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Abstract: Mitral valve prolapse (MVP) is the most frequent valvulopathy in the general population, with usually a favourable prognosis. Although it can be associated with some complications, ventricular arrhythmias (VA) and sudden cardiac death (SCD) are the most worrying. The estimated risk of SCD in MVP is between 0.2% to 1.9% per year, including MVP patients with and without severe mitral regurgitation (MR). The association between SCD and MVP is expressed by a phenotype called “malignant MVP” characterized by transthoracic echocardiography (TTE) findings such as bileaflet myxomatous prolapse and mitral annulus disjunction (MAD), ECG findings such as repolarization abnormalities, complex ventricular arrhythmias (c-VAs) and LV fibrosis of papillary muscles (PMs) and inferobasal wall visualized by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Therefore, attention is raised for patients with “arrhythmic MVP” characterized from an ECG point of view by frequent premature ventricular contractions (PVCs) arising from one or both PMs as well as by T-wave inversion in the inferolateral leads. In athletes, SCD is the most frequent medical cause of death and in young subjects (< 35 years) usually is due to electrical mechanism affecting who has a silent cardiovascular disease and are not considered per se a cause of increased mortality. In MVP, SCD was reported to happen during sports activity or immediately after and valve prolapse was the only pathological aspect detected. The aim of the present paper is to explore the association between SCD and MVP in athletes, focusing attention on ECG, TTE in particular, and CMR findings that could help to identify subjects at high risk for complex arrhythmias and eventually SCD. In addition, it is also examined if sports activity might predispose patients with MVP to develop major arrhythmias.

Purpose To investigate the prevalence of orthostatic hypertension and the association of the blood pressure (BP) level, supine BP decline, and white-coat effect with the orthostatic pressor response. Methods We studied 1275 young-to-middle-age individuals with stage-1 hypertension. Orthostatic response was assessed three times over a 3 month period. The white-coat effect was assessed at baseline and after 3 months, and was calculated as the difference between office and average 24 h BP. In 660 participants, urinary epinephrine and norepinephrine were also measured. Results An orthostatic systolic BP increase ≥ 20 mmHg was observed in 0.6–1.2% of the subjects during the three visits. Using the 20 mmHg cut-off, the prevalence of orthostatic hypertension was 0.6%. An orthostatic BP increase of ≥ 5 mmHg was found in 14.4% of participants. At baseline, the orthostatic response to standing showed an independent negative association with the supine BP level (p p p p = 0.002 versus rest of the group). Conclusion An orthostatic systolic BP reaction ≥ 20 mmHg is rare in young adults. However, even lower BP increases may be clinically relevant. The BP level, the supine BP decline over repeated measurement, and the white-coat effect can influence the estimate of the BP response to standing and should be considered in clinical and pathogenetic studies.

Aims The role of increased blood pressure (BP) variability and a blunted day-night BP drop is still being debated, particularly in young hypertensive subjects. We investigated the contribution of BP variability and day-night BP changes combined to cardiovascular events in initially untreated young hypertensive individuals. Methods and results We selected 1794 subjects aged ≤45 years from the HARVEST and the PIUMA studies, two long-term observational studies in subjects with hypertension. The outcome was a composite pool of non-fatal myocardial infarction or stroke, heart failure needing hospitalization, death from cardiovascular causes, and myocardial or limb revascularization procedures. During an 11.3-year follow-up, 140 cardiovascular events were accrued. A multivariable Cox model which included BP variability and non-dipping was more informative (Akaike Information Criterion = 1536.9) than the model which included average of 24-h BP (Akaike Information Criterion = 1553.6). A higher hazard ratio (HR) was observed for non-dipping [HR 2.22; 95% confidence interval (CI): 1.55–3.17; P Conclusion In young hypertensive individuals, prognostic models including BP variability and non-dipping pattern provide better information than models with average 24-h ambulatory BP alone. More consideration should be given to BP variability and the day-night BP pattern beyond the average 24-h ambulatory BP in young hypertensive subjects.

Aim: To evaluate the association of alcohol and smoking combined with cardiovascular and renal events and investigate whether moderate and heavy alcohol consumption have a different impact on this association. Methods: The study was conducted in 1208 young-to-middle-age stage 1 hypertensive patients. Subjects were classified into three categories of cigarette smoking and alcohol use, and the risk of adverse outcomes was assessed over a 17.4-year follow-up. Results: In multivariable Cox models, smoking showed a different prognostic impact on alcohol drinkers and abstainers. In the former, an increase in the risk of cardiovascular and renal events was observed compared to nonsmokers (hazard ratio, 2.6, 95% CI, 1.5–4.3, p < 0.001), whereas in the latter, the risk did not achieve the level of statistical significance (p = 0.27) with a significant interaction between smoking and alcohol use (p < 0.001). Among the heavy smokers who also drank alcoholic beverages, the hazard ratio from the fully adjusted model was 4.3 (95% CI, 2.3–8.0, p < 0.0001). In the subjects with moderate alcohol consumption, the risk of smoking and alcohol combined was similar to that found in the whole population (hazard ratio, 2.7; 95% CI, 1.5–3.9, p < 0.001). Among the subjects with heavy alcohol consumption, the hazard ratio was 3.4 (95% CI, 1.3–8.6, p = 0.011). Conclusion: These findings indicate that the detrimental cardiovascular effects of smoking can be worsened by concomitant alcohol use. This synergistic effect occurs not only for heavy alcohol consumption but also for moderate use. Smokers should be aware of the increased risk associated with concomitant alcohol consumption.

The pathophysiologic mechanisms of masked hypertension are still debated. The aim of this study was to investigate whether the blood pressure response to standing is a determinant of masked hypertension in young individuals.We studied 1078 individuals (mean age 33.2 ± 8.5 years) with stage-1 untreated hypertension at baseline. Orthostatic response was defined as the difference between six SBP measurements in the orthostatic and supine postures. People with a response more than 6.5 mmHg (upper decile) were defined as hyperreactors. After 3 months of follow-up, 24-h ambulatory BP was measured and the participants were classified as normotensives (N = 120), white-coat hypertensive individuals (N = 168), masked hypertensive individuals (N = 166) and sustained hypertensive individuals (N = 624). In 591 participants, 24-h urinary epinephrine was also measured.Orthostatic response was an independent predictor of masked hypertension after 3 months (P = 0.001). In the whole group, the odds ratio for the Hyperreactors was 2.5 [95% confidence interval (95% CI) 1.5-4.0, P 0.001]. In the participants stratified by orthostatic response and urinary epinephrine, the odds ratio for masked hypertension was 4.2 (95% CI, 1.8-9.9, P = 0.001) in the hyperreactors with epinephrine above the median and was 2.6 (95% CI, 0.9-7.3, P = 0.069) in those with epinephrine below the median. The association between orthostatic response and masked hypertension was confirmed in the cross-sectional analysis after 3 months (P 0.001).The present findings indicate that hyperreactivity to standing is a significant determinant of masked hypertension. The odds ratio for masked hypertension was even quadrupled in people with an orthostatic response more than 6.5 mmHg and high urinary epinephrine suggesting a role of sympathoadrenergic activity in the pathogenesis of masked hypertension.

The coronavirus-19 disease (COVID-19) related pandemic have deeply impacted human health, economy, psychology and sociality. Possible serious cardiac involvement in the infection has been described, raising doubts about complete healing after the disease in many clinical settings. Moreover, there is the suspicion that the vaccines, especially those based on mRNA technology, can induce myopericarditis. Myocarditis or pericarditis related scars can represent the substrate for lifethreatening arrhythmias, triggered by physical activity. A crucial point is how to evaluate an athlete after a Covid-19 infection ensuring a safe return to play without increasing the number of unnecessary disqualifications from sports competitions. The lack of conclusive scientific data significantly increases the difficulty to propose recommendations and guidelines on this topic. At the same time, the psychological and physical negative consequences of unnecessary sports restriction must be taken into account. The present document aims to provide an updated brief review of the current knowledge about the COVID-19 cardiac involvement and how to recognize it and to offer a roadmap for the management of the athletes after a Covid-19 infections, including subsequent impact on exercise recommendations. Our document exclusively refers to cardiovascular implications of the disease, but pulmonary consequences are also considered.

A sedentary lifestyle is globally recognised as one of the main risk factors for cardiovascular diseases and today’s society, along with its behaviour, tends to favour it. To spread awareness about this, the World Health Organization has set the minimum level of physical activity an individual should undertake in order to significantly reduce the risk of developing such diseases. Considering walking for its ease and reproducibility, the exercise threshold is represented by the number of steps a person should take on average in a day and is identified to be ten thousand steps. The aim of our project is to tackle sedentary behaviour by encouraging physical activity and promoting a correct lifestyle for the citizens of Friuli Venezia-Giulia. The lack of the public spaces in which to practice physical activity safely is one of the main factors that discourages people from exercising. As such, with the promotion and implementation by Regione Friuli Venezia Giulia and Federsanità ANCI FVG alongside with the collaboration of Direzione Centrale Salute and PromoTurismo FVG, several walking routes within the regional territory have been redeveloped and improved by the addition of plentiful signage. In order to better reach out to the various communities about this project, an advertising campaign about the routes themselves and the importance of the exercise was started on a variety of websites as well as the most popular social media platforms. Furthermore, walking groups from different municipalities interested in the project have been directly involved and training courses have been set up in conjunction with volunteer doctors and professionals with a degree in Physical Education to inform people about specific muscle exercises that will target the general well-being. As a result of our project, fifty-nine routes have been created in all Friuli Venezia-Giulia, all of which contain historical, social and cultural value, and will give people the opportunity to exercise in an easy and safe way that will ultimately reduce their risk of developing cardiovascular diseases. Moreover, a statistical analysis conducted by the Department of Economic and Statistical Sciences of University of Udine on media coverage and use of the routes, showed that the project has reached a great percentage of the population and is used by many people. Positive results have so far been produced in Friuli Venezia-Giulia and such a project has not only attracted the attention of other Italian Regions, but has also interested other European Countries. Our next goal is to readapt “Ten thousand steps for Health” so it can be applied in other environments.

Molecular genetic testing is an increasingly available test to support the clinical diagnosis of inherited cardiovascular diseases through identification of pathogenic gene variants and to make a preclinical genetic diagnosis among proband's family members (so-called "cascade family screening"). In athletes, the added value of molecular genetic testing is to assist in discriminating between physiological adaptive changes of the athlete's heart and inherited cardiovascular diseases, in the presence of overlapping phenotypic features such as ECG changes, imaging abnormalities or arrhythmias ("grey zone"). Additional benefits of molecular genetic testing in the athlete include the potential impact on the disease risk stratification and the implications for eligibility to competitive sports. This position statement of the Italian Society of Sports Cardiology aims to guide general sports medical physicians and sports cardiologists on clinical decision as why and when to perform a molecular genetic testing in the athlete, highlighting strengths and weaknesses for each inherited cardiovascular disease at-risk of sudden cardiac death during sport. The importance of early (preclinical) diagnosis to prevent the negative effects of exercise on phenotypic expression, disease progression and worsening of the arrhythmogenic substrate is also addressed.

The prognostic significance and the mechanisms of blood pressure (BP) hyperreactivity to standing remain controversial. This study aims to evaluate the association of orthostatic hyperreactivity with major adverse cardiovascular and renal events in a cohort of young hypertensive subjects. We studied 1207 untreated subjects screened for stage I hypertension with a mean age of 33.1±8.6 years. The orthostatic BP change was calculated as the difference between 6 standing and 6 supine BP readings obtained during 2 separate visits. Hyperreactivity to standing was defined as the standing-supine systolic BP difference in the top decile. The mean difference in the whole group was −2.5±7.3/4.6±5.4 mm Hg. Ambulatory hypertension evaluated with 24-hour recordings was more common in Hyperreactors than Normoreactors (90.8% versus 76.4%, P =0.001). In 630 participants in whom 24-hour urinary catecholamines were measured, epinephrine/creatinine ratio was higher in hyperreactors (118.4±185.6 versus 77.0±90.1 nmol/mol, P =0.005). During a 17.2-year follow-up, 105 major adverse cardiovascular and renal events were accrued. In a multivariate Cox model, hyperreactivity to standing was an independent predictor of major adverse cardiovascular and renal events with a hazard ratio of 1.97 (95% CI, 1.10–3.52). Hyperreactivity remained an independent predictor of adverse events even when ambulatory BP data and incident hypertension during follow-up were included in the Cox model (hazard ratio, 1.94 [95% CI, 1.10–3.44]). Our data indicate that in young-to-middle-age hypertensive subjects an exaggerated systolic BP response to standing is associated with sympatho-adrenergic hyperreactivity and is an independent predictor of major adverse cardiovascular and renal events. Orthostatic BP assessment gives the advantage of simple acquisition and provides prognostic information on top of ambulatory BP.

Aim. To assess the effect of leisure time versus vigorous long-term dynamic physical activity (PA) on carotid stiffness in normotensive versus hypertensive subjects. Methods. The study was conducted on 120 leisure-time exercisers and 120 competitive athletes. One hundred and twenty sedentary subjects served as controls. In addition, participants were classified according to whether their systolic blood pressure was ≥130 mmHg (hypertensives, n = 120) or normal (normotensives, n = 240) according to the ACC/AHA 2017 definition. Carotid artery stiffness was assessed with an echo-tracking ultrasound system, using the pressure-strain elastic modulus (EP) and one-point pulse wave velocity (PWVβ) as parameters of stiffness. Results. The effect of the two levels of PA differed in the normotensives and the hypertensives. Among the normotensives, there was an ongoing, graded reduction in EP and PWVβ from the sedentary subjects to the athletes. By contrast, among the hypertensives, the lowest levels of EP and PWVβ were found among the leisure-time PA participants. EP and PWVβ did not differ between the hypertensive sedentary subjects and the athletes. A significant interaction was found between PA and BP status on EP (p = 0.03) and a borderline interaction on PWVβ (p = 0.06). In multiple regression analyses, PA was a negative predictor of EP (p = 0.001) and PWVβ (p = 0.0001). The strength of the association was weakened after the inclusion of heart rate in the models (p = 0.04 and 0.007, respectively). Conclusions. These data indicate that in people with hypertension, leisure-time PA has beneficial effects on carotid artery stiffness, whereas high-intensity chronic PA provides no benefit to vascular functions.

International audience; Aortic valve stenosis (AS) shares similarities with the atherosclerotic process but little is known about the effect of the mechanical properties of large arteries on outcome in patients with AS. The aims of this study were (1) to determine the relationship between indexes of carotid stiffness/compliance and the severity of AS and (2) to identify whether local arterial stiffness is independently associated with mortality. 133 patients with moderate to severe isolated AS and preserved LV ejection fraction (LVEF) were included. All underwent transthoracic echocardiography and local carotid stiffness evaluation by means of high-definition echo-tracking ultrasound with the calculation of stiffness/compliance parameters included augmentation index (AIx). None of the carotid stiffness parameters were significantly associated with AS severity parameters. During a mean follow-up of 51.6 ± 39.4 months, 70 patients received aortic valve replacement, 45 died and 18 were alive with no surgery. Who died were older (79.2 ± 6.9 vs. 73 ± 8.8 years, p < 0.0001), had higher carotid AIx (21.3 ± 14 vs. 16 ± 12%, p = 0.028). In multivariate Cox regression analysis AIx was independently associated with mortality (HR 1.048, 95% CI 1.01-1.07, p = 0.001), also after inclusion of age and creatinine. There was a significant association between the level of AIx and mortality in those patients who did not have surgery (p = 0.016). In severe AS and a normal LVEF, carotid AIx measured by echo-tracking system was independently associated with death. No relationship between AS severity and local carotid stiffness was found. These data emphasize the importance of arterial stiffness has a hallmark of long-term atherosclerotic burden and impaired prognosis.

Since 1989, SIC Sport and a FMSI, in partnership with leading Italian Cardiological Scientific Associations (ANCE, ANMCO and SIC) have produced Cardiological Guidelines for Completive Sports Eligibility for athletes with heart disease (COCIS -- 1989, 1995, 2003, 2009 and 2017). The English version of the Italian Cardiological Guidelines for Competitive Sports Eligibility for athletes with heart disease was published in 2013 in this Journal. This publication is an update with respect to the document previously published in English in 2013. It includes the principal innovations that have emerged over recent years, and is divided into five main chapters: arrhythmias, ion channel disorders, congenital heart diseases, acquired valve diseases, cardiomyopathies, myocarditis and pericarditis and ischemic heart disease. Wherever no new data have been introduced with respect to the 2013 publication, please refer to the previous version. This document is intended to complement recent European and American guidelines but an important difference should be noted. The European and American guidelines indicate good practice for people engaging in physical activity at various levels, not only at the competitive level. In contrast, the COCIS guidelines refer specifically to competitive athletes in various sports including those with high cardiovascular stress. This explains why Italian guidelines are more restrictive than European and USA ones. COCIS guidelines address 'sports doctors' who, in Italy, must certify fitness to participate in competitive sports. In Italy, this certificate is essential for participating in any competition.

Background Whether blood pressure variability (BPV) measured with ambulatory monitoring (short-term BPV) or computed from office visits (long-term BPV) are related to each other and carry similar prognostic information is not well known. We investigated the independent determinants of short-term and long-term BPVs and their predictive capacity for the development of major adverse cardiovascular and renal events (MACEs) in a cohort of young hypertensive participants. Methods Long-term BPV was calculated as visit-to-visit SD and average real variability from office blood pressure (BP) measured during 7 visits, within 1 year. Short-term BPV was calculated as weighted 24-hour SD and coefficient of variation. Hazard ratios (HRs) for risk of MACE were computed from multivariable Cox regressions. Results 1,167 participants were examined; mean age was 33.1 ± 8.5 years. Variables independently associated with 24-hour systolic SD were 24-hour systolic BP, low physical activity, smoking, baseline office pulse pressure, systolic BP dipping, and diastolic white coat effect, while those associated with long-term BPV were mean systolic BP, age, female gender, and baseline office heart rate. During a median follow-up of 17.4 years 75 MACEs occurred. In Cox analysis only short-term BPV resulted a significant predictor of MACE (HR, 1.31 (1.07–1.59); P = 0.0086), while no index of long-term BPV was independently associated with outcome. Conclusions In young hypertensive subjects only short-term BPV resulted a significant predictor of MACE on top of traditional ambulatory BP monitoring parameters. Whether reduction of short-term BPV with therapy may reduce the cardiovascular risk independently from the effects on 24-hour BP is a matter for future research.

The clinical significance of isolated systolic hypertension (ISH) in youth is controversial. One main confounding factor is the strong white-coat effect often observed in ISH patients. The aim of this study was to investigate the risk of hypertension needing pharmacological treatment in ISH identified with ambulatory 24-h blood pressure (24-h BP).We examined 1206, 18-45-year-old participants from the Hypertension and Ambulatory Recording VEnetia STudy. Based on 24-h BP, 269 participants were normotensive, 209 had ISH, 277 had isolated diastolic hypertension, and 451 had systolic-diastolic hypertension. The predictive role of ISH for incident hypertension was evaluated in Cox survival analyses, adjusting for risk factors and confounders.ISH participants were more frequently young men active in sports, with lower heart rate and cholesterol. During a 6.9-year follow-up, 61.1% of participants developed hypertension. ISH participants had a nonsignificant increase in risk of hypertension compared with normotensive (reference group). In contrast, participants with diastolic hypertension (1.44; 1.13-1.85) or systolic-diastolic hypertension (2.04; 1.59-2.64) had a significant increase in risk. When the ISH participants were divided according to whether 24-h mean BP was normal (97 mmHg) or high, ISH patients with normal mean BP had no increase in risk (1.01; 0.73-1.40), whereas those with high mean BP had a significant increase in risk (1.70; 1.16-2.49).These data obtained with ambulatory BP monitoring show that in ISH people younger than 45 years, only mean BP is a predictor of future hypertension needing treatment, whereas the ISH status per se does not necessarily imply an increase in risk.

BACKGROUND: Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS: This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION: Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding.FUNDING: Bayer AG.

Objective The association of serum uric acid (SUA) with risk of hypertension is controversial and may be modulated by lifestyle factors. We did a prospective study to investigate whether SUA was an independent predictor of hypertension in the young and whether physical activity influences this association. Methods The study was conducted in a cohort of 1156 young to middle-age participants screened for stage 1 hypertension and followed for a median of 11.4 years. In multivariable Cox analyses, participants were stratified by tertiles of uric acid and physical activity habits. Results At follow-up end, 63.3% of the study participants developed hypertension needing treatment. In the whole group, SUA was an independent predictor of future hypertension (P = 0.005). Participants with SUA more than 5.60 mg/dl (top tertile) had a 31% increase in risk compared with those of the bottom tertile. However, the risk of hypertension related to SUA was increased only among the sedentary participants with a hazard ratio of 1.44 (95% confidence interval, 1.11-1.88) for the participants of the top SUA tertile. In contrast, among the active participants no association was found between SUA and risk of hypertension. Alcohol intake was another modulator of the SUA-hypertension relationship (hazard ratio, 95% confidence interval: 1.38, 1.02-1.87). Plasma renin activity, office and ambulatory heart rates, and metabolic variables were proportional to SUA level and were lower in active than sedentary participants. Conclusion These data confirm that SUA is a predictor of hypertension and suggest that exercise may counteract the pathophysiological mechanisms involved in the association between hyperuricemia and future hypertension.

The association of short-term blood pressure (BP) variability (BPV) with cardiovascular events (CVEs) is controversial. Aim of this study was to investigate whether BPV measured as weighted 24-h SD was associated with CVE in a prospective cohort study of young patients screened for stage 1 hypertension.We performed 24-h ambulatory BP monitoring in 1206 participants aged 33.1 ± 8.5 years, untreated at baseline examination. Participants were divided into two categories with low (12.8 mmHg) or high (≥12.8 mmHg) SBPV. Hazard ratios for CVE associated with BPV expressed either as continuous or categorical variable were computed from multivariable Cox models.During 15.4 ± 7.4 years of follow-up there were 69 fatal and nonfatal CVE. In multivariable Cox models, high SBPV was an independent predictors of CVE [2.75 (1.65-4.58); P = 0.0001] and of coronary events [3.84 (2.01-7.35), P 0.0001]. Inclusion in the model of development of hypertension requiring treatment during the follow-up, did not reduce the strength of the associations. Addition of SBPV to fully adjusted models had significant impact on risk reclassification and integrated discrimination (relative integrated discrimination improvement for BPV as continuous variable: 13.5%, P = 0.045, and for BPV as categorical variable: 26.6%, P = 0.001). When the coefficient of variation was used as BPV metric similar results were obtained. Of note, in all Cox models average 24-h BP was no longer an independent predictor of outcome after BPV was included.Short-term BPV adds to the risk stratification for cardiovascular events in young-to-middle-age patients screened for stage 1 hypertension over and above traditional 24-h ambulatory monitoring indexes.

Several studies have shown that the augmentation index (AIx) is negatively correlated with heart rate (HR). This led some authors to claim that the use of HR-lowering drugs may be detrimental in hypertension. The aim of this study was to assess the longitudinal and cross-sectional relationships of HR with AIx and central blood pressure (BP) in 346 subjects from the HARVEST (mean age 30.7 ± 8.5 years). At baseline, HR was measured with 24-h ambulatory recording. Central hemodynamics were evaluated with Specaway DAT system after a median of 8.0 years from baseline. In multivariate linear regression analyses, AIx and central systolic BP were used as dependent variables and night-time HR or office HR as predictors adjusting for several risk factors and confounders. In fully adjusted models, baseline night-time HR was a significant positive predictor of AIx (p

Summary Background Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. Methods In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. Findings Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55–0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55–1·53; p=0·76). Interpretation Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication. Funding Boehringer Ingelheim and Canadian Institutes of Health Research.

BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, pINTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.FUNDING: Bayer AG.

Carcinoid syndrome is the constellation of symptoms mediated by humoral factors produced by some carcinoid tumors. It consists primarily of vasomotor symptoms, gastrointestinal hypermotility, hypotension, and bronchospasm, due to the production and release of vasoactive substances. Carcinoid heart disease occurs in more than 50% of patients with carcinoid syndrome; in some cases, it represents the initial manifestation of the disease. We report the case of a 75-year-old woman with a metastatic neuroendocrine tumor admitted to the emergency room for fatigue and heart failure. Transthoracic echocardiography showed severe tricuspid and pulmonic regurgitation suggesting carcinoid heart disease. A hypervascular retroperitoneal mass was found on abdominal computed tomography, which seemed to arise from the mesenteric artery, anteriorly to the abdominal aorta. Unfortunately, our patient was neither a candidate for mass resection nor for cardiac surgery due to advanced metastatic disease and poor clinical condition. Additionally, we performed a systematic literature review of carcinoid heart disease focusing on typical echocardiographic findings.

The role of pulse pressure in young individuals remains controversial. The aim of the present study was to investigate the clinical significance of elevated pulse pressure in young- to middle-aged subjects screened for stage 1 hypertension. We examined 1241 subjects (mean age, 33.1±8.4 years) from the HARVEST (Hypertension Ambulatory Recording Venetia Study), during a median follow-up of 12.1 years. To evaluate the predictive value of pulse pressure and mean blood pressure for future hypertension needing treatment and for cardiovascular events, participants were grouped into pressure tertiles. Significant determinants of pulse pressure were male sex ( P =0.029), younger age ( P P =0.003), heart rate ( P P P P =0.003). In contrast, participants in the top mean blood pressure tertile had an increase in risk (1.91; 1.57–2.33; P P =0.005) and those in the top mean blood pressure tertile had an increase in risk (3.06; 1.32–7.09; P =0.009). Our data show that in subjects

An interactive effect of tobacco and alcohol use has been described for cancer. The aim of this study was to investigate the joint effect of smoking and alcohol intake on major adverse cardiovascular and renal events (MACE) in young subjects screened for stage 1 hypertension.A total of 1204 untreated patients aged from 18 to 45 years (mean 33.1) were included in this prospective cohort study. Subjects were classified into 4 categories of cigarette smoking and 3 classes of alcohol use. Main outcome variable was risk for MACE.During a 12.6-year follow-up, there were 74 fatal and nonfatal MACE. In multivariable Cox models, current smoking and alcohol drinking were associated with risk of MACE. In a multivariable model also including follow-up changes in blood pressure and body weight, hazard ratio (HR) was 1.48 (95% confidence interval [CI], 1.20-1.83) for smoking and was 1.82 (95% CI, 1.05-3.15) for alcohol use. In addition, an interactive effect was found between smoking and alcohol on risk of MACE (P.001). Among the 142 smokers who also drank alcoholic beverages, the risk of MACE (HR 4.02; 95% CI, 1.98-8.15) was more than doubled compared with the 112 smokers who abstained from drinking (HR 1.64; 95% CI, 0.63-4.27). In the group of heavy smokers who also were alcohol drinkers (n = 51), the risk of MACE was even quadrupled (HR 7.79; 95% CI, 4.22-14.37).Alcohol use potentiates the deleterious cardiovascular effects of heavy smoking in stage 1 hypertensive subjects younger than 45 years. These results call for prompt intervention addressed to improve unhealthy behaviors in these subjects.

AIMS To describe the actual incidence, prevalence among acute coronary syndrome patients and rate of recurrences of tako-tsubo cardiomyopathy in an emergency department of a community hospital. METHODS We report the in-hospital and long-term clinical course (7.5 years follow-up) of 25 consecutive tako-tsubo cardiomyopathy patients (mean age 66.8 ± 11.76 years; F/M: 21/4) admitted to a community hospital (referring population: 97,000 inhabitants). RESULTS The incidence rate of tako-tsubo cardiomyopathy was 0.03 cases per 1000 person-years; the prevalence was 3.0% among those with acute coronary syndrome and 7.6% among ST elevation myocardial infarction patients. Clinical presentations included mainly chest pain (n = 16, 64%) and dyspnea (n = 3, 12%). Precipitating conditions were emotional (n = 10, 40%), physical stress (n = 5, 20%) or both (n = 1, 4%); no stressors were recorded in nine patients (36%). Two patients died during hospitalization (8%). At the end of follow-up (mean time: 960.24 ± 724.34 days), all patients (n = 23) were alive and no major cardiovascular events were observed. Five patients had recurrences (22%). The mean time of recurrence was 105.4 ± 82.92 days and the clinical presentation was less severe compared with the first event: ECG had less ST involvement, ejection fraction was higher and cardiac injury biomarkers were lower. CONCLUSIONS In our population incidence and prevalence of tako-tsubo cardiomyopathy among acute coronary syndrome patients, as well as the recurrence rate of tako-tsubo cardiomyopathy, were higher than previously reported, suggesting that probably this syndrome often passes undiagnosed.

Background Controversy still exists about the long-term cardiovascular effects of coffee consumption in hypertension. Methods The predictive capacity of coffee use for cardiovascular events (CVEs) was investigated in 1204 participants from the HARVEST, a prospective cohort study of non-diabetic subjects aged 18–45years, screened for stage 1 hypertension. Subjects were grouped into three categories of coffee drinking, non-drinkers (none), moderate drinkers (1 to 3cups/day) and heavy drinkers (4or more cups/day). Multivariate Cox proportional hazards models were developed adjusting for possible confounding variables and risk factors. Results During a median follow-up of 12.6years, CVEs were developed by 60 participants. CVEs were more common among coffee drinkers than abstainers (abstainers, 2.2%; moderate drinkers, 7.0%; heavy drinkers, 14.0%; p for trend=0.0003). In a multivariable Cox regression model, coffee use was a significant predictor of CVE in both coffee categories, with a hazard ratio of 2.8 (95% CI, 1.0–7.9) in moderate coffee drinkers and of 4.5 (1.4–14.2) in heavy drinkers compared to abstainers. After inclusion of change in body weight (p=ns), incident hypertension (p=0.027) and presence of diabetes/prediabetes (p=ns) at follow-up end, the association with CVE was attenuated but remained significant in heavy coffee drinkers (HR, 95% CI, 3.4, 1.04–11.3). Conclusions These data show that coffee consumption increases the risk of CVE in a linear fashion in hypertension. This association may be explained in part by the association between coffee and development of hypertension. Hypertensive patients should be discouraged from drinking coffee.

The aim of this study was to investigate the effect of cigarette smoking on peripheral and central blood pressure (BP) in a group of young stage I hypertensives. A total of 344 untreated subjects from the HARVEST study were examined (mean age 37±10 years). Patients were divided into three groups based on smoking status: non-smokers, light smokers (⩽5 cigarettes/day) and moderate-to-heavy smokers (>5 cigarettes/day); and into three groups by age: 18–29, 30–39 and ⩾40 years. Central BP measurements and augmentation index (AIx) were calculated from brachial pressure waveform, with applanation tonometry, by means of the Specaway DAT System plus a Millar tonometer. The central waveform was derived from peripheral BP using the same software system of the SphygmoCor System pulse wave analysis. In addition, two indirect measurements of arterial stiffness were calculated: pulse pressure (PP) and systolic BP amplification. Central systolic BP and PP were higher in smokers than in non-smokers (systolic BP: 121.9±13.1 mmHg in non-smokers, 127.2±16.5 mmHg in light smokers, 126.7±15.3 mmHg in those who smoked >5 cigarettes/day, p=0.009; PP: 37.7±9.8 mmHg, 41.5±13.1 mmHg, 41.9±10.5 mmHg, respectively, p=0.005). Lower systolic BP amplification ( p

Background: The prion diseases are characterized by sleep disruption, with FFI typically characterized also by severe autonomic dysfunction and sympathetic hyperactivity. We report the results of an extensive neurophysiological and autonomic assessment in a CJD patient carrying the D178 mutation with the uncommon homozygosity for valine at codon 129, mutation with long disease duration. Results: A 47years old female presented with a memory impairment followed by progressive cognitive deficits and ataxia. The clinical picture slowly worsened to a state of akinetic mutism in about 2 years, and the patient died six years after the onset of symptoms. Repeated PSG and long-term actigraphic recordings, showed a peculiar, previously undescribed, pattern characterized by conservation of a rudimental circadian and ultradian rhythm, despite dramatic sleep micro-structure deterioration. We also observed a normal autonomic physiological response to orthostatic challenge and normal dynamic autonomic modulation during wake and sleep. The post-mortem brain pathology study, showed that neuronal loss was substantial in the cerebral cortex, diencephalon and thalami, but not in brainstem nuclei. Conclusions: We hypothesize that, despite a dramatic neurological picture (i.e. akinetic mutism) and a severe sleep micro-structural alteration, the persistence of an autonomic modulation and the persistence of a rudimental circadian and ultradian oscillation, are related to the relatively conserved anatomo-functional integrity of foundamental neuronal systems in the brainstem.

Glomerular hyperfiltration predicts development of nephropathy in hypertension but the factors responsible for increased glomerular filtration rate (GFR) are not well known. Aim of this study was to examine which clinical variables influence GFR in the early stage of hypertension.Participants were 1,106 young-to-middle-age hypertensive adults with creatinine clearance60 ml/min/1.73 m(2). Clinic and ambulatory blood pressures (BPs) were measured and the difference between clinic and 24-h systolic BP was defined as the white-coat effect (WCE). In 606 participants, 24-h urinary epinephrine and norepinephrine were also measured. Glomerular hyperfiltration, defined as a GFR ≥150 ml/min/1.73 m(2), was present in 201 subjects.Patients' mean age was 33.1 ± 8.5 years and office BP was 146 ± 10.5/94 ± 5.0 mm Hg. In multivariable linear regression, significant predictors of GFR were younger age (P0.0001), male gender (P0.0001), 24-h systolic BP (P = 0.0001), body mass (P0.0001), WCE (P = 0.02), log-epinephrine (P = 0.01), and coffee use (P0.01). In a logistic model, independent predictors of glomerular hyperfiltration were obesity (odds ratio, 95% confidence interval = 6.1, 3.8-9.8), male gender (2.9, 1.8-4.9), age33 years (2.1, 1.5-3.1), ambulatory hypertension (2.0, 1.4-3.0), WCE15 mm Hg (1.6, 1.1-2.3), heavy coffee use (2.0, 1.1-3.8), and epinephrine25 mcg/24 h (1.9, 1.2-3.1).The novel finding of this study is that hyper-reactivity to stress, as determined by urinary epinephrine level and WCE, and coffee use contribute to determining glomerular hyperfiltration in the early stage of hypertension. Our data may help to identify a subset of patients with glomerular hyperfiltration, who may be at increased risk of chronic kidney disease and may benefit from antihypertensive treatment.

Introduction: Controversy still exists about the long-term cardiovascular and metabolic effects of coffee consumption in hypertension. Aim of the study was to assess the predictive capacity of coffee use for cardiovascular events (CVE) and to ascertain whether the coffee-CVE association was mediated by the long-term effects of coffee on blood pressure (BP) and glucose metabolism. Design and methods: The analysis was made in 1201 participants from the HARVEST, a prospective cohort study of non-diabetic subjects aged 18-45 years, screened for stage 1 hypertension. BP was measured with ambulatory monitoring in all. Results: Among participants, 26.3% were abstainers, 62.7% were moderate coffee drinkers (1-3 cups/day) and 10.0% were heavy coffee drinkers (>3 cups/day). During a 12.5 year follow-up there were 60 CVE. In multivariable Cox analyses, coffee was a significant predictor of development of hypertension needing treatment with hazard ratios (HR) of 1.5 (CI,1.1-1.9) for heavy drinkers and 1.1 (0.9-1.3) for moderate drinkers compared to abstainers. Also, coffee was a predictor of future prediabetes with HRs of 2.0 (1-3-3.1) and 1.3 (0.9-1.7), in the heavy and moderate drinkers, respectively. In multivariable Cox analyses, including other lifestyle factors, age, sex, parental CVE, BMI, total cholesterol, 24h ambulatory BP, 24h ambulatory heart rate and follow-up changes in body weight, both coffee categories were independent predictors of CVE with HRs of 4.3 (1.3-13.9) for heavy coffee drinkers and 2.9 (1.04-8.2) for moderate drinkers. Inclusion of hypertension development in the regression attenuated the strength of the coffee-CVE association with HRs of 3.9 (1.2-12.5) for heavy and of 2.8 (0.99-7.8) for moderate drinkers. When future prediabetes was also incorporated, the relationship was of boderline significance for heavy coffee drinkers (HR, 3.2, 0.94-10.9) and was no longer significant for moderate drinkers (HR, 2.3, 0.8-6.5). Conclusions: Coffee use is linearly associated with increased risk of CVE in stage 1 hypertension. The effect of coffee on CVE seems to be at least partially mediated by its long-term effects on BP and glucose metabolism. Coffee consumption should be reduced in young-to-middle-age patients with hypertension.

Abnormal vascular reactivity contributes to the pathophysiology of hypertension and hypertension-related organ damage. As the dietary content of fatty acids may affect the vascular responses, we investigated the relationship of endothelium-independent and endothelium-dependent vasodilation with the fatty acid composition of red blood cell (RBC) membranes in hypertension.In 45 uncomplicated hypertensive patients, we measured the content of fatty acids in RBC membrane as a marker of dietary intake of fatty acids, and the vasodilatory response of the brachial artery to both nitrate-donor compound (nitrate-mediated vasodilation, NMD) and postischemic reactive hyperemia (flow-mediated vasodilation, FMD).Baseline diameter of the brachial artery was significantly lower and vasodilatory response to NMD was significantly greater in patients with RBC membrane polyunsaturated-to-saturated fatty acid (PUFA/SFA) ratio above the median of the distribution than in patients with PUFA/SFA ratio below the median, whereas no difference was observed in FMD. n-3 PUFA and n-6 PUFA content, and the PUFA/SFA ratio of RBC membranes were related inversely with brachial artery diameter and directly with maximal NMD, whereas no relationship of fatty acid components of RBC membrane with FMD was observed. Multivariate analysis that included demographic, anthropometric, clinical, and biochemical variables indicated that the RBC membrane PUFA/SFA ratio was an independent determinant of brachial artery diameter and NMD response.The endothelium-independent brachial artery vasodilation is independently related to the PUFA content of RBC membranes in patients with hypertension. This suggests the possible benefits of PUFA-enriched diets on the regulation of vascular tone and blood pressure in these patients.

Background Conflict still exists over whether patients with white-coat hypertension are at increased risk of developing target organ damage compared with normotensive individuals. Methods We studied vascular distensibility in 117 young-to-middle age patients with white-coat hypertension, 174 patients with sustained hypertension, and 51 normotensive controls. To obtain a measure of compliance, a model was used that divides the total systemic compliance into large artery (C 1 ) and small artery (C 2 ) compliance. With this aim, radial arterial pulse waves were recorded with a tonometer sensor array by means of an HDI CR2000 device (Eagan, Minnesota, USA). Moreover, pulse wave velocity and the augmentation index were measured using the Specaway DAT system (St Pauls, Sydney, Australia). Results Patients with sustained hypertension had a greater body mass index than patients with white-coat hypertension (P=0.04) or the normotensive individuals (P=0.01). C 1 and C 2 were decreased in the two hypertensive groups as compared with those in the normotensive group (P=0.0002 and 0.03, respectively, versus sustained hypertension; P=0.00007 and 0.0004, respectively, versus white-coat hypertension). Pulse wave velocity and aortic augmentation index were increased in the white-coat hypertension patients compared with the normotensive individuals (P= 0.02 and 0.004, respectively). Aortic augmentation index (P= 0.008) but not pulse wave velocity was increased in the sustained hypertensive patients compared with that in the normotensive individuals. All indexes of arterial distensibility were similar in the two hypertensive groups. Conclusions Indexes of arterial distensibility are impaired in the white-coat hypertensive group and similar to those in the sustained hypertensive group, indicating that early changes in the arterial wall can occur in white-coat hypertension. This may account for the higher risk of stroke that has been described in this condition.

Background: Increased carotid intima media thickness (CIMT) is frequently associated with established modifiable and non-modifiable cardiovascular risk factors, and is thought to be an independent predictor of ischemic cerebrovascular and cardiac events. The presence of carotid plaque is considered an established feature of atherosclerosis. There exist few longitudinal data on the predictive role of CIMT in the occurrence of carotid plaque. Methods: We restudied the survivors of a cohort of the San Daniele Project, a large randomized general population study, investigated in 1990 regarding the prevalence and determinants of carotid atherosclerosis. Using ultrasonography, we determined in 1,193 subjects (548 men and 645 women), the common carotid IMT and the presence of non-stenotic and stenotic plaque. Results: In 795 subjects without plaques or previous ischemic events at baseline, we found in multivariate analysis that CIMT ≧1 mm, age, hypertension and history of smoking are significant predictive elements of the occurrence of a new carotid plaque. The incremental probability of plaque occurrence is greater in midlife. CIMT and age are the most predictive risk factors with ORs of 3.66 (95% CI 1.4–9.4) and 3.02 (95% CI 2.4–3.7), respectively. The ORs for hypertension and smoking account for 1.5 (95% CI 1.1–3.4) and 1.7 (95% CI 1.1–2.8), respectively. Conclusions: Age, hypertension, history of smoking and B-mode detection of CIMT increases in subjects without carotid atherosclerosis and free of previous vascular events predict the occurrence of carotid atherosclerotic plaque.

Little is known about the clinical significance of isolated ambulatory hypertension, a condition characterized by low office but elevated ambulatory blood pressure. This study aimed to investigate the prevalence and the predictive value of isolated ambulatory hypertension diagnosed after 3 months of observation for the development of sustained hypertension within a cohort of 871 never-treated stage-1 hypertensive subjects. The study end point was progression to more severe hypertension and need of antihypertensive medication. In 244 subjects (28%), clinic blood pressure declined to P P =0.02) increase in the risk of reaching the end point in comparison with the nonhypertensive subjects. Final ambulatory systolic blood pressure was also higher in the former than the latter ( P =0.03). Our results indicate that among subjects screened for stage 1 hypertension, individuals with isolated ambulatory hypertension after 3 months of observation have increased risk of developing sustained hypertension in later life compared with subjects in whom both clinic and ambulatory blood pressures are normal.