Habitual coffee consumption and office, home, and ambulatory blood pressure: results of a 10-year prospective study.

OBJECTIVES: Heterogeneous are the results of the published studies aimed at determining the long-term effects of habitual coffee consumption on blood pressure (BP). Specifically, no data are available on the longitudinal association between habitual coffee consumption and office, home and 24 h BP profile and variability. METHODS: In 1408 subjects recruited in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, followed for a 10 year follow-up period and classified as coffee consumers and nonconsumers (self-reporting), we prospectically investigated the association between habitual coffee consumption and office, home and 24-h ambulatory BP; 24-h BP variability; and development of a new hypertensive state. Data were also analysed according to gender. RESULTS: When data were adjusted for confounders habitual coffee nonconsumers and consumers displayed similar long-term BP changes during the follow-up in office, home, and ambulatory BP. No difference was found between heavy and moderate coffee consumers. Furthermore, also new-onset hypertension and patterns of BP variability were superimposable in coffee nonconsumers and consumers, independently on confounders including gender, number, and characteristics of the antihypertensive drug treatment. CONCLUSION: The present study, which is the first longitudinal investigation never performed examining in a prospective fashion the long-term (10 year) effects of coffee consumption on office, home, and ambulatory BP, provides conclusive evidence that habitual coffee consumption is associated with neutral effects on in-office and out-of-office BP values and related variabilities. This is the also the case for the new-onset hypertensive state.

Pheochromocytoma as a Clinical Model of Peripheral Sympathetic Overdrive: Old and New Findings.

PURPOSE OF REVIEW: The present paper will review the results of experimental and clinical studies aimed at defining the functional behavior of the central and peripheral nervous system in adrenal pheochromocytoma. RECENT FINDINGS: The contribution of sympathetic neural influences to the development of high blood pressure values in pheochromocytoma is complex. Studies performed in experimental animal models have shown that hypertension and the concomitant high circulating levels of catecholamines can lead to inhibition of central sympathetic neural outflow by reflex mechanisms and direct stimulation of central adrenergic receptors, respectively. However, these studies have also shown that high circulating levels of catecholamines favor a downregulation of alpha- and beta-adrenergic receptors, lessening their response to endogenous and exogenous adrenergic stimulation. The present paper reviews results of human studies performed by our group and others on the behavior of the central and peripheral nervous system in human pheochromocytoma. We discuss data collected in patients with different levels of peripheral sympathetic drive, i.e., before and after surgical removal of the adrenal pheochromocytoma. In the presence of elevated plasma catecholamine level, such as that characterizing adrenal pheochromocytoma, microneurography shows that central sympathetic neural activity is normal or even inhibited. At the peripheral vascular level, pheochromocytoma is characterized by a reduced vascular reactivity to exogenous sympathetic stimulation but a normal response by the vessels to endogenous adrenergic stimulation.

Sympathetic Neural Overdrive in the Obese and Overweight State.

Nerve traffic recordings (muscle sympathetic nerve traffic [MSNA]) have shown that sympathetic activation may occur in obesity. However, the small sample size of the available studies, presence of comorbidities, heterogeneity of the subjects examined represented major weaknesses not allowing to draw definite conclusions. This is the case for the overweight state. The present meta-analysis evaluated 1438 obese or overweight subjects recruited in 45 microneurographic studies. The analysis was primarily based on MSNA quantification in obesity and overweight, excluding as concomitant conditions hypertension, metabolic syndrome, and other comorbidities. Assessment was extended to the relationships of MSNA with other neuroadrenergic markers, such as plasma norepinephrine and heart rate, anthropometric variables, as body mass index, waist-to-hip ratio, presence/absence of obstructive sleep apnea, and metabolic profile. Compared with normoweights MSNA was significantly greater in overweight and more in obese individuals (37.0±4.1 versus 43.2±3.5 and 50.4±5.0 burts/100 heartbeats, P<0.01). This was the case even in the absence of obstructive sleep apnea. MSNA was significantly directly related to body mass index and waist-to-hip ratio ( r=0.41 and r=0.64, P<0.04 and <0.01, respectively), clinic blood pressure ( r=0.68, P<0.01), total cholesterol, LDL (low-density lipoprotein) cholesterol, and triglycerides ( r=0.91, r=0.94, and r=0.80, respectively, P<0.01) but unrelated to plasma insulin, glucose, and homeostatic model assessment for insulin resistance. No significant correlation was found between MSNA, heart rate, and norepinephrine. Thus, obesity and overweight are characterized by sympathetic overactivity which mirrors the severity of the clinical condition and reflects metabolic alterations, with the exclusion of glucose/insulin profile. Neither heart rate nor norepinephrine appear to represent faithful markers of the muscle sympathetic overdrive.

Sympathetic and baroreflex abnormalities in the uncomplicated prediabetic state.

BACKGROUND: Neurogenic abnormalities characterize overt diabetic state. However, how early is their appearance in the clinical course of the disease is unclear. METHODS: In 26 normotensive and normoweight prediabetic patients, aged 45.2 ±â€Š3.2 years (mean ±â€ŠSEM), we assessed efferent postganglionic muscle sympathetic nerve traffic (MSNA, microneurography), spontaneous baroreflex sensitivity, and a number of hemodynamic and metabolic variables, including homeostatic model assessment (HOMA) index. Measurements were compared with those obtained in a group of 30 healthy controls of similar age. RESULTS: For similar clinic and ambulatory blood pressure and BMI values, prediabetic patients displayed significantly greater MSNA values than controls, both when expressed as bursts incidence over time (33.3 ±â€Š2.0 vs. 25.6 ±â€Š1.2 bursts/min, P < 0.01) and when corrected for heart rate values (49.6 ±â€Š1.9 vs. 36.7 ±â€Š1.4 bursts/100 heart beats, P < 0.01). This neurogenic abnormality was associated with a reduced spontaneous baroreflex MSNA sensitivity (-3.20 ±â€Š0.2 vs. -4.72 ±â€Š0.2 a.u., P < 0.01) and significantly greater HOMA index values (3.73 ±â€Š0.1 vs. 1.65 ±â€Š0.1 a.u., P < 0.01). In the multivariate analysis, performed in prediabetic patients, MSNA values were directly and significantly related to HOMA index and inversely and significantly to baroreflex-MSNA sensitivity. CONCLUSION: These data provide evidence that sympathetic and reflex abnormalities are of early appearance in the clinical course of the diabetic disease. The adrenergic overdrive and the baroreflex impairment may thus participate at the disease progression, favoring the development of the hypertensive state and adversely affecting the disease prognosis.

Multicenter Randomized Double-Blind Comparison of Nebivolol plus HCTZ and Irbesartan plus HCTZ in the Treatment of Isolated Systolic Hypertension in Elderly Patients: Results of the NEHIS Study.

INTRODUCTION: The present study was aimed at comparing the antihypertensive efficacy, tolerability, and side effects profile of nebivolol/hydrochlorothiazide (NH) vs irbesartan/hydrochlorothiazide (IH) combination in elderly patients with isolated systolic hypertension (ISH). METHODS: 124 ISH patients aged 69.1 ± 5.1 years (mean ± SD) were enrolled by 13 general practitioners in Netherlands and Belgium and randomized in a double-blind fashion to receive either NH (5/12.5 mg day, n = 62) or IH (150/12.5 mg day, n = 62) for a 12-week period. The primary efficacy endpoint of the study was the comparison of the two combinations in terms of sitting office systolic blood pressure (BP) reduction after 12 weeks of treatment. In addition ambulatory BP, 24-h BP variability, tolerability, and safety profile were also investigated. RESULTS: 122 patients were included in the intention-to-treat analysis. After 12 weeks of treatment the reduction of systolic BP with NH was significantly greater than IH (-25.8 ± 12 vs -21.2 ± 14 mm Hg, P < 0.03). Diastolic BP reduction was significantly greater with NH after 4 and 8 weeks of treatment but similar at the end of the study (or after 12 weeks). In contrast, the magnitude of the 24-h, daytime, and nighttime systolic and diastolic BP reduction was almost similar in the two groups, while heart rate reduction induced by NH was significantly (P < 0.001) greater during the 24-h, daytime, and nighttime period than that induced by IH. NH caused a reduction in 24-h BP variability significantly greater than IH (standard deviation -4.4 ± 2.7 vs -2.2 ± 5.1 mm Hg, P < 0.02, variation coefficient -2.0 ± 2.6 vs -0.3 ± 3.4%, P < 0.01). Both treatment regimens were well tolerated. CONCLUSIONS: These data provide evidence that NH reduces office BP more than IH but has similar effects on 24-h BP. NH reduces 24-h systolic and diastolic BP variability more than IH, suggesting a greater protective effect on a variable known to adversely affect prognosis. TRIAL REGISTRATION: EU clinical Trials Register identifier, 2010-023104-28. FUNDING: Menarini International Operations Luxembourg.

Long-term chronic baroreflex activation: persistent efficacy in patients with heart failure and reduced ejection fraction.

AIMS: Baroreflex activation therapy (BAT) has recently been shown to reduce muscle sympathetic nerve activity and hospitalization rate while improving clinical variables through 6 months of therapy in patients with heart failure and reduced ejection fraction (HFrEF). The objective of the present study is to extend the information on this patient cohort over a long-term follow-up. METHODS AND RESULTS: Eleven patients were enrolled in the study and presented with optimized, stable medical therapy, New York Heart Association Class III HFrEF with left ventricular ejection fraction 40% or less, impaired functional capacity and no active cardiac resynchronization therapy. For the present report, muscle sympathetic nerve activity, baroreflex sensitivity data and hospitalization rate together with standard clinical data were collected at 12 and 21.5 ±â€Š4.2 months following BAT activation. Two patients died during long-term follow-up. The remaining nine patients maintained the improvements observed at 6 months, including reduced sympathetic activity and rates of hospitalization. CONCLUSION: BAT provides long-term chronic reductions in sympathetic activity and utilization of hospital resources in patients with HFrEF. General clinical presentation, quality of life and functional capacity are likewise improved and maintained. The temporal association of BAT with sympathetic drive diminution and improvement in objective clinical measures suggests a cause-and-effect relationship that will be verified in future randomized controlled trials of outcome.

Asymmetric and Symmetric Dimethylarginine and Sympathetic Nerve Traffic after Renal Denervation in Patients with Resistant Hypertension.

BACKGROUND AND OBJECTIVES: The plasma concentration of the endogenous inhibitor of nitric oxide synthase asymmetric dimethylarginine (ADMA) associates with sympathetic activity in patients with CKD, but the driver of this association is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this longitudinal study (follow-up: 2 weeks-6 months), repeated measurements over time of muscle sympathetic nerve activity corrected (MSNAC), plasma levels of ADMA and symmetric dimethylarginine (SDMA), and BP and heart rate were performed in 14 patients with drug-resistant hypertension who underwent bilateral renal denervation (enrolled in 2013 and followed-up until February 2014). Stability of ADMA, SDMA, BP, and MSNAC over time (6 months) was assessed in two historical control groups of patients maintained on stable antihypertensive treatment. RESULTS: Time-integrated changes in MSNAC after renal denervation ranged from -40.6% to 10% (average, -15.1%), and these changes were strongly associated with the corresponding changes in plasma ADMA (r= 0.62, P=0.02) and SDMA (r=0.72, P=0.004). Changes in MSNAC went along with simultaneous changes in standardized systolic (r=0.65, P=0.01) and diastolic BP (r=0.61, P=0.02). In the historical control groups, no change in ADMA, SDMA, BP, and MSNAC levels was recorded during a 6-month follow-up. CONCLUSIONS: In patients with resistant hypertension, changes in sympathetic activity after renal denervation associate with simultaneous changes in plasma levels of the two major endogenous methylarginines, ADMA and SDMA. These observations are compatible with the hypothesis that the sympathetic nervous system exerts an important role in modulating circulating levels of ADMA and SDMA in this condition.

Total cardiovascular risk, blood pressure variability and adrenergic overdrive in hypertension: evidence, mechanisms and clinical implications.

In hypertensive patients the risk of developing cardiovascular events and complications depends not only on the magnitude of the blood pressure elevation, but also, and to a consistent extent, on the presence of associated cardiovascular risk factors, concomitant disease and target organ damage. Recent findings suggest that also sympathetic overdrive and alterations in blood pressure variability (which are detected in hypertension) may participate at the increased cardiovascular risk of the patients with high blood pressure. This review will discuss the evidence collected over the past few years on the relationships between sympathetic activation and blood pressure variability and their impact on cardiovascular risk profile.

Blood pressure control and antihypertensive treatment.

Several lines of evidence show that blood pressure (BP) control in treated hypertensive patients is largely unsatisfactory and that this depends on a variety of factors, such as the poor patient's compliance, insufficient use of combination drug treatment as well as true difficulties in achieving well controlled BP. This review article will be focused on the main features of BP control by discussing the data obtained in clinical trials as well as the results available in clinical practice. The paper will also discuss the possible factors responsible for these findings as well as the favourable outcome on cardiovascular risk profile of an effective control of elevated BP. The possible approaches for controlling elevated BP values will be highlighted.

Long-term risk of diabetes, hypertension and left ventricular hypertrophy associated with the metabolic syndrome in a general population.

OBJECTIVES: Metabolic syndrome is accompanied by an increased risk of developing diabetes mellitus. Limited or no evidence exists on whether and to what extent metabolic syndrome increases the risk of developing office hypertension, daily-life hypertension and left ventricular hypertrophy. METHODS: In 1412 individuals representative of the population of Monza, plasma glucose, office, home and ambulatory blood pressure, and echocardiographic left ventricular mass index were measured between 1990 and 1992 and 10 years later. New onset diabetes mellitus, new onset office, home and ambulatory hypertension as well as new onset left ventricular hypertrophy were assessed in individuals with and without metabolic syndrome (Adult Treatment Panel criteria) at the first examination. RESULTS: New onset diabetes mellitus, hypertension and left ventricular hypertrophy were all much more frequent in individuals with metabolic syndrome than in those without. In patients with metabolic syndrome, the adjusted risk of new onset diabetes mellitus was five to six times greater (P < 0.001), that of new onset office, home or ambulatory hypertension 3.5, 2.9 and 3.2 times greater (P < 0.001), respectively, and that of new onset left ventricular hypertrophy 2.6 times greater (P < 0.001). The most important predictors of new onset diabetes mellitus, hypertension and left ventricular hypertrophy were the baseline blood glucose, blood pressure and left ventricular mass index, respectively, with an independent contribution, in each condition, from other metabolic syndrome components. The metabolic syndrome as such did not have an additional predictive value. CONCLUSION: In the general population, metabolic syndrome is associated with a marked increase in the risk not only of new onset diabetes mellitus but also of new onset office and daily-life hypertension, and left ventricular hypertrophy. This may account for the increased rate of cardiovascular morbidity and mortality exhibited with this condition in long-term studies.

Primary and secondary prevention of stroke by antihypertensive treatment in clinical trials.

High blood pressure represents one of the leading risk factors for the development of stroke and its recurrence. This explains why blood pressure control is a major objective of antihypertensive treatment, both in primary and secondary prevention of this cerebrovascular disease. This paper reviews the evidence provided by randomized clinical trials on the favorable effects exerted by blood pressure reduction on this end point. Emphasis is given to the results of recently published clinical trials documenting that drugs acting on the renin-angiotensin system may exert cerebrovascular protective effects additive to the ones associated with blood pressure reduction.

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.

Long-term prognostic value of blood pressure variability in the general population: results of the Pressioni Arteriose Monitorate e Loro Associazioni Study.

The hypothesis has been advanced that cardiovascular prognosis is related not only to 24-hour mean blood pressure but also to blood pressure variability. Data, however, are inconsistent, and no long-term prognostic study is available. In 2012 individuals randomly selected from the population of Monza (Milan), 24-hour ambulatory blood pressure (Spacelabs 90207) was measured via readings spaced by 20 minutes. Systolic and diastolic blood pressure variability was obtained by calculating the following: (1) the SD of 24-hour, day, and night mean values; (2) the day-night blood pressure difference; and (3) the residual or erratic blood pressure variability (Fourier spectral analysis). Fatal cardiovascular and noncardiovascular events were registered for 148 months. When adjusted for age, sex, 24-hour mean blood pressure, and other risk factors, there was no relationship between the risk of death and 24-hour, day, and night blood pressure SDs. In contrast, the adjusted risk of cardiovascular death was inversely related to day-night diastolic BP difference (beta coefficient=-0.040; P<0.02) and showed a significant positive relationship with residual diastolic blood pressure variability (beta coefficient=0.175; P<0.002). Twenty-four-hour mean blood pressure attenuation of nocturnal hypotension and erratic diastolic blood pressure variability all independently predicted the mortality risk, with the erratic variability being the most important factor. Our data show that the relationship of blood pressure to prognosis is complex and that phenomena other than 24-hour mean values are involved. They also provide the first evidence that short-term erratic components of blood pressure variability play a prognostic role, with their increase being accompanied by an increased cardiovascular risk.

Metabolic syndrome in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study: daily life blood pressure, cardiac damage, and prognosis.

The prevalence of the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and its relationships with daily life blood pressures, cardiac damage, and prognosis were determined in 2013 subjects from a Northern Italian population aged 25 to 74 years. Home blood pressure, 24-hour blood pressure, and left ventricular mass index (echocardiography) were also measured. Cardiovascular and noncardiovascular deaths were registered over 148 months. Metabolic syndrome was found in 16.2% of the sample, an office blood pressure elevation being the most frequent (95.4%) and the blood glucose abnormality the least frequent (31.5%) component. There was in metabolic syndrome a frequent elevation in home and/or 24-hour average blood pressure, as well as a greater left ventricular mass index and prevalence of left ventricular hypertrophy, which was manifest even when data were adjusted for between-group differences, including blood pressure. The adjusted risk of cardiovascular and all-cause mortality was greater in metabolic syndrome subjects (+71.0% and +37.0%; P<0.05), a further marked increase being observed with left ventricular hypertrophy or "in-office" and "out-of-office" blood pressure elevations. The increased risk was related to the blood pressure and the blood glucose component of metabolic syndrome, with no contribution of the remaining components. Thus, metabolic syndrome is common in a Mediterranean population in which it significantly increases the long-term risk of death. Cardiac abnormalities and increases in home and 24-hour blood pressure are common in metabolic syndrome, and their occurrence further enhances the risk. The contribution of metabolic syndrome components to the risk, however, is unbalanced and mainly related to blood pressure and glucose abnormalities.

Baroreflex function in hypertension: consequences for antihypertensive therapy.

Studies performed in experimental animal models of hypertension as well as in human hypertension have unequivocally shown that reflex cardiovascular control undergoes profound changes with high blood pressure and participates throughout direct and indirect mechanisms at the development and progression of hypertension-related target organ damage. This explains why investigation of the effects of antihypertensive drugs on neural cardiovascular control has a significant impact on hypertension treatment. This review will examine the main features of cardiovascular reflex control in hypertension and the effects of the different classes of antihypertensive drugs in uncomplicated and complicated hypertension.

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.

Sustained sympathoinhibitory effects of cardiac resynchronization therapy in severe heart failure.

Evidence is available that in heart failure, cardiac resynchronization therapy by biventricular pacing improves myocardial function and exercise capacity. Whether this is accompanied by a sustained inhibition of heart failure-dependent sympathoexcitation is uncertain. In 11 heart failure patients (mean+/-SEM age, 68.4+/-1.5 years) in New York Heart Association (NYHA) class III and IV under medical treatment with an intraventricular conduction delay (QRS duration > or =130 ms), with a markedly depressed left ventricular ejection fraction, and undergoing implantation of a biventricular pacemaker, we measured beat-to-beat blood pressure and muscle sympathetic nerve traffic. Measurements, which also included echocardiographic and clinical variables, were performed before and approximately 10 weeks after successful resynchronization therapy. Ten age- and NYHA class-matched heart failure patients who were under medical treatment for the same time period served as controls. Long-term resynchronization therapy improved cardiac function and caused a significant increase in systolic blood pressure coupled with an improvement in maximal oxygen consumption and exercise capacity. These effects were coupled with a significant and marked reduction in sympathetic nerve traffic when expressed both as burst frequency over time (44.1+/-3.6 vs 30.7+/-3.0 bs/min, -30.5%, P<0.02) and as burst frequency corrected for heart rate (68.3+/-5.9 vs 47.3+/-4.3 bs/100 beats, -32.1%, P<0.02). No significant change in the aforementioned parameters was seen in the control group. These data provide the first direct evidence that in severe heart failure, resynchronization therapy exerts a marked and sustained sympathoinhibition. Because in heart failure sympathetic overactivity adversely affects prognosis, this may have important clinical implications.