipine (10 mg/d, n=14) or lercanidipine (10 mg/d, n=14). Acute administration of both drugs induced pronounced BP reductions and marked increases in HR, NE, and MSNA. After 8 weeks of treatment, BP reductions were similar to those observed after acute administration, whereas HR, NE, and MSNA responses were markedly attenuated (-7%, -32%, and -14%, respectively; P<0.05). There was a small residual increase in sympathetic activity in the felodipine group, whereas in the lercanidipine group, all adrenergic markers returned to baseline values. Baroreflex control of HR and MSNA was markedly impaired (-42% and -48%, respectively) after acute drug administration, with a recovery and complete resetting during chronic treatment. Thus, the sympathoexcitation induced by 2 different dihydropyridines is largely limited to the acute administration. The 2 drugs have, nevertheless, a different chronic sympathetic effect, indicating that dihydropyridines do not homogeneously affect this function. The acute sympathoexcitation, but not the small between-drugs differential chronic adrenergic effect, is accounted for by baroreflex impairment.