|Home | About | Journals | Submit | Contact Us | Français|
Prehypertension (defined by JNC-7) frequently evolves to hypertension (HTN) and increases cardiovascular risk. It is unclear whether metabolic and/or cardiac characteristics favor development of HTN in prehypertensive subjects. We evaluated baseline anthropometric, laboratory and echocardiographic characteristics of 625 untreated prehypertensive participants in the Strong Heart Study (SHS), without prevalent cardiovascular disease (63% women; 22% diabetes; mean age 59±7 years) to identify predictors of 4-year incidence of hypertension. Diabetes was assessed by ADA criteria and diabetes-specific definition of hypertension was used. Four-year incidence of HTN was 38%. Incident HTN was independently predicted by baseline systolic blood pressure (OR= 1.60 per 10 mmHg, 95% CI=1.30-2.00; p<0.0001), waist circumference (OR=1.10 per 10 cm, 95% CI=1.01-1.30; p=0.04) and diabetes (OR= 2.73, 95% CI=1.77-4.21; p<0.0001), with no significant effect for age, gender, HbA1c, HOMA index, CRP, fibrinogen, LDL-HDL cholesterol, tryglicerides, plasma creatinine or urine albumin/creatinine. Higher left ventricular mass index (OR=1.15 per 5 g/m2.7, 95% CI=1.01-1.25; p= 0.03) or stroke volume index (OR=1.25 per 5 ml/m2.04, 95% CI=1.10-1.50; p= 0.03) were also identified, together with baseline systolic blood pressure and presence of diabetes, as independent predictors of incident HTN, without additional predictive contribution from other anthropometric, metabolic or echocardiographic parameters (all p>0.10). Thus, progression to HTN in 38% of SHS pre-hypertensive participants could be predicted by higher left ventricular mass and stroke volume in addition to baseline systolic blood pressure and prevalent diabetes.
Elevated blood pressure (BP) is a major risk factor for cardiovascular (CV) disease (1-3). The Framingham Heart Study showed that 4-year incidence of hypertension (HTN) was higher in participants with high-normal BP than with normal BP (4). There is substantial evidence that systolic BP is continuously related to adverse outcome and that the risk of CV disease extends below 140 mmHg, so that “non hypertensives” (<140/90mm Hg) also harbor increased risk proportional to their BP level (2,5,6). Accordingly, the 7th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7), acknowledging the continuous relationship between BP and CV disease, introduced the new category of “prehypertension” (preHTN), defined as systolic BP of 120 to139 mm Hg and/or diastolic BP of 80 to 89 mm Hg (7). Based on JNC-7, preHTN requires attention and health-promoting lifestyle modifications to prevent progression to HTN (7). PreHTN is often associated with other CV risk factors such as obesity, insulin resistance, diabetes, dyslipidemia and the phenotypes of metabolic syndrome (8-9), resulting in early vascular abnormalities and progressive atherosclerosis (10). However, it remains uncertain whether prehypertensive BP by itself or other associated risk factors is more important in determining the best preventive strategy (11).
A high-risk metabolic profile associated with abnormal cardiac geometry and function is often found in prehypertensive individuals (12-14), even at a young age (15-16). Obesity, inflammation, metabolic risk factors, including dyslipidemia and impaired glucose turnover, have vascular and hemodynamic effects that may contribute to the progression to arterial HTN (17-21). In addition, cardiac geometry and function might also have some impact on the progression from preHTN to overt HTN (22-25). It is still unclear whether phenotypes at higher risk of developing HTN are already recognizable in preHTN. Accordingly the present analysis was performed to identify metabolic and cardiovascular predictors of incident arterial hypertension in prehypertensive participants of the Strong Heart Study (SHS) cohort, a population with high prevalence of diabetes and obesity.
The Strong Heart Study (SHS) is a population-based cohort study, designed to estimate cardiovascular disease mortality and morbidity and the prevalence of cardiovascular disease and risk factors in American Indians. A total of 4549 American Indian men and women, aged 45 to 74 years, from 3 communities in Arizona, 7 in Southwestern Oklahoma and 3 in South and North Dakota, participated the SHS first examination from 1989 to 1991 (Phase I). The cohort was followed and reexamined in 1993–1995 (Phase II) and 1998–1999 (Phase III), respectively. SHS used a standard methodology at each examination, including standardized anthropometric, clinical and laboratory measurements. A detailed description of the study design and methods of the SHS has been extensively reported (26-30). The Phase II-SHS exam evaluated 89% of all surviving members of the original cohort and included also standard Doppler-echocardiogram. The 2nd SHS exam was therefore used as baseline for the present analysis.
Incident HTN was assessed at the time of the 3rd SHS exam (Phase III), 4 years later. For the purpose of this study, we selected participants with baseline preHTN who also participated at the follow-up re-examination. PreHTN was defined by JNC-7 guidelines: systolic BP of 120 to139 mmHg and/or diastolic BP of 80 to 89 mmHg in participants without diabetes. In participants with diabetes, preHTN was defined as systolic BP between 120 and 129 mmHg and diastolic BP<80 mmHg. Participants with diabetes and systolic BP≥130 mmHg and/or diastolic BP≥80 mmHg were considered HTN and excluded (7). Exclusion criteria were: baseline use of antihypertensive drugs, presence of normal BP (systolic BP<120 and diastolic BP<80 mmHg) or HTN (defined as: systolic BP≥140 and/or diastolic BP≥ 90 mmHg [or systolic BP≥ 130 mmHg and/or diastolic BP≥80 mmHg in diabetic] or current antihypertensive treatment) (7), significant aortic and/or mitral valvular disease or prevalent CV disease. Prevalent CV disease (stroke, TIA, congestive heart failure, myocardial infarction or other manifestations of coronary heart disease) was adjudicated by the Strong Heart Study Mortality and Morbidity Committees, using specified criteria for causes of fatal and nonfatal CV events, as previously reported (31).
Four-year incidence of HTN in participants with initial preHTN was evaluated at the time of the 3rd SHS exam, 46±9 months after the baseline visit. Institutional Review Boards of the participating institutions and the participating tribes approved the study.
During both II and III Phase-SHS exams, following standardized collection of data was performed to each participants. Clinical examinations and collection of blood samples after a 12-hour fast were done in the morning at local Indian Health Service hospitals and clinics by the study staff and consisted of a personal interview and a physical examination. Questionnaires administered during the interview assessed demographic information, medical history, tobacco and medication use. Physical examination included measures of weight, height, body circumferences and blood pressure, examination of the heart, lungs, pulses, bruits and a 12-lead resting electrocardiogram (ECG). Three consecutively measurements of systolic and diastolic blood pressures (1st and 5th Korotkoff sounds) in a single office visit were taken on the right arm with an appropriately sized cuff using a Baum mercury sphygmomanometer (W.A. Baum Co) after the participant had been resting in a seated position for 5 minutes. The average of the 2nd and 3rd systolic and diastolic blood pressure measurements were used in the analysis (26). Laboratory tests were performed by standard methods (30).
Diabetes was classified by 1997 American Diabetes Association recommendations (32). HOMA-index was used to estimate insulin resistance (33). Obesity was identified based on 1998 NIH guidelines (34), and waist circumference was used as an indicator of central adiposity (34). Glomerular filtration rate (GFR) was estimated by the simplified MDRD formula (35). Albuminuria was measured on a single spot urine sample and was expressed in relation to grams of urinary creatinine (mg/g) (27). Albuminuria was defined as urinary albumin/creatinine ratio ≥30 mg/g. Renal dysfunction was defined as GFR <60 ml/min/1.73m2 and/or the presence of albuminuria (36). Incidence of hypertension was defined by the evidence of systolic BP ≥140 mmHg and/or diastolic BP≥ 90 mmHg (or BP ≥130/80 mmHg in diabetic participants), and/or current antihypertensive therapy. Quality control measures for blood pressure include repeated measures, observation of data collection by supervisors and a sphygmomanometer maintenance program. The Coordinating Center performs quarterly quality analysis of blood pressure data, comparing means for each technician with the values for all technicians, in each center (26).
Primary echocardiographic measurements were taken from M-mode tracings or 2-D parasternal long-axis images, according to standardized methods (37-38). To evaluate concentricity of LV geometry, myocardial thickness (posterior wall plus septum) was divided by minor axis (diameter) to generate relative wall thickness (RWT) (39). RWT was normalized for age (RWTa), using a previous reported equation (40). LV concentricity was defined as RWTa greater than 0.40 (40). LV mass (LVM) was calculated by a necropsy-validated formula (41) and was normalized for height in m2.7(42). LV hypertrophy (LVH) was defined by sex-specific partition values (>46.7 g/m2.7 for women and >49.2 g/m2.7 for men) (43). Stroke volume (SV) was computed as the difference between end-diastolic and end-systolic volumes by the z-derived method (44) and used as an indicator of LV volume load. Cardiac output (CO) was calculated as the product of stroke volume and heart rate; SV and CO were also normalized for height to allometric powers (i.e. height2.04 and height1.83, respectively ). Stroke work, a measure of cardiac workload, was calculated as systolic blood pressure in mm Hg (pressure load) × stroke volume in milliliters per beat (volume load) and converted into gram-meters per beat by multiplying by the conversion factor 0.014. The ratio between pulse pressure and SV (PP/SV) was used as a raw indicator of total arterial stiffness.
Data were analyzed using SPSS 12.0 software (SPSS, Chicago, IL) and expressed as mean ± one standard deviation. Variables without normal distribution are presented as median and interquartile range, and their logarithmic values were used for parametric statistics. Indicator variables were included in all multivariate analyses for the three different field centres. Baseline characteristics and potential metabolic predictors of arterial hypertension were compared between groups with or without incident hypertension by t-test or χ2 for categorical variables. Repeated measures analysis of variance was performed in order to evaluate modifications of continuous variables over time.
All variables associated with follow-up incident HTN in the above exploratory analyses were tested in stepwise forward binary logistic regression models using a building procedure with primary block formed by age, gender, center, systolic BP and waist girth and a second block with metabolic parameters, including lipid profile, glucose status, inflammation markers and indicators of renal function (p-to-enter<0.05 and p-to-remove ≥0.1). Thus, echocardiographic variables were alternatively forced to evaluate whether or not they added to the prediction of HTN. Interaction terms between diabetes and both systolic BP and LVM were also generated and tested. Two-tailed p<0.05 was considered statistically significant.
Among the 2894 participants without prevalent CV disease at the time of the Phase II-SHS exam, 625 (22%) had preHTN (59±7 years; 394 [63%] women). Prevalence of CV risk factors was high: 22% had diabetes, 55% were obese, 33% were current smokers; 17% had LV hypertrophy and 8% had concentric LV geometry. Renal dysfunction was detected in 9% based on decreased GFR (GFR<60 ml/min/1.73 m2) and in 20% based on the presence of albuminuria.
At the follow-up (3rd SHS exam), arterial hypertension had developed in 235 (38%) of 625 initially prehypertensive participants. At baseline, participants developing HTN during follow-up had higher body mass index, waist circumference, systolic BP and pulse pressure, and were more frequently diabetic than those who did not (0.03 ≤ p< 0.0001). No significant differences were found in gender distribution, smoking status, age, diastolic BP or heart rate (Table1). Incidence of HTN was 53% among diabetic and 33% among non-diabetic participants (p<0.0001).
Table 2 shows that participant with incident HTN had higher plasma glucose, insulin resistance and HbA1c than participants without follow-up HTN (all p<0.001). These differences were due to the greater prevalence of diabetes among participants developing HTN since no difference was found among preHTN participants without baseline diabetes (data not shown). Compared to participants without incidence of HTN, participants developing HTN had higher levels of inflammatory markers, higher triglycerides and lower HDL cholesterol (all p<0.05), whereas no significant differences were found for LDL cholesterol or renal function.
Table 3 shows that participants developing HTN had higher baseline LV mass index, RWTa, SV index, stroke work and greater prevalence of LVH than those who did not (all p<0.05), whereas no significant differences were found for the other echocardiographic parameters. The incidence of HTN was higher in participants with initial LVH compared to those without LVH (50% versus 35% respectively, p=0.006),
After 4 years, development of arterial HTN was predicted by higher baseline systolic BP (OR= 1.60 per10 mmHg, 95% CI=1.30-2.00), presence of diabetes (OR= 2.73, 95% CI=1.77-4.21; both p<0.0001) and waist circumference (OR= 1.10 per 10cm, 95% CI=1.01-1.30; p=0.04) without significant effect for age, gender, HbA1c, HOMA index, CRP, fibrinogen, LDL or HDL cholesterol, tryglicerides, plasma creatinine or urine albumin/creatinine (p≥0.1).
When echocardiographic parameters were forced into the previous model, LV mass index (table 4a) provided additional, independent prediction for incident HTN (p=0.03). Similarly, risk of 4-year incidence HTN increased by 78% in the presence of baseline LVH (p=0.01, table 4b). In alternative models, SV index (table 4c) was also independently associated with incident HTN (p=0.03). No other echocardiographic variables showed significant predictive effect (p≥0.1). The interactions between diabetes and LV mass or systolic BP respectively for prediction of HTN were not significant (p≥0.1).
Among 625 participants with baseline pre-HTN, 86 (14%) showed normal BP at the follow-up examination. Compared to those who developed HTN, preHTN participants with follow-up normal BP had lower baseline waist circumference (104 ± 14 versus 108 ± 14, p=0.008). At follow-up, waist circumference of participants with regression to normal BP was also significantly lower compared to those with incident HTN and substantially decreased from baseline value (102 ± 14 versus 109 ± 14, respectively, all p=0.002). Compared to participants developing HTN, those becoming normotensive had lower baseline systolic BP (124± 4.7 versus 127 ± 5.9 mmHg, p=0.001), PP (50 ± 9.0 versus 53 ± 8.9 mmHg, p=0.01), LV mass index (38 ± 7.4 versus 42 ± 8.7 g/m2.7, p=0.002), SV index (25 ± 3.6 versus 26 ± 4.3 ml/beat/m2.04, p=0.004) and stroke work (121± 18 versus 132 ± 24 mmHg×ml, p=0.001). Higher baseline systolic BP (OR=0.92 per mmHg, 95% C.I. 0.87-0.97; p=0.002), LV mass index (OR=0.95 per g/m2.7, 95% C.I. 0.92-0.99; p=0.02) or SV index (OR=0.91per ml/beat/m2.04, 95% C.I. 0.84-0.98; p=0.01) were associated with lower likelihood of regression to normal BP, with no significant effect of age, gender, waist circumference, presence of diabetes and other metabolic or echocardiographic variables (all p>0.1).
This is the first prospective analysis to identify cardio-metabolic phenotypes associated with a higher risk of progression from preHTN to overt HTN in a population-based cohort, characterized by a high prevalence of diabetes and obesity and high incident rate of HTN. Our results show that previous evidence in normotensive individuals of the effect of baseline systolic BP on the probability of developing arterial hypertension (4,5,21) is also applicable in the setting of preHTN. In addition we provide evidence that, also in this setting, LV mass is a strong predictor of 4-year incident arterial hypertension, independent of other metabolic and anthropometric factors associated with incident HTN.
Increase LV mass in preHTN is possibly associated with greater daily hemodynamic load that could not be detected by office BP measurements. Pressure variability (e.g. increased BP fluctuations, failure of BP to “dip” at night, etc) or prolonged sustained exposure to higher BP during daily activities could explain the greater values of LV mass in many pre-hypertensive participants. Despite the standardized protocol used in SHS for measurements of BP (27), the true hemodynamic load cannot be captured by single office measurements. Similar to other epidemiological studies (8, 9, 14,17,18,19,46,47), classification of preHTN has been based on measurements of BP taken in a single session, and, therefore, there was a chance of misclassification of subjects with masked hypertension. Echocardiographic modifications in diabetic subjects with office preHTN and 24-h ABPM masked hypertension have been recently reported (48). Masked hypertension has been shown to be associated with significant target organ damage, such as increased LV mass (49,50). Progression of preHTN to HTN has been associated to increased arterial stiffness (18). In this study the ratio of pulse pressure to stroke volume was used as raw estimated of arterial stiffness. The possibility that the evolution from preHTN to HTN was sustained by progressive increase in arterial stiffness cannot be demonstrated in this study since baseline PP/SV was similar in groups with or without incident HTN and did not show a significant impact on prediction of HTN and because of lack of a control echocardiogram. However, pulse pressure was substantially increased at the time of the 3rd exam in participants developing HTN compared to those who did not (61 ± 16 versus 51 ± 10 mmHg, p<0.0001). A consistent increase in stroke volume at the 3rd exam to maintain PP/SV similar to baseline value was unlikely and therefore a consistent increase in arterial stiffness may be speculated.
Finally, in addition to the above scenario, similar to what is already reported in unselected populations (21-23) and in population samples with optimal BP (51), our study cannot exclude the possibility of reverse causation (i.e. LV mass as a factor determining evolution toward hypertension, through greater developed force), not necessarily alternative to the possibility that some or many of our participants had masked hypertension. Although prehypertensive participants of this study exhibited relatively high prevalence of baseline LVH (17%), reinforcing the possibility of prevalent masked hypertensive, several previous studies have reported association of preHTN with LVH (13-16). In the MONIKA study, the prevalence of LVH in preHTN was 21% (14), and similar prevalence of LVH was also reported in preHTN children and adolescents (16). Prevalence of LVH was more than 11% in adolescents and young prehypertensive SHS adults (15).
The evidence that, independently of cause-effect relationship, LV mass is a predictor of hypertension when the baseline variability of BP is constrained to the preHTN range and, therefore, substantially limited, is relevant. In addition, our results suggest that among adults with preHTN, the combination of initially higher systolic BP and LV mass offsets the effects of metabolic factors that others and we [17-21] have shown to be associated with the rise of BP over time, probably due to the progressive alteration of the arterial tree due to atherosclerosis. In the ATTICA study, Pitsavos et al (17) reported significant independent contribution of age, waist girth and inflammation markers in the progression from preHTN to HTN. Although we did not found any significant contribution of age in the risk of development of HTN, probably due to more limited age range in our population, similar to the ATTICA study, we found a significant association of higher waist girth and CRP with incident hypertension in univariate analysis, but their effect in the multivariate model was obscured by other cofactors, including LV mass index, suggesting that an increased LV mass might integrate at least part of the effect of alteration of body size on incident hypertension in this population with high prevalence of obesity. As a mirror of the phenotype predicting HTN, regression of BP to normal value was associated with lower baseline systolic BP and LV mass. The evidence that prehypertensive participants with regression to normal BP had lower baseline body size and significant reduction of waist girth during time, might reflect a better weight control and suggest improvement in dietary habits and possibly increase in physical activity, extending the established indications of lifestyle modifications for arterial hypertension to the management of preHTN.
Among the potential metabolic predictors of incident hypertension, diabetes emerged as the only major metabolic predictor. Association of preHTN with diabetes is known to markedly increase CV risk (9). Combination of diabetes with two other major predictors (systolic BP and LV mass index), strongly support the current guidelines recommendations for antihypertensive treatment of preHTN in these high risk patients (7,11).
Given the ethnic peculiarity of the SHS, these findings might not be necessarily generalizable and need to be verified in other populations with different genetic and environmental backgrounds, especially because algorithms for risk prediction might be substantially affected by prevalence and distribution of individual risk factors (52).
We provide evidence that initial systolic BP, diabetes and LV mass are predictors of 4-year incident arterial hypertension in a population-based sample with preHTN and high prevalence of CV risk factors. Results of the present study may help stratify risk associated with preHTN and suggest that particular attention should be paid to prehypertensive individuals with diabetes and/or increased LV mass.
There are implications of these findings for primary cardiovascular prevention. Hypertension is the leading risk factor for cardiovascular mortality and morbidity. Interventions to prevent development of arterial hypertension might help reducing cardiovascular risk and direct and indirect costs related to hypertension-related morbidity. The possibility of refining identification of preHTN phenotypes at high risk of future hypertension, by pooling metabolic and cardiac information, increases the chance to target preHTN individuals who might benefit from aggressive BP management, while reducing the possibility of over-treating patients with lower-risk cardiovascular phenotypes. Specifically, preHTN diabetic patients and/or those with increased LV mass are at high risk of hypertension and might be referred to more extensive clinical evaluation (ABPM) and possibly treated to prevent it. Our results also suggest that particular attention should be paid to force preHTN individuals to programs to decrease body weight to successfully prevent arterial hypertension. Further studies are warranted to examine the utility of echocardiography as an aid in the risk stratification of preHTN determining the need for antihypertensive therapy and to assess the effect of earlier intervention on the course of progression to hypertension.
The authors wish to thank the Indian Health Service, the Strong Heart Study participants, the participating tribal communities and the Strong Heart Study Center coordinators for their help in the realization of this project.
Sources of Fundings: This work has been supported by grants HL41642, HL41652, HL41654, HL65521 and M10RR0047-34 (GCRC) from the National Institutes of Health, Bethesda, Maryland, USA.
The views expressed in this paper are those of the authors and do not necessarily reflect those of the Indian Health Service.