Current Hypertension Reviews (v.7, #2)

Editorial by Ramiro Sanchez (59-59).
Despite the large amount of information collected over the past years, several aspects related to the link between bloodpressure and metabolic abnormalities remain unclear. This is particularly the case for the pathophysiology of the bloodpressure/metabolic relationships and, more specifically, for the hypothesis that abnormalities in sympathetic cardiovascularfunction may represent the driving force responsible on one side for the blood pressure elevation and on the other for thehypertension-related metabolic disarray.First, direct and indirect evidence suggest that high blood pressure states are characterized by an adrenergic overactivity.Overdrive is present in the hypertensive state of the young, middle-age and elderly patients, in which it parallels the clinicalseverity of the hypertensive state.On the other hand, the obese state displays signs of adrenergic activation, such as increased resting heart rate values andelevated plasma norepinephrine values. An augmented sympathetic neural discharge to skeletal muscle as well as an increasedspillover rate of norepinephrine from sympathetic nerve endings has been shown.As Dr Guido Grassi et al., mentioned in this issue, the mechanisms responsible for the hyperadrenergic drive described inhypertension, obesity, diabetes and in the other metabolic disease which may include both metabolic, humoral and reflexfactors, such as the insulin resistance condition, the hyperleptinemic state, the activation of the renin-angiotensin system and thechemoreflex stimulation are parasympathetic impairment and sympathetic drive over expression.In the PAMELA study by Bombelli et al., blood glucose and serum cholesterol levels progressively increase while HDL-Cprogressively decreases with increasing clinic blood pressure category or home and 24-hour blood pressure quartile. Thepercentage of subjects with impaired fasting glucose or diabetes mellitus also progressively increases from the lowest to thehighest category of clinic blood pressure and quartile of home or 24-hour blood pressure. By a multivariate analysis systolicand diastolic clinic, home and 24-hour blood pressure all appeared among factors independently associated to blood glucoseand serum cholesterol level in the PAMELA population.Dr Patricio Lopez Jaramillo et al., in its paper reflects also that cardiac autonomic function is altered in subjects with one ormore metabolic abnormalities, but without insulin resistance. Thus, they proposed that an over autonomic function may precedeinsulin resistance in the initiation of the Metabolic Sindrome. Furthermore, Nitric oxide seems to be also involved in therelationship between authonomic nervous system and endothelial dysfunction. Neuronal Nitric Oxide contributes to theregulation of renal function and NO performs an important role in kidney protection in opposing the effects of chronic renalrenin-angiotensin system over activation, which contributes to renal hypertension and injury. Furthermore, the vascular andcardio protective functions of NO extend beyond the endothelium to involve neuronal NO and its role as a neuromodulator ofthe autonomic nervous system, maintaining vagal tone and suppressing sympathetic nervous system over activity through bothcentral and peripheral nervous system signaling......

Sympathetic Activation in Hypertension and in Hypertension-Related Metabolic Disease by Guido Grassi, Gianmaria Brambilla, Gino Seravalle (60-65).
Cardiometabolic diseases, such as hypertension, obesity, diabetes and metabolic syndrome, are characterizedby well known abnormalities in the hemodynamic profile. Only in recent years, however, evidence has been collected thatcardiometabolic diseases are also characterized by neuroadrenergic alterations, the most important being the sympatheticoveractivity. The neuroadrenergic abnormality 1) occurs early in the clinical course of the hypertensive and metabolicdiseases, 2) follows the blood pressure elevation and 3) is paralleled by marked metabolic abnormalities, such ashyperinsulinemia, hyperleptinemia and insulin resistance. These neuroametabolic changes can be favourably affected bothby non pharmacological and pharmacological interventions.

The Pamela Study: Old and New Findings by Michele Bombelli, Guido Grassi, Danilo Fodri, Gianmaria Brambilla, Rita Facchetti, Roberto Sega, Giuseppe Mancia (66-72).
The paper will review the contribution of the PAMELA Research Project to the epidemiology, pathophysiologyand treatment of hypertension and hypertension-related cardiometabolic disease. This will be firstly done by examiningthe results of the PAMELA studies planned and performed in the past 20 years aimed at defining normality values forhome and ambulatory blood pressure values as well as at determining precise figures for blood pressure control, takinginto account different blood pressure measurements. It will also be done by taking into account different “weight” ofclinic, home and ambulatory blood pressure values in determining end-organ damage and in assessing the capability of thedifferent pressures to reflect the regression of target organ damage induced by antihypertensive drug treatment. Thereview will finally address three further issues of major clinical relevance, i.e. the definition and clinical implication of“white-coat” and “masked” hypertension, the prognostic significance over the long-term period of alterations in home andambulatory blood pressures as compared to the clinic ones and finally the close relationships between blood pressure andmetabolic alterations, including metabolic syndrome.

Role of the Autonomic Nervous System in the Endothelial Dysfunction of the Metabolic Syndrome by Patricio Lopez-Jaramillo, Dora Ines Molina, Alba Aguillon, Diego Gomez-Arbelaez, Aristides Sotomayor-Rubio, Jose Lopez-Lopez (73-79).
In the last decade there has been an accelerated growth in the prevalence of metabolic syndrome (MS),especially in Latin American countries, which has led an increased risk of cardiovascular disease (CVD) and type 2diabetes mellitus (DM2). Recently has been raised the relationship between the autonomic nervous system (ANS),endothelial dysfunction (ED) and the appearance of MS. In the present article we review the evidence that support theproposal that abdominal obesity (AO) produce adypokines that result in insulin resistance and low degree inflammation,which increase the activity of ANS, causing vasoconstriction, hypertension, decreased peripheral glucose uptake, anddecreased secretion of insulin, leading to hyperglycemia and increased lipolysis and hypertriglyceridemia. All thesefactors cause ED, explaining the higher risk of the patients with MS of developing DM2 and CVD.

Elderly Hypertensive Patients: Silent White Matter Lesions, Blood Pressure Variability, Baroreflex Impairment and Cognitive Deterioration by Agustin J. Ramirez, Gianfranco Parati, Paolo Castiglioni, Damian Consalvo, Patricia Solis, Marcelo R. Risk, Paola Waissman, Marco DiRienzo, Giusepe Mancia, Ramiro A. Sanchez (80-87).
Introduction: Hypertension may increase the risk for stroke and is frequently associated with subcortical andperiventricular white matter lesions (WML). This is considered a prognostic factor for the development of stroke andcognitive impairment, particularly in attention processes. Additionally, in elderly subjects, it is known the implications ofalterations in the neural cardiovascular regulation and the cardiovascular risk.Aims: To evaluate, in asymptomatic elderly hypertensives, the association of ambulatory blood pressure values andautonomic activity with neurocognitive impairment and WML. In addition, we also evaluated the role of the autonomicnervous system particularly the vagal component, in the pathogenesis of white matter lesions.Methods: We studied 22 elderly essential hypertensive patients (69±1.1y) and as control group, 16 normotensive elderlysubjects (age 67±3.2y) were also enrolled. To each one of them, a cerebral MRI was performed to classify them, by aneuro-radiologist blinded of the subject clinical status, using a 0 to 9 scale where 0 denoted no WML and 9 the mostsevere lesions.Twenty four hours arterial blood pressure monitoring was performed to each one of the subjects under study. Office bloodpressure was measured 3 times and the mean value reported. Beat to beat finger arterial pressure monitoring (Finapres)was performed for a 2h period. During the first hour the patient remained lying supine in a quiet darkened room andduring the second hour four manoeuvres: stand-up, cold pressor test, handgrip and quiet activity were randomlyperformed. Mean blood pressure and pulse interval values, from the two periods, and their respective variabilities,baroreflex sensitivity and power spectral analysis were calculated.Regarding neuropsychological assessment: Minimental test, attention evaluation, RAVLT, visual memory, language andexecutive function, geriatric depression scale, cognitive deficit rate tests were performed in all subject.Results: We found a closer correlation of WML with 24hs ABPM than with office BP readings being more evident withsystolic blood pressure during the night time period. WML failed to show any correlation with SBP average valuesderived from the Finapres recordings in either the supine or the upright position, while it was positively and significantlyrelated to PP in both conditions. However, beat to beat SBP variability, either in the supine or in the upright position,showed a positive and significant correlation with WML.During the resting period, BRS calculated through the sequence method (Time Domain) was similar in HT and NTsubjects. However when BRS was assessed in the frequency domain a significant reduction was observed in HT comparedwith NT. In addition, At the time of laboratory manoeuvres implying sympathetic activation, BRS was significantlyreduced as compared to the resting values being particularly evident for the HF values.In hypertensive subjects, only semantic fluency showed a significant difference (p=0.01), when compared tonormotensives. When the patients were divided in older and younger than 75 years, a significant difference was observedin the delayed analysis of words, and in the phonological fluency showing a significant higher rate of pathological resultsin the group of patients older than 75 years.Conclusions: As previously shown, incidental WML, suggestive of silent cerebrovascular disease, is a frequent finding inelderly hypertensives. Night-time BP mean values and SBP variability in upright position seems to be the best predictoron silent cerebral WML. The vagal component of the autonomic nervous system seems to be involved in the pathogenesisof these lesions. Finally, the neurocognitive alterations are multifactorial in origin where the aging process seems to be theprincipal component.

Epidemiological and clinical evidence have shown a close association between hypertension, obesity, IGT orNIDDM, and dyslipidemia. The activation of sympathetic nervous system plays a role in the pathogenesis of essentialhypertension and its inhibition is of a therapeutic value.Rilmenidine is an oxazoline compound with antihypertensive properties that acts mainly on the brain stem but also in thekidneys, where it selectively binds to I1 imidazoline receptors, distinguishing it from reference ..2-agonists. As aconsequence, anti-hypertensive treatments that reduce the sympathetic response could also have effects on the metabolicabnormalities of hypertensive patients with metabolic disorders.The aim of the present study was to evaluate the effect of rilmenidine or placebo on insulin resistance and sympatheticactivity, in essential hypertensive patients untreated or non-adequately treated. Our results have shown that Rilmenidinewas able to decrease sympathetic activity expressed by both a decrease in SBP variability and an increase in baroreflexsensitivity. Together with these effects a significant improvement of insulin resistance index (HOMA), which was notobtained by the adjusted conventional treatment, was also observed.In conclusion, these beneficial effects observed support the idea that Rilmenidine could be comparable to establisheddrugs for first-line therapy in hypertension.

Hypertension is common in the elderly, and with an increasing ageing population in the industrialised world,has become a major public health issue. Hypertension in the elderly may have many different patterns of presentation suchas Systolic-Diastolic Hypertension, Isolated Systolic Hypertension, Nocturnal Hypertension, Hypertension accompaniedby Postural Hypotension and Supine Hypertension in the back ground of autonomic dysfunction.Management of hypertension in the elderly is not straightforward due to the presence of a variety of patterns ofpresentation, Pathophysiological changes associated with hypertension and aging, co-existing medical problems andPolypharmacy. This article deals with the management of commonly encountered problems such as orthostatichypotension, orthostatic hypotesnion accompanied by supine hypertension, erectile dysfunction and also covers issuessuch as controversy surrounding the [alleged] association between hypertension and its treatment and the risk of dementiaas well as management of hypertension in the very elderly.

The Amlodipine Cohort study by Internet-based research for Evaluation of Efficacy (ACHIEVE) wasconducted to assess the efficacy of amlodipine 10mg daily. Hypertensive patients, who were up-titrated from amlodipine5mg to 10mg daily, were enrolled by medical practitioners using web-based registration between March 9 and July 31,2009. The primary outcomes were the blood pressure (BP) at clinic and at home, and the secondary outcome was rates ofachievement who reached their target BP levels at clinic after 3 months. Seven-hundred and fifty three hypertensivepatients were enrolled and 583 patients completed the follow-up study. Mean clinic BP decreased from 156.4/86.3 mmHgat baseline to 137.5/76.5mmHg, whereas mean home BP decreased from 151.5/83.9 mmHg at baseline to139.6/75.2mmHg after 3 months of treatment. The reduction of these BPs was more pronounced among the patients withhigher baseline BP values than among those with lower baseline levels. Sufficiently controlled hypertension, which isdefined as a systolic BP <140 mmHg for clinic BP and <135 mmHg for home BP is 1.2% at baseline to 43.1% after 3months of treatment. The survey showed that among poorly controlled hypertensive Japanese, high-dose titration from 5 mg to 10 mg daily ofamlodipine showed marked reduction in both clinic and home BPs.

Cardiotonic Steroids, Hypertension and Cardiovascular Disease by Sabry Gohara, Sandeep Vetteth, Deepak Malhotra, Joseph. I. Shapiro (111-117).
It has been known for some time that dietary salt intake correlates with the prevalence of cardiovasculardisease. However, the molecular link between dietary salt and cardiovascular disease is poorly understood. On thisbackground, it has been observed that there are a class of hormones called cardiotonic steroids whose concentrationsincrease in response to increases in dietary salt. We have shown that some of these hormones may be natriuretic, but wehave also shown that they may also be responsible for progressive renal and cardiac injury. Based on data summarized inthis review, we propose cardiotonic steroids may serve as the molecular link between dietary salt and cardiovasculardisease.

Management of Prehypertension: Current Status and Future Strategies by Hiroyuki Sasamura, Hiroshi Itoh, Stevo Julius (118-124).
Prehypertension is known to be a risk factor for hypertension and cardiovascular disease. If prehypertension isleft untreated, the blood pressure continues to increase due to multiple accelerators which facilitate the development ofhypertension. Studies using animal models of hypertension suggested that interruption of these mechanisms by transientinhibition of the renin-angiotensin system (RAS) attenuates the development of hypertension. The TROPHY studyprovided clinical evidence that pharmacological intervention in the prehypertensive stage may suppress subsequentdevelopment of hypertension. Recently, we reported that high dose angiotensin inhibition in spontaneously hypertensiverats (SHR) with established hypertension caused a significant regression of hypertension, and we have started aprospective, multi-center clinical study (STAR CAST study) to examine if regression from hypertension back toprehypertension may also be feasible in humans. Since prehypertension is increasingly recognized as an important publichealth issue, further studies to assess strategies for attenuating the progression from prehypertension to hypertension arerequired.