Raffaella Dell’Oro

Short- and long-term neuroadrenergic effects of moderate dietary sodium restriction in essential hypertension.

Background—In essential hypertension, marked restrictions in dietary sodium intake cause in the short-term period an increase in muscle sympathetic nerve traffic (MSNA) and a baroreflex impairment. The present study was set out to assess on a long-term basis the neuroadrenergic and reflex effects of moderate sodium restriction. Methods and Results—In 11 untreated mild to moderate essential hypertensive patients (age 42.0±2.6 years, mean±SEM), we measured beat-to-beat blood pressure (Finapres), heart rate (ECG), and MSNA (microneurography) at rest and during stepwise intravenous infusions of phenylephrine and nitroprusside. Measurements were performed at regular sodium intake, after 1 and 8 weeks of low-sodium diet (80 mmol NaCl/d), and repeated again at regular sodium intake. After 1 week, urinary sodium excretion was markedly reduced. This was accompanied by a slight blood pressure reduction, no heart rate change, and a significant increase in plasma renin activity, aldosterone, and MSNA (+23.0±4.6%P <0.05). Whereas baroreflex heart-rate control was unchanged, baroreflex modulation of MSNA was reduced by 46.8±5.1% (P <0.01). At the end of the 8-week low-sodium diet, the neurohumoral and baroreflex responses were similar to the ones observed after 1 week of the dietary intervention. All changes disappeared when regular sodium diet was restored. Conclusions—Thus, a moderate dietary sodium restriction triggers a sympathetic activation and a baroreflex impairment. Maintenance of low-sodium diet for several weeks does not attenuate these adverse adrenergic and reflex effects.

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.

Impairment of Thermoregulatory Control of Skin Sympathetic Nerve Traffic in the Elderly

Background—Human aging is characterized by a marked increase in muscle sympathetic nerve traffic (MSNA). No information exists, however, on the effects of aging on skin sympathetic nerve traffic (SSNA) and on its reflex modulation by thermoregulatory mechanisms. Methods and Results—In 13 young, 11 middle-aged, and 12 elderly healthy subjects, we measured arterial blood pressure (Finapres), skin temperature (thermocouples), and resting MSNA and SSNA (microneurography). Measurements also included the SSNA responses to (1) an acute increase and reduction (±8°C) in room temperature, each lasting 45 minutes and (2) an acoustic stimulus capable to trigger an emotional arousal. Although resting MSNA was progressively and significantly (P <0.05) increased from young to middle-aged and elderly groups, SSNA was significantly (P <0.05) reduced in the latter compared with the former 2 groups. Cold exposure induced a SSNA increase that was significantly (P <0.01) smaller in the elderly than in young and middle-aged subjects. Conversely, heat exposure induced a SSNA reduction that was significantly (P <0.05) smaller in elderly than in young and middle-aged subjects. Compared with SSNA in young individuals, the SSNA change from cold to warm temperature was reduced by 61% in the elderly group. This was not the case, however, for the SSNA responses to the arousal stimulus, which were superimposable in the 3 groups. Conclusions—These data provide the first demonstration of a dichotomy in the MSNA and SSNA responses to aging. They also show that aging markedly impairs thermoregulatory control of SSNA and that this impairment might participate at the age-related SSNA decrease.

Relationship Among Morning Blood Pressure Surge, 24-Hour Blood Pressure Variability, and Cardiovascular Outcomes in a White Population

Cardiovascular events have their greatest prevalence in the early morning period. Whether this is attributable to an arousal-dependent blood pressure (BP) increase is far from being clear. It is also not clear to what extent this phenomenon reflects overall 24-hour BP variability. In 2051 subjects (aged 25–74 years) representative of the population of Monza (Italy), we measured 24-hour ambulatory systolic BP (SBP) and calculated the difference between the 2-hour average values after morning arousal and the lowest 3 or average 2-hour values before arousal (morning BP surge 1 and 2, respectively). For either measure, we sought the relationship with a variety of indices of 24-hour SBP variability and collected information on (1) the occurrence of cardiovascular and all cause deaths during a follow-up of ≈16 years and (2) the appearance of echocardiographic left ventricular hypertrophy after 10 years from the baseline visit. Morning SBP surge 1 was directly related to indices of 24-hour SBP variability, including those made independent on the magnitude of the day–night SBP difference. There was a weak positive relationship between morning SBP surge 1 and the risk of cardiovascular and all-cause death, which disappeared after adjustment for confounders. This was the case also for development of left ventricular hypertrophy. Morning SBP surge 2 was smaller, inconsistently related to 24-hour SBP variability and not at all related to fatal events or new-onset left ventricular hypertrophy. In a white population, morning BP surge was not found to be an independent predictor of cardiovascular death, all-cause death, or development of high cardiovascular risk (as documented by new-onset cardiac damage) even when appropriately assessed by measures that reflect its association with 24-hour BP variability.

Long-Term Sympathoinhibitory Effects of Surgically Induced Weight Loss in Severe Obese Patients

Weight loss improves insulin sensitivity and exerts sympathomodulatory effects. No data, however, are available on the effects of the weight loss induced by vertical sleeve gastrectomy on sympathetic neural drive, insulin sensitivity, and their reciprocal cross talks. In 10 severe obese hypertensives (age, 54.0±2.3 years [mean±SEM]), we measured sphygmomanometric blood pressure, heart rate, body mass index, homeostatic model assessment index, plasma leptin, muscle sympathetic nerve traffic (microneurography), and baroreflex sensitivity (vasoactive drug technique). Measurements were performed 2 to 3 days before surgery and repeated 6 and 12 months after the procedure. Ten matched hypertensive obeses not undergoing gastrectomy served as controls. Six months after bariatric surgery, a significant (P<0.05) reduction in body mass index (−9.1±1.4 kg/m2), sphygmomanometric systolic blood pressure (−10.2±4.5 mm Hg), heart rate (−11.0±2.4 bpm), homeostatic model assessment index (−3–3±1.3 AU), plasma leptin (−53.6±8.8 &mgr;g/L), and muscle sympathetic nerve traffic (−15.0±3.4 bursts/100 heart beats) was observed. The weight loss, the plasma leptin reduction, and the sympathetic inhibition were maintained after 12 months, whereas homeostatic model assessment index showed a tendency to return toward presurgery values. A significant improvement in baroreflex control of sympathetic nerve traffic was observed both 6 (+32.1%; P<0.05) and 12 months (+60.7%; P<0.01) after gastrectomy. No significant changes in the above-mentioned variables were detected in the control group. These data provide evidence that massive weight loss induced by sleeve gastrectomy triggers profound sympathoinhibitory effects, associated with a stable and significant reduction in plasma leptin levels, whereas the improvement in insulin sensitivity was attenuated with time and unrelated to the sympathoinhibition.

Comparison of angiotensin II receptor blockers: impact of missed doses of candesartan cilexetil and losartan in systemic hypertension.

Blood pressure remains poorly controlled in the hypertensive population due in large part to low or unsatisfactory patient compliance. Clinical studies that incorporate an intentionally missed dose have been designed to evaluate the impact of poor patient compliance on the effectiveness of antihypertensive medications. In these studies, ambulatory blood pressure monitoring is continued throughout the dosing interval and beyond in order to determine when systolic and diastolic blood pressure increase into the hypertensive range. In an 8-week, randomized, double-blind, placebo-controlled trial in patients with mild-to-moderate hypertension, the antihypertensive effects of candesartan cilexetil 16 mg were maintained after a missed dose, whereas systolic and diastolic blood pressure increased toward baseline levels after a missed dose of losartan 100 mg. Candesartan cilexetil provided a significantly greater reduction in sitting systolic (p = 0.004) and diastolic blood pressure (p = 0.008) than losartan when measured 48 hours after the last dose. Moreover, the homogeneity of antihypertensive effects was greater after candesartan cilexetil than losartan based on calculation of the smoothness index from ambulatory systolic and diastolic measurements during the first 24-hour period after dosing and during the 12-hour period after the missed dose. These results demonstrate that missing or delaying a dose of candesartan cilexetil has less impact on antihypertensive efficacy than missing or delaying a dose of losartan.

Reliability of heart rate as neuroadrenergic marker in the metabolic syndrome.

Background: Metabolic syndrome is characterized by a pronounced sympathetic overactivity as documented by the marked increase in muscle sympathetic nerve traffic (MSNA) as well as in plasma norepinephrine values reported in this condition. Whether and to what extent heart rate (HR) reflects the abovementioned adrenergic alterations in metabolic syndrome remains largely undefined. It is also undefined the validity of the abovementioned adrenergic markers in reflecting the main features of the metabolic syndrome. Methods: In 65 metabolic syndrome patients, aged 56.5 ± 1.3 years (mean ± SEM), we measured over a 30-min resting period blood pressure, HR (ECG), venous plasma norepinephrine (HPLC) and MSNA (microneurography). We also evaluated anthropometric and metabolic variables including HOMA index, correlating them with the adrenergic markers. The same measurements were also made in 48 age-matched healthy controls. Results: HR was significantly greater in the metabolic syndrome patients than in controls (74.6 ± 1.5 versus 67.5 ± 1.5 bpm, P < 0.001) and significantly and directly correlated with the elevated norepinephrine and MSNA values (r = 0.25 and 0.33, P < 0.05 and 0.01, respectively). MSNA was significantly and directly related to blood pressure (r = 0.27 and 0.31 SBP and DBP, respectively, P < 0.05 for both), BMI (r = 0.36, P < 0.01), waist circumference (r = 0.34, P < 0.01), waist-to-hip ratio (r = 0.49, P < 0.01) and plasma insulin (r = 0.57, P < 0.01). In contrast, no significant correlation was detectable between HR or norepinephrine and the abovementioned anthropometric and metabolic variables. Conclusion: Our data show that in the metabolic syndrome not only peripheral but also cardiac sympathetic drive is markedly potentiated and HR can be regarded as a marker of adrenergic overdrive characterizing this clinical condition. The reliability of HR (and of plasma norepinephrine) as sympathetic marker appears to be limited, however, this variable being unable to reflect, at variance from MSNA, the main metabolic and anthropometric abnormalities characterizing the metabolic syndrome.

Long-term changes in left ventricular mass echocardiographic findings from a general population

Aim: We sought to assess the long-term changes in left ventricular (LV) mass in a population-based sample, focusing on new onset, persistence, regression and severity of LV hypertrophy (LVH), as well as on the demographic and clinical variables independently related to this dynamic process. Methods: A total of 1113 participants with measurable echocardiographic parameters at baseline and after a 10-year follow-up were included in the analysis. Cut points for LVH were derived from current echocardiographic guidelines. Results: LVH prevalence significantly increased from 13 to 33% as a result of LVH new onset in 254 and LVH regression in 31 cases. Severe LVH prevalence increased by 4.3 times from baseline, a trend mainly related to transition from mild-moderate-to-severe LVH in patients with preexisting cardiac hypertrophy. Variables such as age, female sex, baseline SBP, as well as delta follow-up-baseline SBP, BMI, metabolic syndrome and use of antihypertensive drugs were independently related either to new-onset or to persistent LVH. Conclusion: Long-term LV mass changes in a general population are associated with a marked increase in the prevalence and severity of LVH, and this unfavourable trend was more frequent in women. As blood pressure, metabolic variables and BMI emerged as key correlates of this adverse process, our findings suggest that interventions aimed to modify such risk factors may have a role in preventing new onset and progression LVH, as well as a marked worsening of cardiovascular risk profile at the community level.

Response to Sympathetic Activity, Heart Failure, Obesity, and Metabolic Syndrome: Is There Any Role for Sleep Apnea?

We appreciate the interest expressed by Drager et al1 for our recent article on the sympathoexcitatory effects of metabolic syndrome (MS) in heart failure patients.2 In brief, in our study we found that sympathetic nerve traffic was markedly increased in heart failure and more so in patients combining this disease with MS. It should be worthy of mention that in our study the additive sympathoexcitation was evident for a similar impairment in left ventricular ejection fraction in the 2 groups, and the major determinants of this exceedingly high adrenergic drive …