Gianmaria Brambilla

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 (2.8u2003mmHg for systolic and 2.2u2003mmHg 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.

The Pamela Study: Main Findings and Perspectives

PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) is an epidemiological study, originally designed to determine the normality of home and ambulatory blood pressure values. The study was performed on 3,200 subjects, aged 25 to 74xa0years, randomly selected from the general population of Monza (Milan, Italy). In the study context we performed clinical, home and ambulatory blood pressure measurements, echocardiographic assessment of cardiac structure and function as well as laboratory examinations (glucose and lipids). Personal and family histories were collected. The same procedures were repeated 10xa0years later. During a 12-year follow-up, the incident cardiovascular events were validated. Cardiovascular and all-cause fatal events were collected for a 16-year follow-up. This article will review the main results of the PAMELA study, with particular emphasis on (1) the prognostic value of the different blood pressure measurements, (2) the relationships between metabolic variables and blood pressure and (3) the clinical relevance and prognostic importance of left ventricular mass values and alterations.

Left ventricular diastolic dysfunction in newly diagnosed untreated hypertensive patients

Abstract Essential hypertension is characterized by a left ventricular dysfunction. However, the majority of the studies performed so far investigated patients under drug treatment and/or with concomitant diseases, such as obesity, diabetes, metabolic syndrome or coronary heart disease, which per se may affect diastolic function independently on the blood pressure elevation. The present study aimed at investigating left ventricular diastolic function in untreated, uncomplicated and newly diagnosed hypertensive patients by employing both routine echo-Doppler and pulse tissue-Doppler technique. Data were collected in 86 middle-aged essential hypertensive patients and in 18 sex-matched normotensive controls. At the echo-Doppler approach, about half of the hypertensive patients displayed a diastolic dysfunction (n =u200944, E/A: 0.79u2009±u20090.02). They showed body mass index values slightly greater than hypertensive patients without diastolic dysfunction but superimposable blood pressure values and metabolic variables. When assessed via the pulse tissue-Doppler approach, patients with a reduced E/A displayed an Em/Am ratio significantly lower than patients without diastolic dysfunction and control subjects. This was the case when the data were related to the lateral and septal mitral annulus or averaged together. Furthermore, whereas myocardial systolic peak velocity (Sm) was lower in hypertensive patients than in control subjects, no significant between-groups difference in E/Em ratio was observed. Differently from the data obtained via the echo-Doppler approach, the tissue-Doppler method in patients without diastolic dysfunction showed a significant higher deceleration and isovolumetric relaxation times, with a lower Em velocity compared with the normotensive subjects. At the stepwise multiple regression analysis E/A ratio and E’/A’ values were related with left ventricular mass index and body mass index after correction for age. These data provide evidence that diastolic dysfunction is of frequent detection in the earlier uncomplicated phases of the disease and that tissue Doppler detects an initial impairment of left ventricular relaxation in the patients in which at echo Doppler is still normal.

Differential effects of enalapril–felodipine versus enalapril–lercanidipine combination drug treatment on sympathetic nerve traffic and metabolic profile in obesity-related hypertension

Scanty information is available on the effects of combination drug treatment based on an ACE inhibitor and a calcium channel blocker on the neurometabolic alterations characterizing obesity-related hypertension (OHT). After 2-week run-in with enalapril (20 mg), 36 OHTs were randomized according to a double-blind crossover design to a combination therapy with either lercanidipine 10 mg (L) or felodipine extended release 5 mg (F), each lasting 8 weeks. Measurements included clinic and ambulatory blood pressure (BP) and heart rate, homeostasis model assessment index, plasma norepinephrine, and muscle sympathetic nerve activity. Patients with uncontrolled BP were then uptitrated to 20 mg/d (L) and 10 mg/d (F) combined with enalapril 20 mg, respectively, for further 8 weeks. For similar BP reductions, enalapril-lercanidipine (EL) caused norepinephrine and MSNA increases significantly less pronounced than those seen with enalapril-felodipine, the lesser sympathoexcitation observed with EL being coupled with a significant improvement in homeostasis model assessment index. This was the case also when L and F were uptitrated in the combination. In OHT, at variance from enalapril-felodipine, EL combination is almost entirely devoid of any major sympathoexcitatory effect and is associated with an improvement in insulin sensitivity.

Effects of chronic carotid baroreceptor activation on arterial stiffness in severe heart failure

BackgroundHeart failure with reduced ejection fraction (HFrEF) is characterized by activation of the sympathetic nervous system and increased arterial stiffness, leading to an impaired ventricular-vascular coupling. Baroreflex activation therapy (BAT) has been shown to reduce muscle sympathetic nerve activity (MSNA) and improve clinical status of patients with HFrEF. The purpose of this investigation was to determine the effects of BAT on arterial stiffness in HFrEF.Methods and resultsMSNA, clinical variables, and parameters of central blood pressure (BP) and arterial stiffness were collected in 18 NYHA Class III HFrEF patients, nine receiving BAT and nine continuing with optimal medical management alone. Patients were followed for 3xa0months, with measurements at that time compared to baseline evaluation. Baseline characteristics of the groups were well matched. At 3xa0months, BAT did not improve central BP and arterial stiffness despite a significant amelioration of MSNA, NYHA class, Minnesota living with heart failure questionnaire score, number of heart failure medications and six-minute walking distance. The control group exhibited no significant changes in all the measured variables.ConclusionsDespite significant reductions in MSNA and clinical improvement, BAT does not appear to chronically modify arterial stiffness within this HFrEF cohort. Additional study is required to determine if this result applies to the HFrEF population as a whole.

Decreased adrenergic tone in acromegaly: evidence from direct recording of muscle sympathetic nerve activity

Sympathovagal imbalance has been shown in acromegaly by indirect measurements of adrenergic tone. Data regarding direct measurement of sympathetic activity are lacking as yet. Aim of this study was to assess the adrenergic tone through direct recording of muscle sympathetic nerve activity (MSNA) in acromegalic patients.

Targets for Body Fat, Blood Pressure, Lipids, and Glucose-Lowering Interventions in Healthy Older People

Improving cardiovascular (CV) risk profile, by lowering elevated body weight, blood pressure (BP), plasma cholesterol, and blood glucose (BG) levels, is of relevance for decreasing fatal and nonfatal CV events in young and middle-aged patients (1–4). Evidence also exists that the above-mentioned interventions are also highly effective in older patients, i.e., in subjects >65 years of age (3–6). However, it is unclear whether the same therapeutic approaches should be always used to treat old patients, taking into account on one hand the heterogeneity of the aged population and on the other the fact that frequently there is a discrepancy between chronological and biological age values. In addition, it is still undefined whether the threshold values used for initiating treatment of patients of younger ages should also apply to the older patients. Finally, it is debated whether the targets for treatment used for younger patients should be used for the older ones.nnHere, we aim to provide a general review on the above-mentioned issues, giving, whenever possible, indications useful for current clinical practice and having as a specific target the general population of healthy older patients. The review will be focused on aged individuals without major disabilities, such as multiple comorbidities, severe cognitive impairment, and in general, systemic diseases that will require continuous medical and nursing assistance. With this aim, the information available for the various variables, such as BMI, BP, blood cholesterol (BC), and BG, will be analyzed separately in the following sections.nn### BMI in healthy older subjectsnnObesity is becoming a global epidemic, causing a sharp rise in many chronic diseases including diabetes, hyperlipidemia, and hypertension (7). Among older adults, the rate of obesity has also risen dramatically over the last few decades, independent of sex, race, and educational level (8). Obesity has significant implications on the health status of …

Differential patterns of regional neuroadrenergic cardiovascular drive in acromegalic disease.

It has been shown that acromegaly is characterized by an autonomic imbalance and by marked sympathoinhibition. However, there is no information available as to whether adrenergic inhibition is confined to selected vascular districts or, rather, is generalized. We examined 17 newly diagnosed active acromegalic patients without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy and 14 healthy subjects matched for age, sex and body mass index. For each subject, we collected information regarding anthropometric parameters and echocardiography, and collected plasma samples to investigate anterior pituitary function, glucose and lipid metabolism and plasma leptin levels. Beat‐to‐beat mean arterial pressure, heart rate and efferent post‐ganglionic muscle and skin sympathetic nerve traffic (MSNA and SSNA, respectively; determined by microneurography) were measured. Both MSNA and SSNA were recorded in a randomized sequence over two 30 min periods. Measurements also included evaluation of SSNA responses to emotional stimulus. In addition to significant reductions in plasma leptin levels, acromegalic patients had markedly decreased MSNA compared with the healthy controls. There were no significant differences in SSNA between the two groups, either under basal conditions or in responses to arousal stimuli. There was a significant and direct correlation between MSNA and plasma leptin levels, but not between plasma leptin and SSNA. These data provide the first evidence that the sympathetic inhibition characterizing the early phase of acromegaly is not generalized to the entire cardiovascular system.

[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 56.1u200a±u200a2.5 years (meanu200a±u200aSEM) 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 (62.5u200a±u200a4 vs 48.2u200a±u200a3u200abursts/100 heart beats, Pu200a<u200a0.02) and significantly lower baroreflex sensitivity values (1.23u200a±u200a0.2 vs 2.09u200a±u200a0.2 a.u., Pu200a<u200a0.03). 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.

White Coat Hypertension, Metabolic Risk Factors and Cardiovascular Risk Profile

Several studies have investigated the cardiovascular risk profile of individuals with white coat hypertension, focusing not only on the prevalence of asymptomatic organ damage (Chapter) but also on the concomitance of metabolic and other classical cardiovascular risk factors [1–8]. This chapter will address the evidence that has been obtained on this issue, largely based on the data provided by the PAMELA population in which the association of white coat hypertension with cardiovascular risk factors has been examined more in depth than in other studies, via both a cross-sectional and a longitudinal approach. The conclusion will be that white coat hypertension is associated with an unfavourable cardiovascular risk profile, which supports its abnormal nature and adverse clinical significance.