Sympathetic nerve traffic and blood pressure changes after bilateral renal denervation in resistant hypertension: a time-integrated analysis.

BACKGROUND: Renal denervation reduces blood pressure (BP) and sympathetic drive in experimental animal models, but the effect of this intervention on sympathetic activity in patients with treatment-resistant hypertension is still unclear. METHODS: In an incident series of 29 patients with treatment-resistant hypertension, we performed serial measurements (n = 123) of muscle sympathetic nerve activity (MSNA, microneurography) and standardized BP measurements. Data were analysed by mixed linear modelling (MLM) and by regression analysis of time-integrated changes of both MSNA and synchronous, standardized (in-lab) BP measurements. RESULTS: Bilateral renal denervation was accompanied by a marked reduction in MSNA (P = 0.01 by MLM), which was parallelled by a reduction in systolic (from 175 ± 14 to 156 ± 16 mmHg) and, to a lesser extent, in diastolic (from 96 ± 12 to 87 ± 6 mmHg) BP over time. Neither systolic nor diastolic BP associated to a significant extent with corrected MSNA (MSNAC) in the MLM analysis (systolic BP versus MSNAC: ß = -0.08, P = 0.08; diastolic BP versus MSNAC: ß = -0.007, P = 0.75). However, the study of time-integrated changes in MSNA and BP showed a robust association between proportional changes in MSNA over time and simultaneous changes in systolic and diastolic BP (ß = 0.61, P < 0.001 and ß = 0.37 P < 0.05). CONCLUSIONS: Time-integrated changes in MSNAC and BP after bilateral renal denervation document a close link between the sympathetic activity and BP responses to this procedure. These findings further strengthen the relevance of the sympathetic nervous system both in the pathophysiology of resistant hypertension and in the BP-lowering effect of the procedure.

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.

New-onset left atrial enlargement in a general population.

AIM: Increased left atrium diameter (LAD) is associated with elevated risk of cardiovascular morbidity and mortality. We evaluated new-onset left atrium enlargement (LAE) and their correlates over a 10-year period in participants of the general population enrolled in the Pressioni Monitorate e Loro Associazioni study. METHODS: The study included 1045 participants with normal LAD at baseline evaluation having a readable echocardiogram at the end of follow-up. Cut-points for abnormal LAD were derived from reference values recommended by American Society of Echocardiography. RESULTS: Over a 10-year period, 123 participants (11.8%) progressed to LAE. The incidence of new-onset LAE increased significantly from the lowest to the highest tertile of baseline office, home and 24-h blood pressure (BP); BMI; fasting blood glucose and left ventricular mass index (LVMI). In multivariate analysis, baseline LAD [odds ratio (OR) 3.18, confidence interval (CI) 2.26-4.47, P < 0.001], female sex (OR 3.68, CI 2.20-6.18, P < 0.001), office SBP (OR 1.36, CI 1.08-1.70, P = 0.008), BMI (OR 1.35, CI 1.07-1.69, P = 0.01 and LVMI (OR 1.29, CI 1.01-1.64, P = 0.04) emerged as key correlates of new-onset LAE. CONCLUSION: The study shows that in the population, long-term changes from normal LAD to LAE are independently driven by several risk factors such as the female sex and an increased baseline LAD, BMI, LVMI and BP, with no predictive superiority of home and ambulatory versus office values. Preventing BP elevations, overweight/obesity and left ventricular hypertrophy may thus all be important for LAE prevention.

Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights.

Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients.

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

BACKGROUND: Heart 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 RESULTS: MSNA, 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 3 months, with measurements at that time compared to baseline evaluation. Baseline characteristics of the groups were well matched. At 3 months, 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. CONCLUSIONS: Despite 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.

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.

Blood pressure responses to renal denervation precede and are independent of the sympathetic and baroreflex effects.

It is still largely unknown whether the neuroadrenergic responses to renal denervation (RD) are involved in its blood pressure (BP)-lowering effects and represent predictors of the BP responses to RD. In 15 treated true resistant hypertensives, we measured before and 15 days, 1, 3, and 6 months after RD clinic, ambulatory and beat-to-beat BP. Measurements included muscle sympathetic nerve traffic (MSNA), spontaneous baroreflex-MSNA sensitivity, and various humoral and metabolic variables. Twelve treated hypertensives served as controls. BP, which was unaffected 15 days after RD, showed a significant decrease during the remaining follow-up period. MSNA and baroreflex did not change at 15-day and 1-month follow-up and showed, respectively, a decrease and a specular increase at 3 and 6 months after RD. No relationship, however, was detected between baseline MSNA and baroreflex, MSNA changes and BP changes. At the 6-month follow-up, the MSNA reduction was similar for magnitude in patients displaying a BP reduction greater or lower the median value. Similarly, the BP reduction detected 6 months after RD was similar in patients displaying a MSNA reduction greater or lower median value. No significant BP and MSNA changes were detected in the control group. Thus, the BP reduction associated with RD seems to precede the MSNA changes and not to display a temporal, qualitative, and quantitative relationship with the MSNA and baroreflex effects. Given the small sample size of the present study further investigations are warranted to confirm the present findings.

Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension.

BACKGROUND: An increase in sympathetic drive to the heart and the peripheral circulation characterizes mild and severe essential hypertension. However, it remains unsettled whether sympathetic cardiovascular influences are potentiated in true resistant hypertension (RHT). METHODS: In 32 RHT patients treated with 4.6 ± 0.3 drugs (mean ± SEM) and aged 58.6 ± 2.1 years, 35 non-resistant treated hypertensives (HT) and 19 normotensive controls (NT), all age-matched with RHT, we measured clinic, 24-hour ambulatory and beat-to-beat blood pressures (BP), heart rate (HR, EKG), muscle sympathetic nerve traffic (MSNA, microneurography) and spontaneous baroreflex MSNA-sensitivity. RESULTS: BP values were markedly greater in RHT patients than in NT and HT (172.2 ± 1.7/100.7 ± 1.2 vs 132.1 ± 1.3/82.1 ± 0.9 and 135.5 ± 1.2/83.6 ± 0.9 mmHg, P < 0.01). This was paralleled by a significant and marked increase in MSNA (87.8 ± 2.0 vs 46.8 ± 2.6 and 59.3 ± 1.7 and bursts/100 heartbeats, P < 0.01). In multiple regression analysis the MSNA increase observed in RHT was significantly related to hemodynamic, hormonal and metabolic variables. It was also significantly related to plasma aldosterone values as well as spontaneous baroreflex MSNA-sensitivity, which were the variables that at the multivariate analysis were more closely related to the adrenergic activation of RHT after adjustment for confounders, including antihypertensive treatment (r(2)partial=0.04405 and r(2)partial=0.00878, P<0.05 for both). CONCLUSIONS: These data represent the first evidence that RHT is a state of marked adrenergic overdrive, greater for magnitude than that detectable in HT. They also suggest that impaired baroreflex mechanisms, along with hemodynamic and neurohumoral factors, may be responsible for the phenomenon.

Prognostic significance of left atrial enlargement in a general population: results of the PAMELA study.

We estimated the risk of cardiovascular events, cardiovascular mortality, and all-cause mortality associated with left atrium (LA) enlargement alone or combined with echocardiographic left ventricular hypertrophy (LVH) in 1785 representatives of the general population of Monza recruited for the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study. LA enlargement was assessed by measuring LA diameter via echocardiography. LA enlargement was defined as a LA diameter>2.3 cm/m2, whereas LVH was defined as a left ventricular mass index≥114 g/m2 and 99 g/m2 in men and women, respectively. Death certificates and hospital diagnoses were collected over an average 148 months follow-up. During follow-up, there were 175 deaths (of which 59 for cardiovascular causes) and 139 cardiovascular fatal and nonfatal events. Compared with subjects with neither LA enlargement nor LVH, subjects with isolated LA enlargement exhibited a significant increase in the adjusted risk of combined fatal and nonfatal cardiovascular events (hazard ratio, 2.0; confidence interval, 1-4.1; P=0.04), although not of cardiovascular death or all-cause death. The adjusted (for baseline covariates, including ambulatory blood pressure) risk of fatal and nonfatal cardiovascular events, cardiovascular death, and all-cause death was significantly increased also in subjects with isolated LVH (hazard ratio, 2.2, 3.4, 2.1, respectively; P=0.001 for all), whereas no further increase was seen in subjects with both LA and left ventricular abnormalities. Thus, like LVH, LA enlargement is an independent long-term predictor of cardiovascular events. The cardiovascular risk, however, is not further increased when LA enlargement is superimposed on an increase of LV mass.

Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study.

AIMS: Heart failure (HF) pathophysiology is believed to be mediated by autonomic dysfunction, including chronic sympathoexcitation and diminished baroreflex sensitivity, which correlate with mortality risk. Baroreflex activation therapy (BAT) is a device-based treatment providing chronic baroreflex activation through electrical stimulation of the carotid sinus. BAT chronically reduces sympathetic activity in resistant hypertension. The purpose of this investigation is to determine BAT effects in clinical HF. METHODS AND RESULTS: In a single-centre, open-label evaluation, patients with NYHA class III HF, EF <40%, optimized medical therapy, and ineligible for cardiac resynchronization received BAT for 6 months. Efficacy was assessed with serial measurement of muscle sympathetic nerve activity (MSNA) and clinical measures of quality of life and functional capacity. Eleven patients participated in the trial. MSNA was reduced over 6 months from 45.1 ± 7.7 to 31.3 ± 8.3 bursts/min and from 67.6 ± 12.7 to 45.1 ± 11.6 bursts/100 heartbeats, decreases of 31% and 33%, respectively (P < 0.01). Concomitant improvements occurred in baroreflex sensitivity, EF, NYHA class, quality of life and 6 min hall walk (6 MHW) distance (P ≤ 0.05 each). On an observational basis, hospitalization and emergency department visits for worsening HF were markedly reduced. One complication, perioperative anaemia requiring transfusion, occurred during the study. CONCLUSION: BAT was safe and provided chronic improvement in MSNA and clinical variables. Based on present understanding of HF pathophysiology, these results suggest that BAT may improve outcome in HF by modulating autonomic balance. Prospective, randomized trials to test the hypothesis are warranted.

Neuroadrenergic disarray in pseudo-resistant and resistant hypertension.

Several studies have investigated the behavior of sympathetic cardiovascular drive in essential hypertension, providing conclusive evidence of the adrenergic activation characterizing this condition. These studies have also shown the importance of neuroadrenergic overdrive in the development and progression of the hypertensive state as well as in the pathogenesis of hypertension-related end-organ damage. The information available on the sympathetic nervous system's behavior in 'pseudo-resistant' and 'true resistant' hypertension is much more scarce. This paper will review the available knowledge on this issue by examining the data collected via indirect and direct approaches to investigate adrenergic function in resistant hypertension as well as the effects of pharmacological and non-pharmacological interventions.

Regional differences in sympathetic activation in lean and obese normotensive individuals with obstructive sleep apnoea.

OBJECTIVE: Obstructive sleep apnoea (OSA) is characterized by a marked sympathetic overdrive, as documented by the elevated sympathetic nerve firing rate detected in peripheral muscle nerves. No data are available, however, on the behaviour of sympathetic drive in vascular regional districts other than the muscle circulation. DESIGN AND METHODS: In 66 middle-aged normotensive individuals classified according to BMI, waist-to-hip ratio and apnoea-hypopnea index as lean individuals without (n = 20) or with (n = 14) OSA and as obese individuals without (n = 13) or with (n = 19) OSA, we measured blood pressure, heart rate, muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA), respectively, via microneurography. Measurements also included SSNA responses to an emotional stimulus. RESULTS: The four groups were matched for age, sex and blood pressure values. Both in lean and obese individuals, presence of OSA was accompanied by MSNA values significantly greater than those found in non-OSA individuals. In contrast, no significant difference was found in SSNA values between OSA and non-OSA patients both in the lean and in the obese groups. This was the case also for the SSNA responses to an emotional arousal. CONCLUSION: These data provide the first evidence that in OSA, the adrenergic overdrive seen in the muscle circulation is not detected in cutaneous circulation and thus it cannot be regarded as a generalized phenomenon affecting the whole cardiovascular system. Further studies are needed to clarify whether in OSA, sympathetic drive of other vascular districts, such as the coronary, renal or cerebral circulation, is activated or normal.

Similarities and differences between renal sympathetic denervation and carotid baroreceptor stimulation.

The two novel approaches recently introduced for the treatment of resistant hypertension, i.e. carotid baroreceptor stimulation and renal denervation, share a number of similarities but are also characterized by important differences. The similarities include the evidence that both interventions have as common pathophysiological background the state of sympathetic overdrive characterizing essential hypertension. In addition both procedures 1) are invasive, 2) exert in the short-term period clearcut blood pressure lowering effects and 3) still face a number of open questions, particularly related to the long-term blood pressure lowering effects, impact on end-organ damage and on cardiovascular events. The differences include the fact that two procedures act on distinct targets that trigger sympathetic activation and consequently blood pressure increase. In addition, only in the case of carotid baroreceptor stimulation the blood pressure effects can be easily assessed immediately following the implantation. Finally, the economic costs, metabolic effects and impact on vagal modulation of heart rate are different between the two interventions. This paper will provide a comparison of the background, effects and outcome of renal denervation and carotid baroreceptor stimulation, stressing whenever possible the clinical implications of the main features of the two interventions.

Striking improvement in a case of reduced ejection fraction heart failure with baroreflex activation therapy.

A patient experiencing chronic New York Heart Association (NYHA) Class III heart failure with reduced left ventricular ejection fraction and signs of right ventricular dysfunction is treated with baroreflex activation therapy (BAT). Despite optimal medical therapy, the patient had repeatedly decompensated and was approaching a refractory terminal stage. BAT chronically reduced muscle sympathetic nerve activity and dramatically improved clinical presentation of the patient to NYHA Class I through 12 months of therapy. BAT may hold promise for patients with advanced heart failure and reduced ejection fraction who have exhausted conventional therapy options. .

Comparative effects of nebivolol and metoprolol on red cell distribution width and neutrophil/lymphocyte ratio in patients with newly diagnosed essential hypertension.

High level of circulating red cell distribution width (RDW) and neutrophil/lymphocyte (N/L) ratio may reflect ongoing vascular inflammation and play an important role in pathophysiology of hypertension. We evaluate the effects of nebivolol and metoprolol on the RDW and N/L in new essential hypertensive patients. After baseline assessment, 72 patients were randomly allocated to 5 mg/d of nebivolol (n = 37, 20 men) or 100 mg/d of metoprolol (n = 35, 18 men) and treated for 6 months. Blood pressure (BP), heart rate (HR), RDW, and N/L were measured before and after treatment. BP significantly decreased with both drugs (P < 0.001). Analog reduction was observed for resting HRs (P < 0.001), but metoprolol caused greater HR fall as compared with nebivolol (P < 0.001). After 6 months of treatment, nebivolol significantly lowered not only RDW but also the total white blood cell and N/L (P < 0.001, P = 0.023, P = 0.017, respectively). No changes were observed in metoprolol group. Percent decrease in RDW was found to be significantly higher in nebivolol than in the metoprolol group (P = 0.001) and remained also after correction for confounders (P = 0.012). Nebivolol improved RDW and N/L to a greater extent than metoprolol in patients with hypertension. These favorable effects may participate, together with the BP reduction, at the favorable properties of the drug in hypertension.

Impact of blood glucose variability on carotid artery intima media thickness and distensibility in type 1 diabetes mellitus.

AIMS: Diabetes mellitus is characterized by structural and functional alterations of the large- and medium-size arteries. Whether blood glucose variability, i.e. the glycemic oscillations occurring during the 24-h period, represents a risk factor for vascular alterations additional to and independent on HbA1c in type 1 diabetes mellitus is still undefined. The present study was carried out with the aim at investigating the impact of different measures of blood glucose variability on arterial structure and function. We studied 17 non-complicated type 1 diabetic patients (11 males, six females) with an age of 40.8 ± 7.6 years (mean ± SD). In each patient, 24-h glucose profile was obtained by continuous glucose monitoring system and glucose variability was expressed as mean ± SD of 24-h blood glucose levels, mean amplitude of glycemic excursions and postprandial hyperglycemic spikes. Arterial structure and function was measured as carotid IMT and stiffness. MAJOR FINDINGS: The different approaches to assessing blood glucose variability well correlated between and with HbA1c. Carotid IMT and stiffness showed significant correlations with age, blood pressure, heart rate and daily insulin intake but a non- significant correlation with blood glucose variability. PRINCIPAL CONCLUSION: Thus, in type 1 diabetes mellitus, measures of glycemic variability are useful in predicting both actual and long-lasting glycemic control. In absence of diabetes-related complications and of any intima-media thickness alterations, the major predictors of arterial distensibility are represented by traditional risk factors beside glycemic 24-h control.

Prevalence and clinical characteristics of patients with true resistant hypertension in central and Eastern Europe: data from the BP-CARE study.

OBJECTIVE: Scanty information is available on the clinical characteristics of resistant hypertension in Central and East European countries. The Blood Pressure (BP) control rate and CArdiovascular Risk profilE (BP-CARE) study allowed us to assess the prevalence and the main clinical features of resistant hypertension in this population. DESIGN AND METHOD: The study was carried out in 1312 treated hypertensive patients living in nine Central and East European countries. RESULTS: Four hundred and twenty-three patients had apparent resistant hypertension, of whom 168 had pseudo-resistant hypertension (noncompliant/white-coat) and 255 were true treatment-resistant hypertension patients (TRH). Clinical BP values in TRH amounted to 157.4±16.9/91.8±10.0 mmHg despite the daily use of 3.6±0.7 drugs. Their 24-h BP values were 149.5±16.5/97.5±9.8 mmHg. Compared to controlled hypertensive patients (n=368) and uncontrolled nonresistant hypertensive patients (n=521), TRH were older with a greater prevalence of women. They showed a higher rate of previous cardiovascular events and a very high cardiovascular risk profile. Estimated glomerular filtration rate was significantly lower in TRH as compared to controlled hypertensive patients and uncontrolled nonresistant hypertensive patients. Overall, target organ damage was more frequently detected in TRH than in controlled hypertensive patients and uncontrolled nonresistant hypertensive patients. The factor most frequently associated with TRH was severity of hypertension followed by age, total cholesterol, BMI and history of heart failure. CONCLUSIONS: The present study provides evidence that the prevalence of TRH in Central and East European countries is similar to that found in Western Europe and USA. It also shows the very high cardiovascular risk of TRH and the elevated association of this condition with obesity, renal failure, organ damage and history of cardiovascular events.

Long-term prognostic value of white coat hypertension: an insight from diagnostic use of both ambulatory and home blood pressure measurements.

The prognostic value of white coat hypertension (WCH) is still debated. In 2051 subjects representative of the general population of Monza, we measured office, ambulatory, and home blood pressure (BP). The risk of cardiovascular and all-cause mortality was assessed over 16 years in normotensive, sustained hypertensive, and WCH subjects, the last group being defined as usually done in clinical practice (ie, by normality of 1 out-of-office [ambulatory or home] BP with an office BP elevation). Compared with normotensive subjects, the risk of cardiovascular mortality, as adjusted for potential confounders, showed a progressive significant increase in WCH and sustained hypertensive subjects (2.04 and 2.94; P=0.006). In either group, a significant increase in adjusted risk was also seen for all-cause mortality. However, when the WCH group was subdivided into 2 subgroups, that is, subjects in whom both out-of-office BPs were normal (true WCH, 42%) or one BP was normal whereas the other was elevated (partial WCH, 58%), only the latter showed a significantly greater adjusted risk of cardiovascular and all-cause mortality (2.76 and 1.58; P<0.03). Compared with normotensive subjects, the partial WCH group also exhibited a marked increase in adjusted risk of developing sustained hypertension over a 10-year time period (2.58; P<0.0001), but in this case the risk was also increased in true WCH subjects (2.89; P<0.0001). Thus, WCH includes subjects with a widely different long-term risk of a cardiovascular event. To identify those at higher risk, measurements of both out-of-office BPs are desirable.