Analysis of Recent Papers in Hypertension
Jan Basile, MD, Senior Editor

Authors

  • Michael J. Bloch MD,

    1. From the Division of General Internal Medicine/Division of Cardiology, University of Nevada School of Medicine, Reno, NV;1 the Risk Reduction Center, Saint Mary's Regional Medical Center, Reno, NV;2 the Primary Care Service Line, Ralph H. Johnson VA Medical Center;3 and the Division of General Internal Medicine/Geriatrics, Medical University of South Carolina, Charleston, SC4
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  • and 1,2 Jan N. Basile MD 3,4

    1. From the Division of General Internal Medicine/Division of Cardiology, University of Nevada School of Medicine, Reno, NV;1 the Risk Reduction Center, Saint Mary's Regional Medical Center, Reno, NV;2 the Primary Care Service Line, Ralph H. Johnson VA Medical Center;3 and the Division of General Internal Medicine/Geriatrics, Medical University of South Carolina, Charleston, SC4
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Michael J. Bloch, MD, Risk Reduction Center, Saint Mary's Regional Medical Center, 645 North Arlington Street, Suite 460, Reno, NV 89503

MASKED HYPERTENSION IS ASSOCIATED WITH MICROALBUMINURIA AND INCREASED LEFT VENTRICULAR WALL THICKNESS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Increasing evidence suggests that blood pressure (BP) measurements taken outside of the office, particularly those using 24-hour ambulatory BP measurements (ABPM), are more predictive of target organ damage than those taken in the office. As opposed to white-coat hypertension, patients with normal BP taken in the office and elevated readings when casually measured outside of the office have been termed masked hypertensive (MH). This is often undetected because of our failure to recommend BP measurements outside of the office for patients whose office BP was below the cut-off for diagnosing hypertension. MH is being recognized more frequently with the use of ABPM. Recent studies have found that MH is associated with increased left ventricular wall thickness and cardiovascular disease mortality. Whether these same effects of MH occur in patients with type 2 diabetes mellitus (T2DM) has yet to be examined. The present study was designed to investigate the impact of MH on urinary albumin excretion rate (UAER), left ventricular mass index (LVMI), and the incidence of diabetic retinopathy in T2DM patients with normal in-office BP using ABPM.

A prospective cross-sectional observational study was performed in 135 patients with T2DM from a cohort of 270 patients followed since 1994 at a single outpatient center in Brazil. To be eligible for the study, subjects had to have T2DM, be older than 30 years, and have no previous episodes of ketoacidosis or ketonuria. If being treated with insulin, treatment had to have started at least 5 years after the diagnosis of T2DM was first made. BP levels at office evaluation had to be <140/90 mm Hg on at least 2 occasions during a 6-month period and on the day of the study visit. Exclusion criteria included a serum creatinine >1.5 mg/dL, other renal disease, any cardiac arrhythmias, or postural hypotension (exact definition not provided). Subjects underwent an interview to record demographic and anthropometric data, dilated eye examinations performed by an ophthalmologist, and office BP measurement taken 1 week after withdrawal of all antihypertensive medication according to a prespecified protocol. Additional tests included echocardiograms (n=101) interpreted by a cardiologist blinded to BP readings and laboratory values, fasting plasma glucose and hemoglobin A1c, and estimated glomerular filtration rate using the Modification of Diet in Renal Disease study formula. UAER was determined by using 2 of 3 timed, 24-hour urine samples performed at least 6 months apart. No information is provided as to how UAER was determined, which of the 3 samples were used for data analyses, or when the samples were obtained in relation to BP measurement. ABPM was performed using a SpaceLabs model 90207 device (Spacelabs Medical, Redmond WA) using a 15-minute interval in the daytime and 20-minute interval at night. All ABPM evaluations were performed on a normal workday, and subjects were instructed to continue their usual daytime activities. The means of 24-hour, daytime and nighttime systolic and diastolic BP were recorded, as well as BP loads (percentage of 24-hour and daytime BP measurements ≥140/90 mm Hg and nighttime ≥120/80 mm Hg). The patients, BP status was classified according to ABPM into normotension, defined as a mean daytime ambulatory BP of <135/85 mm Hg, and MH was defined as a mean daytime ambulatory BP ≥135/85 mm Hg.

MH was found in 41 (30%) of the study sample. Compared with those who were normotensive on ABPM, subjects with MH did not differ in regard to age, duration of T2DM, smoking, body mass index, or waist circumference. In addition, there was no difference between the groups in their glycemic or lipid profiles, serum creatinine, or estimated glomerular filtration rate. Patients with MH were more likely to be men (71% vs 45%) and to have higher mean office systolic BP (127.8±7.5 vs 122.9±10.2 mm Hg, P=.003).

UAER was increased in subjects with MH (21.3[2.5–1223.5] vs 8.1 [1.0–1143.0] µ/min, P=.001) compared with people with normotension. The prevalence of MH increased with increasing levels of UAER, reaching an incidence of 50% in subjects with macroalbuminuria (defined as UAER of at least 200 µ/min). Multiple linear regression analysis found average daytime ambulatory systolic BP, but not office BP, significantly associated with UAER. When subjects were divided into 2 groups based on average office systolic BP, 130 to 140 mm Hg vs <130 mm Hg, there was no significant difference in UAER.

In subjects with MH, there was a trend toward an increased LVMI that did not reach significance (150.2±32.9 vs 140.5±26.5 g per 1.73 cm2), but there was a significantly greater intraventricular septum and posterior wall thickness in subjects with MH. The prevalence of diabetic retinopathy was similar in both groups (30% vs 34%).

In patients with T2DM and normal office BP, approximately 1 of every 3 individuals in this study had MH. MH is associated with target organ damage, as evidenced by higher UAER and greater interventricular septum and posterior wall thickness. The authors believe that failure to consider the use of 24-hour ABPM readings in patients with T2DM and normal office BP readings may under-appreciate the associated vascular risk in these individuals.—Leitão CB, Canani LH, Kramer CK, et al. Masked hypertension, urinary albumin excretion rate, and echocardiographic parameters in putatively normotensive type 2 diabetic patients.
Diabetes Care. 2007;30:1255–1260.

COMMENT

Before we obtain ABPM on all normotensive patients with T2DM, it should be noted that this particular trial has some very significant methodologic limitations. The most important of these is inclusion of subjects taking antihypertensive medications. The 1-week washout period for antihypertensive medication(s) before measurement of BP and of UAER is clearly not of sufficient duration to exclude the influence of previous antihypertensive therapy. While the authors state that a “sub-analysis” excluding the 23% of patients who previously took antihypertensive medication(s) showed similar results, the exact data and statistical analyses are not provided. Additionally, using office BP <140/90 mm Hg at the study visit as an inclusion criteria leads to a potential inclusion bias; patients with previous normotension who may have had higher office BPs at the time of the study visit would have been excluded, potentially biasing the results. Although the authors suggest that their data demonstrate that end-organ damage is more common in patients with MH, no significant differences were noted in overall LVMI or on retinal eye examination. Future studies should evaluate the correlation between MH and UAER and LVMI in drug-naïve patients (or at least after a longer antihypertensive drug washout period) and should include patients with a history of normal BP readings regardless of their office BP reading at the time of the study visit.

The hypertension community needs to reach a consensus regarding a consistent definition of ambulatory hypertension. Similar to previous studies, this investigation used a mean daytime ambulatory BP >135/85 mm Hg, while other studies have used different definitions and cut-offs. Despite these limitations, the present study adds to a growing body of evidence suggesting that 24-hour ambulatory BP measurement may be a better predictor of target organ damage than office-based BP determination. Advantages of 24-hour ABPM include the attainment of a larger dataset (ie, more readings) and avoidance of the stress or white-coat response to office BP measurement.

In previous studies using ABPM, MH has emerged as an interesting phenomenon believed to be clinically important. The Pressione Arteriose Monitorate e Loro Associazioni (PAMELA) study found that among nondiabetic individuals free from cardiovascular disease at baseline, MH was present in 9% of the overall cohort and 14% of the population with normal office BP. It was also associated with increased LVMI. Other studies have reported MH in 2% to 26% of the population, with much of the variability possibly due to different definitions of ambulatory hypertension used in the studies.

Even if target organ damage is more closely associated with ambulatory BP than office BP, all diabetic patients with office BP <140/90 mm Hg in the United States should not undergo ABPM. Despite the limitations of casual office BP readings, especially when performed without careful attention to recommended protocol, antihypertensive drug therapy is indicated in all diabetic patients with an office BP >130/80 mm Hg. In the present study, the mean office BP among patients with MH was approximately 128/77 mm Hg. Accordingly, many of these patients would have qualified for antihypertensive drug therapy under our current guidelines without the need for ABPM. Similarly, current guidelines from the American Diabetes Association and other organizations recommend routine measurement of UAER in all patients with T2DM. Patients with an increased UAER, including many of those with MH in the present study, would also have qualified for antihypertensive therapy with agents that block the renin-angiotensin system, and other medications, regardless of their office BP.

Pending the completion of future studies that clarify the role of ABPM for deciding when to initiate antihypertensive therapy, we should continue to carefully measure office BP in patients with T2DM, measure UAER routinely, and offer antihypertensive therapy to patients with office BP of at least 130/80 mm Hg or an increased UAER. ABPM should be reserved for patients with presumed white-coat hypertension or the rare patient in whom MH is suspected due to an incidental finding of left ventricular hypertrophy, retinopathy, cerebrovascular white-matter disease, or other end-organ damage consistent with elevated BP that is not detected on routine office measurement.

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