Francesca Arenare

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.

Early Sympathetic Activation in the Initial Clinical Stages of Chronic Renal Failure

Direct and indirect indices of neuroadrenergic function have shown that end-stage renal disease is characterized by a marked sympathetic overdrive. It is unknown, however, whether this phenomenon represents a peculiar feature of end-stage renal disease or whether it is also detectable in the early clinical phases of the disease. The study has been performed in 73 hypertensive patients, of which there were 42 (age: 60.7±1.8 years, mean±SEM) with a stable moderate chronic renal failure (mean estimated glomerular filtration rate: 40.7 mL/min per 1.73 m2, MDRD formula) and 31 age-matched controls with a preserved renal function. Measurements included anthropometric variables, sphygmomanometric and beat-to-beat blood pressure, heart rate (ECG), venous plasma norepinephrine (high-performance liquid chromatography), and efferent postganglionic muscle sympathetic nerve activity (microneurography, peroneal nerve). For similar anthropometric and hemodynamic values, renal failure patients displayed muscle sympathetic nerve activity values significantly and markedly greater than controls (60.0±2.1 versus 45.7±2.0 bursts per 100 heartbeats; P<0.001). Muscle sympathetic nerve activity showed a progressive and significant increase from the first to the fourth quartile of the estimated glomerular filtration rate values (first: 41.0±2.7; second: 51.9±1.7; third: 59.8±3.0; fourth: 61.9±3.3 bursts per 100 heartbeats), the statistical significance (P<0.05) between groups being maintained after adjustment for confounders. In the population as a whole, muscle sympathetic nerve activity was significantly and inversely correlated with the estimated glomerular filtration rate (r=−0.59; P<0.0001). Thus, adrenergic activation is a phenomenon not confined to advanced renal failure but already detectable in the initial phases of the disease. The sympathetic overdrive parallels the severity of the renal failure, state and, thus, it might participate, in conjunction with other factors, at the disease progression.

Left ventricular hypertrophy increases cardiovascular risk independently of in-office and out-of-office blood pressure values

Objectives Previous studies have shown that left ventricular hypertrophy (LVH) represents a cardiovascular risk factor independently of clinic blood pressure (BP). The present study was aimed at determining the impact of LVH on the incidence of cardiovascular morbid and fatal events taking into account not only classical risk factors but also home and ambulatory BP values, which have been shown to have an important independent prognostic impact. Methods In 1716 patients belonging to the ‘Pressioni Arteriose Monitorate E Loro Associazioni’ population of Monza, we quantified left ventricular mass index and identified LVH by standard cutoff values. We also measured clinic, home and 24-h ambulatory BPs together with serum glucose and lipids. Results During a follow-up of 148 months, the rate of fatal and nonfatal (hospitalizations) cardiovascular events as well as of all-cause death was markedly greater (four-fold to five-fold) in patients as compared with those without LVH. In LVH individuals, the increased risk remained significant even when data were adjusted for a large number of other confounding factors including home BP, 24-h mean BP and ambulatory BP. Results were similar when left ventricular mass was indexed by height and body surface area. A 10% increase in left ventricular mass index was associated with a significant increase in cardiovascular risk or all-cause deaths. In multivariate analysis, left ventricular mass index was always an independent predictor of cardiovascular events and death for any cause. Conclusion Our data provide evidence that LVH is an important risk factor even when the contribution of different BPs to risk is fully taken into account.

Sympathetic and Baroreflex Cardiovascular Control in Hypertension-Related Left Ventricular Dysfunction

The sympathetic overdrive that characterizes essential hypertension is potentiated when left ventricular hypertrophy or congestive heart failure is detected. No information exists, however, on whether this is the case also for left ventricular diastolic dysfunction. In 17 untreated hypertensive subjects with left ventricular diastolic dysfunction (age: 47.7±2.9 years, mean±SEM), we measured sympathetic nerve traffic (microneurography), heart rate (ECG), and beat-to-beat arterial blood pressure (Finapres) at rest and during baroreceptor deactivation and stimulation. Data were compared with those collected in 20 age-matched normotensive and 20 hypertensive subjects without a diastolic function impairment. Muscle sympathetic nerve traffic values were markedly and significantly greater in the 2 hypertensive groups than in the normotensive one (55.3±1.2 and 71.2±1.6 versus 41.7±1.0 bursts per 100 heartbeats, respectively; P<0.01 for both). For a similar blood pressure elevation, however, the sympathetic nerve traffic increase was significantly greater in patients with than without left ventricular diastolic dysfunction (+28.9%; P<0.05). In the population as a whole, muscle sympathetic nerve traffic was significantly and inversely related to various echocardiographic indices of diastolic function. Although baroreflex-heart rate control was significantly attenuated in the 2 hypertensive groups, baroreflex-sympathetic modulation was impaired only in those with diastolic dysfunction. These data provide the first evidence that, in hypertension, activation of the sympathetic nervous system may contribute not only at the blood pressure elevation but also at the development of left ventricular diastolic dysfunction. The sympathetic overactivity, which is likely to be related to the baroreflex impairment, may account for the increased cardiovascular risk characterizing diastolic dysfunction.

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.

Impact of different definitions of the metabolic syndrome on the prevalence of organ damage, cardiometabolic risk and cardiovascular events

Objectives We compared definitions of metabolic syndrome performed by ATPIII [the National Cholesterol Education Program Adult Treatment Panel III; three criteria of the following: systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg, fasting serum glucose ≥110 mg/dl, high-density lipoprotein plasma cholesterol ≤40 mg/dl (men) or ≤50 mg/dl (women), plasma triglycerides ≥150 mg/dl, waist circumference ≥102 cm (men) or 88 cm (women)], AHA (the American Heart Association; same cut-off of ATPIII except serum glucose ≥ 100 mg/dl) and IDF [the International Diabetes Federation; mandatory criteria of visceral obesity with reduced cut-off of 94 cm (men) or 80 cm (women), and at least two criteria with the same cut-off as in AHA] for their impact on metabolic syndrome prevalence, cardiac organ damage, long-term risk of cardiovascular events and death for any cause and risk of developing diabetes mellitus, in-office and out-of-office hypertension and left ventricular hypertrophy (LVH). Methods In 2051 participants, we measured office, home and ambulatory blood pressure as well as metabolic, anthropometric and echocardiographic variables. Measurements were performed between 1990 and 1992 and repeated 10 years later. Information on long-term incidence of cardiovascular events and all-cause deaths was also collected. Results Prevalence of metabolic syndrome was significantly greater when using the AHA and IDF as compared to the ATPIII definition. Prevalence of LVH was higher in participants with than without metabolic syndrome and similar for the three definitions. Over 12-year follow-up, there were 179 cardiovascular events and 233 deaths for any cause. The risk of cardiovascular events and death was markedly greater for participants with as compared with those without metabolic syndrome, regardless of the definition of metabolic syndrome. This was the case also for the risk of new-onset diabetes mellitus, office, home and ambulatory hypertension and new-onset LVH. Conclusion Risks of fatal and nonfatal cardiovascular events, diabetes mellitus, hypertension and LVH were similar for the three definitions of metabolic syndrome. However, the AHA and IDF definitions are more sensitive than that of ATPIII in identifying metabolic syndrome condition.

Sympathetic activation in congestive heart failure: Reproducibility of neuroadrenergic markers

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).

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.

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.

Blood pressure lowering effects of rimonabant in obesity-related hypertension.

Obesity‐related hypertension represents a common clinical condition characterised by complex pathophysiological and therapeutic features. From a pathophysiological view point, results of experimental and animal studies have led to the hypothesis that neurogenic mechanisms participate in the development and progression of the disease. The hypothesis is based on the evidence that metabolic (i.e. insulin‐resistance) and neural (sympathetic activation) alterations frequently co‐exist in the obese hypertensive patient and that they reciprocally potentiate each other. From a therapeutic view point, the 2007 European Society of Hypertension/European Society of Cardiology emphasised the importance in this clinical condition of treatment not only through antihypertensive drugs but also via lifestyle changes and drug‐induced interventions that reduce body weight. The four Rimonabant In Obesity (RIO) studies have shown that rimonabant can decrease body weight. A recent meta‐analysis, based on the RIO results, showed that rimonabant, particularly in obese hypertensive patients, can also decrease − although modestly (2.8 mmHg for systolic and 2.2 mmHg for diastolic) − blood pressure. These effects, which appear to be triggered by the weight reduction induced by the drug, are clinically relevant because they contribute favourably to lower the elevated cardiovascular risk profile of the obese hypertensive patient.