Instability of Healthy Overweight and Obesity Phenotypes over the Long Term in Young Participants in the HARVEST Study: Influence of Sex.

BACKGROUND: Whether healthy metabolic status is stable or only temporary is still controversial. The aim of the present study was to determine the frequency of the transition from metabolically healthy to metabolically unhealthy status, or vice versa, over the long term. METHODS: We examined 970 individuals of 18 to 45 years of age. The participants' mean age was 33.1 ± 8.6 years and mean BP was 145.5 ± 10.6/93.5 ± 5.7 mmHg. Participants were classified into four groups according to whether they had normal weight or overweight/obesity (OwOb) and were metabolically healthy or unhealthy. After 7.5 years, 24.3% of men and 41.9% of women in the metabolically healthy normal-weight group remained metabolically healthy (p < 0.0001). Among the metabolically healthy OwOb participants, 31.9% remained metabolically healthy, with a similar frequency in men and women. However, more OwOb women (19.1%) than men (5.7%) achieved normal weight (p < 0.0001). Among the metabolically unhealthy OwOb subjects, 81.8% of men and 69.3% of women remained metabolically unhealthy, 7.4% of men and 12.0% of women transitioned to OwOb healthy status, and 10.7% of men and 18.7% of women achieved normal weight (men versus women, p < 0.0001). Predictors of transition to unhealthy status were high BP, high BMI, and smoking. Male sex was a borderline predictor of progression to unhealthy status in OwOb participants (p = 0.073). CONCLUSION: These data show that metabolically healthy status is a highly unstable condition in both normal-weight and OwOb individuals. The impairment of metabolic status was more frequent in men than in women. Lifestyle counseling produced beneficial effects in almost one-third of metabolically unhealthy OwOb women and in less than one-fifth of men.

Short-term blood pressure variability outweighs average 24-h blood pressure in the prediction of cardiovascular events in hypertension of the young.

OBJECTIVE: 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. METHODS: We performed 24-h ambulatory BP monitoring in 1206 participants aged 33.1 ±â€Š8.5 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. RESULTS: During 15.4 ±â€Š7.4 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. CONCLUSION: 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.

Clinical characteristics and risk of hypertension needing treatment in young patients with systolic hypertension identified with ambulatory monitoring.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Low night-time heart rate is longitudinally associated with lower augmentation index and central systolic blood pressure in hypertension.

PURPOSE: 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). METHODS: 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. RESULTS: In fully adjusted models, baseline night-time HR was a significant positive predictor of AIx (p < 0.001) and central BP (p = 0.014) measured 8 years later. Adjusted office HR measured at the time of arterial distensibility assessment was inversely correlated with AIx (p = 0.001) a relationship which was attenuated after physical activity (p = 0.004) and left ventricular ejection time (p = 0.015) were taken into account. In addition, office HR was inversely correlated with central BP (p = 0.039) a relationship which was no longer significant after physical activity and ejection time were accounted for. CONCLUSIONS: These data show that HR measured during sleep is longitudinally associated with AIx and central BP. Thus, low HR in the long term may have beneficial effects on central hemodynamics and the wall properties of the large arteries in hypertension.

Office Pulse Pressure Is a Predictor of Favorable Outcome in Young- to Middle-Aged Subjects With Stage 1 Hypertension.

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<0.001), physical activity (P=0.003), heart rate (P<0.001), systolic white coat effect (P<0.001), and stroke volume (n=829; P<0.001). During follow-up, 65.1% of participants developed hypertension requiring pharmacological treatment and 5.1% experienced a cardiovascular event. Participants in the highest pulse pressure tertile had a reduced risk of incident hypertension compared with those of the bottom tertile (hazard ratio, 0.75; 95% confidence interval, 0.62-0.91; 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<0.001). In addition, participants in the highest pulse pressure tertile had a reduced risk of cardiovascular events (0.35; 0.17-0.73; 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 <45 years, only mean blood pressure is a predictor of adverse outcome whereas high pulse pressure even carries a reduced risk.

Alcohol Intake More than Doubles the Risk of Early Cardiovascular Events in Young Hypertensive Smokers.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Coffee consumption and risk of cardiovascular events in hypertensive patients. Results from the HARVEST.

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.

Association of coffee consumption and CYP1A2 polymorphism with risk of impaired fasting glucose in hypertensive patients.

Whether and how coffee use influences glucose metabolism is still a matter for debate. We investigated whether baseline coffee consumption is longitudinally associated with risk of impaired fasting glucose in a cohort of 18-to-45 year old subjects screened for stage 1 hypertension and whether CYP1A2 polymorphism modulates this association. A total of 1,180 nondiabetic patients attending 17 hospital centers were included. Seventy-four percent of our subjects drank coffee. Among the coffee drinkers, 87% drank 1-3 cups/day (moderate drinkers), and 13% drank over 3 cups/day (heavy drinkers). Genotyping of CYP1A2 SNP was performed by real time PCR in 639 subjects. At the end of a median follow-up of 6.1 years, impaired fasting glucose was found in 24.0% of the subjects. In a multivariable Cox regression coffee use was a predictor of impaired fasting glucose at study end, with a hazard ratio (HR) of 1.3 (95% CI 0.97-1.8) in moderate coffee drinkers and of 2.3 (1.5-3.5) in heavy drinkers compared to abstainers. Among the subjects stratified by CYP1A2 genotype, heavy coffee drinkers carriers of the slow *1F allele (59%) had a higher adjusted risk of impaired fasting glucose (HR 2.8, 95% CI 1.3-5.9) compared to abstainers whereas this association was of borderline statistical significance among the homozygous for the A allele (HR 1.7, 95% CI 0.8-3.8). These data show that coffee consumption increases the risk of impaired fasting glucose in hypertension particularly among carriers of the slow CYP1A2 *1F allele.

Regular physical activity is associated with improved small artery distensibility in young to middle-age stage 1 hypertensives.

The aim of the present study was to investigate the association of physical activity with small artery elasticity in the early stage of hypertension. We examined 366 young-to-middle-age stage 1 hypertensives (mean blood pressure 145.6±10.3/92.5±5.8 mmHg), divided into two categories of physical activity, sedentary (n=264) and non-sedentary (n=102) subjects. The augmentation index was measured using the Specaway DAT System. Small artery compliance (C2) was measured by applanation tonometry, at the radial artery, with an HDI CR2000 device. After 6 years of follow-up, arterial distensibility assessment was repeated in 151 subjects. Heart rate was lower in active than in sedentary subjects (71.2±8.9 vs 76.6±9.7 bpm, p<0.001). After adjusting for age, sex, heart rate, smoking, and blood pressure, C2 was higher (8.0±2.6 vs 6.4±3.0 ml/mmHg × 100, p=0.008) in non-sedentary than in sedentary patients. The augmentation index was smaller in the former (8.8±20.1 vs 16.8±26.5%, p=0.044) but the difference lost statistical significance after further adjustment for blood pressure. After 6 years, C2 was still higher in the non-sedentary than sedentary subjects. In addition, an improvement in the augmentation index accompanied by a decline in total peripheral resistance was found in the former. These data show that regular physical activity is associated with improved small artery elasticity in the early phase of hypertension. This association persists over time and is independent of blood pressure and heart rate.

Central blood pressure is an independent predictor of future hypertension in young to middle-aged stage 1 hypertensives.

AIM: The aim of the present study was to evaluate the association of central blood pressure (BP) with organ damage and risk of future hypertension in a cohort of young to middle-aged patients. METHODS: We studied 305 subjects screened for stage 1 hypertension to determine which subjects developed hypertension needing therapy according to current guidelines. Central BP was obtained from radial artery tonometry. Organ damage was the presence of left ventricular hypertrophy and/or microalbuminuria. RESULTS: In a multiple logistic regression including ambulatory 24-h BP, central mean BP was associated with presence of end-organ damage (p = 0.003). In the subjects divided according to whether their central mean BP was above or below the median, subjects with high central mean BP presented an earlier impairment of arterial distensibility and developed sustained hypertension more frequently compared with those with low central mean BP (p < 0.001). In logistic analyses, central mean BP was an independent predictor of future hypertension (p < 0.001) and remained associated with outcome when 24-h BP was included in the same model (p = 0.006). CONCLUSIONS: In young to middle-aged subjects in the early stage of hypertension, central mean BP is a useful adjunct to brachial BPs to better define the individual risk profile.

Relationship between GFR and albuminuria in stage 1 hypertension.

BACKGROUND AND OBJECTIVES: Whether glomerular hyperfiltration is implicated in the development of microalbuminuria in hypertension is not well known. This prospective study investigated the relationship between changes in GFR and microalbuminuria in hypertension. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study assessed 534 stage 1 hypertensive participants from the Hypertension and Ambulatory Recording Venetia Study (n=386 men) without microalbuminuria at baseline, who were recruited from 1990 to 1995 and followed for a median of 8.5 years. Mean age was 33.9±8.6 years and mean BP was 146.6±10.5/94.0±5.0 mmHg. Creatinine clearance and 24-hour urinary albumin were measured at study entry and end. Participants were defined as normofilterers (normo) or hyperfilterers (hyper) according to whether GFR was <150 or ≥150 ml/min per 1.73 m(2), respectively. Participants were divided into four groups based on GFR changes from baseline to follow-up end: normo→normo (n=395), normo→hyper (n=31), hyper→hyper (n=61), and hyper→normo (n=47). RESULTS: Microalbuminuria progressively increased across the four groups and was 5.3% in normo→normo, 9.7% in normo→hyper, 16.4% in hyper→hyper, and 36.2% in hyper→normo (P<0.001). This association held true in a multivariable logistic regression in which several confounders, ambulatory BP, and other risk factors were taken into account (P<0.001). In particular, hyperfilterers whose GFR decreased to normal at study end had an adjusted odds ratio of 7.8 (95% confidence interval, 3.3-18.2) for development of microalbuminuria compared with participants with normal GFR throughout the study. CONCLUSIONS: These data support the hypothesis for a parabolic association between GFR and urinary albumin in the early stage of hypertension.

Factors associated with glomerular hyperfiltration in the early stage of hypertension.

BACKGROUND: 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. METHODS: Participants were 1,106 young-to-middle-age hypertensive adults with creatinine clearance >60 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. RESULTS: 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 (P < 0.0001), male gender (P < 0.0001), 24-h systolic BP (P = 0.0001), body mass (P < 0.0001), WCE (P = 0.02), log-epinephrine (P = 0.01), and coffee use (P < 0.01). 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), age <33 years (2.1, 1.5-3.1), ambulatory hypertension (2.0, 1.4-3.0), WCE >15 mm Hg (1.6, 1.1-2.3), heavy coffee use (2.0, 1.1-3.8), and epinephrine >25 mcg/24 h (1.9, 1.2-3.1). CONCLUSIONS: 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.

Cystatin C as predictor of microalbuminuria in the early stage of hypertension.

BACKGROUND/AIMS: Predictors of microalbuminuria in the early stage of hypertension are not well known. We did a prospective study to investigate whether glomerular hyperfiltration assessed from serum cystatin C predicts development of microalbuminuria in hypertension. METHODS: We assessed 101 treatment-naive subjects screened for stage 1 hypertension and followed-up for a median 3.1 years. Cystatin C was measured at entry and glomerular filtration rate was estimated using the Hoek formula (CystGFR). Urinary albumin and ambulatory blood pressure were measured at entry and during the follow-up. RESULTS: Subjects in the top CystGFR tertile (>115 ml/min/1.73 m(2)) were leaner (p = 0.002) and developed microalbuminuria more frequently (p = 0.02) than the rest of the group. In univariate Cox regression, CystGFR was associated with future microalbuminuria (hazard ratio, 1.06, 95% confidence interval (CI), 1.02-1.10, p = 0.001). After controlling for baseline albumin excretion rate and several confounders, CystGFR remained a significant predictor of microalbuminuria development (hazard ratio, 1.19, 95% CI, 1.03-1.37, p = 0.019). The association between future microalbuminuria and creatinine clearance or glomerular filtration rate estimated with the Cockroft-Gault or the Modification of Diet in Renal Disease formula did not attain the level of statistical significance in this sample. CONCLUSIONS: The present findings indicate that CystGFR is more sensitive than creatinine clearance or estimated glomerular filtration rate for predicting microalbuminuria development in the early stage of hypertension and confirm that hyperfiltration precedes microalbuminuria in this clinical entity.

Heart rate as a predictor of development of sustained hypertension in subjects screened for stage 1 hypertension: the HARVEST Study.

OBJECTIVE: Whether heart rate predicts the development of sustained hypertension in individuals with hypertension is not well known. We carried out a prospective study to investigate whether clinic and ambulatory heart rates assessed at baseline and changes in clinic heart rate during 6 months of follow-up were independent predictors of subsequent blood pressure (BP). METHODS: The study was conducted in a cohort of 1103 white, stage 1 hypertensive individuals from the HARVEST study, never treated for hypertension and followed-up for an average of 6.4 years. Data were adjusted for baseline BP, age, sex, body fatness, physical activity habits, parental hypertension, duration of hypertension, cigarette smoking, alcohol consumption, and change of body weight from baseline. RESULTS: Clinic heart rate and heart rate changes during the first 6 months of follow-up were independent predictors of subsequent systolic blood pressure (SBP) and diastolic blood pressure (DBP) regardless of initial BP and other confounders (all P < 0.01). A significant interaction was found between sex (male) and baseline resting heart rate on final SBP (P = 0.017) and DBP (P < 0.001). The ambulatory heart rate and the heart rate white-coat effect did not add prognostic information to that provided by the clinic heart rate. Patients whose heart rate was persistently elevated during the study had a doubled fully adjusted risk (95% confidence interval 1.4-2.9) of developing sustained hypertension in comparison with subjects with a normal heart rate. CONCLUSIONS: Baseline clinic heart rate and heart rate changes during the first few months of follow-up are independent predictors of the development of sustained hypertension in young persons screened for stage 1 hypertension.

Microalbuminuria, renal function and development of sustained hypertension: a longitudinal study in the early stage of hypertension.

OBJECTIVE: Microalbuminuria (MA) is a marker of adverse outcome in hypertension. The aim of this study was to investigate the association of MA with cardiovascular risk factors and glomerular hyperfiltration in the early stage of hypertension and to assess its predictive value for the development of sustained hypertension requiring antihypertensive treatment. DESIGN AND PARTICIPANTS: We studied 1041 young stage 1 hypertensive subjects. Study variables were 24-h ambulatory blood pressure and heart rate, anthropometric measures, metabolic variables, creatinine clearance and lifestyle factors analyzed as a function of ascending urinary albumin measured from 24-h collections. Subjects were followed until they developed sustained hypertension and were eligible for antihypertensive medication according to current guidelines. SETTING: Seventeen outpatient clinics in Italy. RESULTS: Eighty-five percent of the subjects were normoalbuminuric, 9% had borderline MA, and 6% had overt MA. No between-group differences were found for age, body mass index, heart rate, lifestyle factors and biochemistry in both genders. Creatinine clearance was greater in the subjects with overt MA and borderline MA than in the normoalbuminuric subjects (P = 0.003 and 0.011, respectively). In a two-way ANCOVA, microalbuminuric subjects both with hyperfiltration (P < 0.001) and with normal filtration (P = 0.04) had higher 24-h systolic blood pressure than subjects with normoalbuminuria and normal filtration. In a Cox analysis, neither MA nor hyperfiltration were significant predictors of development of sustained hypertension. CONCLUSION: MA is not associated with an adverse metabolic risk profile in the early stage of hypertension. MA is associated with greater hemodynamic load and with glomerular hyperfiltration in this clinical setting, but does not help in predicting those subjects destined to develop sustained hypertension requiring antihypertensive therapy.