Epidemiologic studies over the last 30 years

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1 AJH 1998;11: Cardiovascular Abnormalities in Never-Treated Hypertensives According to Nondipper Status Aldo L. Ferrara, Fabrizio Pasanisi, Marina Crivaro, Lucio Guida, Vittorio Palmieri, Iole Gaeta, Rita Iannuzzi, and Aldo Celentano Ambulatory blood pressure monitoring allows a better understanding of blood pressure fluctuations over 24 h than simple clinic measurements. In this way the diagnosis of white coat versus sustained hypertension and that of dipper (patient with blood pressure fall during nighttime > 10% of daytime levels) versus nondipper status were made possible. This pilot study has been undertaken to investigate whether patients with recently discovered, never-treated, mild, sustained hypertension have cardiovascular abnormalities according to their dipper/nondipper status. Patients with long-standing (n 123) and newly discovered (n 56) sustained hypertension were classified according to their nighttime blood pressure fall, and compared with normotensive controls. Ambulatory blood pressure monitoring was performed noninvasively. Parameters of left ventricular structure, cardiac systolic and diastolic function, and carotid anatomy were determined noninvasively by echographic methods. Significant increases in parameters of cardiac structure as well as abnormalities in diastolic function were observed in patients with long-standing hypertension, regardless of their dipper status. In the group with newly discovered hypertension, left atrium ( , , cm in dippers, nondippers, and controls, respectively), enddiastolic diameter index ( , , cm/m), and atrial filling fraction ( , , ) were significantly altered only in the nondipper subgroup, in comparison with controls. Significant changes in cardiac structure and diastolic function were observed in nondipper patients with recently discovered hypertension, who, at variance with dippers, show changes similar to those in patients with longstanding hypertension. Hypertensives with the observed abnormalities may benefit from active antihypertensive treatment, which appears, therefore, justified even in an early phase of mild hypertension, in terms of potential reduction of end-organ complications as well as costeffectiveness. Am J Hypertens 1998;11: American Journal of Hypertension, Ltd. KEY WORDS: Dipper, ambulatory blood pressure monitoring, left ventricular structure, cardiac function. Epidemiologic studies over the last 30 years have demonstrated that blood pressure reduction is accompanied by undoubted benefits in terms of cardiovascular morbidity and mortality, more evident in the carotid than in the coronary region. 1 5 However, most of the intervention trials recruited patients solely on the basis of clinic blood pressure (BP), without further information regarding daily fluctuations of their BP levels. Whether this policy makes no difference in the treatment sched- Received September 23, Accepted June 12, From the Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy. Address correspondence and reprint requests to A.L. Ferrara, MD, Department of Clinical and Experimental Medicine, Federico II University, Via S. Pansini, 5, 80131, Naples, Italy; ferrara@unina.it 1998 by the American Journal of Hypertension, Ltd /98/$19.00 Published by Elsevier Science, Inc. PII S (98)

2 AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 CARDIOVASCULAR DAMAGE IN NONDIPPER HYPERTENSIVES 1353 ules of patients with moderate-to-severe hypertension particularly if they already have end-organ complications the inclusion of patients with mild hypertension might have resulted in an underestimation of the beneficial effects of treatment, particularly if normotensive patients were, erroneously, included in the trials. This is relevant in terms of the possible side effects of drug treatment, as well as the cost-effectiveness of therapy. To overcome uncertainty about whether it is possible to better define the profile of patients who urgently need and, probably, will more extensively benefit from pharmacologic intervention, in this pilot study we recruited patients with never-treated, recently discovered mild hypertension, as well as those with longstanding hypertension and normotensive controls. Our aim was to investigate whether there is any difference in function or structure of the cardiovascular system between hypertensives with BP fall during sleep 10% of the values measured during the daytime (so-called dippers) and those with persistently elevated BP levels over 24 h (nondippers). 6 8 PATIENTS AND METHODS We investigated 199 patients with primary arterial hypertension, free from clinical end-organ complications, and 32 normotensive controls. One hundred twenty-three patients had been aware of their hypertensive disease for a long time and had been previously treated by pharmacologic means. Before entering the study, they accepted discontinuation of antihypertensive treatment for a period of 4 weeks. The remaining 76 patients had newly discovered, never-treated arterial hypertension; patients were classified in this group only if normal blood pressure levels had previously been measured no later than 1 year before. On the basis of 24-h ambulatory blood pressure monitoring (ABPM), patients were divided in two subgroups: 1) white coat hypertensives (WCH), those with elevated BP at the clinic or the physician s office and normal BP outside of the office, 9 13 and 2) sustained hypertensives. Twenty of the 76 patients in the group with newly discovered disease were defined as WCH and were excluded from the present analysis; no WCH patient was detected in the other group. Thereafter, the remaining 179 patients with sustained hypertension were classified as dippers and nondippers. Patients were, therefore, divided in four subgroups: patients with long-standing hypertension, dippers and nondippers, and patients with newly discovered hypertension, dippers and nondippers. Exclusion criteria were presence of cardiovascular disease other than hypertension; presence of diabetes, liver cirrhosis, chronic lung disease, renal disease; pregnancy or lactation; use of oral contraceptives; inability to obtain high-quality echography suitable to allow well reproducible measurements. At the end of the 4-week run-in, patients underwent measurements of resting BP, taken three times at 2-week intervals using an automatic Sentron, (Bard Biomedical) sphygmomanometer. Two blood pressure readings were recorded with patients in a seated position for at least 5 min, between 9:00 and 11:00 am; the average of the two readings was considered as the measurement for that visit. Body weight (BW) and height (ht) were also measured and body mass index (BMI BW/ht 2 ) was calculated. Patients were also asked to complete a questionnaire regarding smoking habit. Twenty-four hour ABPM was measured by SpaceLabs (Redmond, WA) during a normal working day. The monitor was fitted in the morning, between 10:00 and 12:00 am. Subjects were asked to perform their normal daily activities and to consume their habitual diet. After calibration, the monitor was programmed to record BP and heart rate (HR) at 15- min intervals during the subjects waking hours and at 20-min intervals during their usual sleeping hours. Subjects were instructed to keep their arm still during recordings. For the analysis of the data, the 24-h measurements were divided into waking (7:00 am 10:45 pm) and sleeping (11:00 pm 6:40 am) periods. The 24-h recording was acceptable if more than 80% of the scheduled readings were available. Patients also filled out a 24-h diary to report daily activities and rest, including the sleeping period. Two-dimensionally targeted M-mode echocardiograms were performed by expert sonographers using a commercially available echocardiograph (AU3 Partner ESAOTE Biomedica, Florence, Italy), connected to a 2.5- to 3.5-MHz annular-array transducer and taperecorded on videotapes. Strip-chart tracings of all patients were obtained at 50 mm/sec velocity and examined by two experienced investigators, who were blinded to the knowledge of the status of patients, using a graphic tablet and a pointer device interfaced with a PC computer and a homemade data-acquisition program. End-diastolic (EDD) and end-systolic (ESD) left ventricular internal diameters, posterior wall (PWT), and septal thicknesses (ST) were measured according to the recommendations of the American Society of Echocardiography. 14 A second set of measurements was also taken according to Penn convention criteria to calculate left ventricular mass (LVM). 15 To take into account body size, LVM was normalized for body height to the power 2.7 (LVMi), an indexation that has been shown to detect deviations from normality also in obese individuals. 16 The presence of left ventricular hypertrophy was defined by a LVMi 51 g/m 2.7, a prognostically validated partition value. 17 Relative wall thickness (RWT), an index of LV geo-

3 1354 FERRARA ET AL AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 TABLE 1. DEMOGRAPHIC PARAMETERS IN DIPPER AND NONDIPPER HYPERTENSIVES AND IN NORMOTENSIVE CONTROLS Long-Standing Hypertension Newly Discovered Hypertension (n 78) (n 11) Controls (n 32) Age (years) * * Gender (M/F) 44/34 25/20 31/14 7/4 22/10 Smokers (%) Body weight (kg) BMI (kg/m 2 ) * * Casual SBP (mm Hg) * * Casual DBP (mm Hg) 98 7* 98 7* Casual HR (beats/min) Long-standing hypertension v controls: * P.001; newly discovered hypertension v controls: P.001. metric pattern, was measured at end diastole, as 2 PWT/EDD. The aortic root (AR) was measured according to the recommendations of the American Society of Echocardiography. 14 Left atrium (LA) was measured from trailing edge to leading edge, by excluding the posterior wall of the aortic root. LV enddiastolic (EDV) and -systolic (ESV) volumes were calculated using Teichholz correction of the cube formula. 18 LV chamber volumes and stroke volume (SV) determined using this approach have been shown to correlate well with invasive and with twodimensional (2D) and Doppler echocardiographic volume measurements in a variety of populations with symmetric LV wall motion. 19 Cardiac output (CO) and total peripheral resistance (TPR mean BP/cardiac output 80) were also calculated. Immediately after M-mode recordings, pulsed Doppler echocardiography was performed. Transmitral flow velocity waveforms were obtained from the apex in the four- and five-chamber projection with sample volume placed at the level of the mitral annulus and at the tip of the mitral valve leaflets. The angle between the Doppler beam and the assumed direction of the transmitral flow was less than 10 in all subjects. The peaks of the early diastolic velocity wave (E) and the late diastolic wave (A) were measured in m/s and their E/A ratio was determined. The flow velocitytime integral of early diastolic flow (Ei), that of late diastolic flow (Ai), and their ratio (atrial filling fraction AFF) were also measured. 20 Carotid ultrasound imaging was performed with a Biosound ultrasound system, 2000 II SA (Bio Dynamics, Indianapolis, IN) according to the methodology already described. 21,22 Ultrasonographic images were accepted for measurement only if they met the following criteria for a high-level examination: presence of the adventitia-media interface and intima-lumen interface in at least two arterial segments; and visualization of anterior, posterior, lateral, and medial wall of the common carotid artery, the bifurcation, and at least 2 cm of the internal carotid artery. The whole scanning procedure was recorded on videotape; a hard print of the distal portion of the common carotid artery, just below the bulb, was thereafter produced. Pictures were displayed on a computer screen (Macintosh II, Apple Computer Corp., Cupertino, CA) by use of a scanner (Epson G 2000 ) and analyzed with software (Image 1.31) that allows quantitative evaluation of the terminal centimer of the vessel intima-media area. Measurement of mean intima-media thickness (IMT) of the common carotid arteries was derived by the ratio of area to 1-cm length. Measurements of the lumen diameter were also performed at the same level. Because the far wall of the common carotid arteries (the carotid wall farthest from the probe) is more constantly visualized with B-mode imaging than the more superficial near wall, the determinations of the thickness were carried out only at the level of the far wall. 21,22 Statistical Analysis Data were stored and analyzed using the SPSS (SPSS Inc., Chicago, IL) statistical package. Data are expressed as mean standard deviation (M SD). Comparisons were performed by one-way analysis of variance with Tukey s multiple comparisons. The strength of correlation between variables was tested by linear correlation and multiple regression analysis. A P.05 was considered significant. RESULTS Among patients with long-standing hypertension 78 were dippers and 45 nondippers; among patients with newly discovered arterial hypertension, 45 were dippers and 11 nondippers. Demographics of the four hypertensive and control groups are shown in Table 1. In patients with long-standing hypertension waking

4 AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 CARDIOVASCULAR DAMAGE IN NONDIPPER HYPERTENSIVES 1355 TABLE 2. ECHOGRAPHIC PARAMETERS OF CARDIAC STRUCTURE AND SYSTOLIC FUNCTION IN DIPPER AND NONDIPPER HYPERTENSIVES AND IN NORMOTENSIVE CONTROLS Long-Standing Hypertension Newly Discovered Hypertension (n 78) (n 11) Controls (n 32) ST (mm) PWT (mm) LVM (g) * * LVMi (g/m 2.7 ) RWT (%) LA (cm) AR (cm) EDDi (cm/m) SV (ml) CO (L/min) EF (%) Long-standing hypertension v controls: *P.001; P.005; newly discovered hypertension v controls: P.04. LVM, left venticular mass; LVMi, LVM normalized for body weight to the power of 2.7; PWT, posterior wall thickness; ST, septal thickness; RWT, relative wall thickness; AR, aortic root; LA, left atrium; CO, cardiac output; SV, stroke volume; EDDi, EDD indexed by height; EF, ejection fraction. BP was 154/96 15/7 and 157/96 20/7 in dippers and nondippers, respectively, whereas corresponding nighttime BP were 126/80 17/8 and 149/91 20/7 mm Hg. In the group with newly discovered hypertension, waking BP were 136/90 14/11 and 141/ 91 14/15 mm Hg, whereas sleeping BP were 114/ 72 12/10 and 135/90 13/6 mm Hg in dippers and nondippers, respectively. Noninvasive parameters of ventricular structure have shown that, in the group of patients with newly discovered hypertension, LA and EDD were significantly increased, and LVM or LVMi approached statistical significance only in nondippers. Accordingly, 4/45 (9%) patients had left ventricular hypertrophy (LVMi 51 g/m 2.7 ) in the dipper, and 4/11 (36%) in the nondipper group. In the subgroup with longstanding hypertension both dippers and nondippers had significantly increased LVM, LVMi, and LA, compared with normotensives, with no differences between each other (Table 2). Regarding diastolic function in patients with longstanding hypertension, both dippers and nondippers had reduced E wave and E/A ratio and increased AFF, whereas in the other group only nondippers had significantly increased AFF (Table 3). To investigate which factors might influence the difference in AFF between dipper and nondipper newly discovered hypertensives, we tried to correlate AFF with some demographic and cardiac parameters. Only age was significantly related to AFF (r 0.47, P.01), in the whole group as well as in the subgroup of nondipper patients (P.01). Age, however, was not shown to significantly predict AFF variability, when tested in the multiple regression analysis along with HR, LVM, and waking BP. The evaluation of carotid area was performed only in the subgroup with newly discovered hypertension. No difference in comparison to normal subjects was detected in IMT ( , , and mm in dippers, nondippers, and controls, respec- TABLE 3. ECHOGRAPHIC PARAMETERS OF CARDIAC DIASTOLIC FUNCTION IN DIPPER AND NONDIPPER HYPERTENSIVES AND IN NORMOTENSIVE CONTROLS Long-Standing Hypertension Newly Discovered Hypertension (n 78) (n 11) Controls (n 32) E wave (cm/s) * * A wave (cm/s) E/A * * AFF * * Long-standing hypertension v controls: * P.01; newly discovered hypertension v controls: P.05. AFF, atrial filling fraction; E/A, ratio of early (E wave) to late (A wave) diastolic waves.

5 1356 FERRARA ET AL AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 tively) and in RWT ( , , and ), whereas diameter was significantly increased only in the subgroup of nondippers ( , , , P.05). Parietal stress in the carotid artery was significantly increased in both dippers and nondippers, compared with controls ( , , N m 1, P.002). DISCUSSION Blood pressure fall during sleep has been well known since the last century, when it was first described. 23 The extensive use of the 24-h ABPM technique has clearly confirmed this finding and allows detection of a minority of subjects in whom this pattern is not present. 24 Therefore hypertensive patients whose daytime systolic or diastolic ambulatory BP decreases by more than 10% at night are called dippers, and those in whom this pattern is not present are known as nondippers. The cause of the abnormal pattern is still unknown, and it has been suggested that it might depend on a lack of sleeping or, at least, of normal sleeping. 25 However, all patients in this study reported that they slept well during most of the nighttime period. There is evidence in the literature that nondipper hypertensive patients are exposed to a greater risk of cardiovascular and cerebrovascular complications than the group of dippers It is stimulating to investigate the susceptibility to structural or functional cardiovascular abnormalities of patients in the early phase of hypertensive disease, according to dipper/nondipper status, in the light of decision-making on therapeutic strategies. For these reasons we have studied both patients with longstanding hypertension and those with recently discovered, never-treated arterial hypertension, in comparison to controls. We have excluded from this report 20 patients with white-coat hypertension, recently discovered, because among them, only three were nondippers. Demographic parameters of the newly discovered hypertensives, both dippers and nondippers, were statistically comparable to those of controls, apart from a significant increase in systolic and diastolic blood pressure. On the other hand, patients with long-standing hypertension were older and heavier than controls. Because of the close relationship between hypertension and obesity, most of our hypertensive patients are overweight. For this reason the cardiac structural parameters were normalized by body size (ie, LVMi, EDD indexed by height [EDDi]). As regards noninvasive parameters of cardiac anatomy, ST, LVMi, EDDi, and LA were significantly increased in patients with long-standing hypertension in comparison to controls, as expected on the basis of their history, without differences between dippers and nondippers. In patients with recent hypertension, LA and EDDi were significantly different from controls in the nondipper subgroup, but not in the dipper one. LVMi was, again, increased in the nondipper subgroup, the difference approaching statistical significance compared with controls. As regards parameters of diastolic function, all of them were altered in patients with long-standing hypertension, regardless of dipper/nondipper status, whereas among those with recent hypertension, the differences were particularly remarkable in the nondipper subgroup. Carotid parameters were substantially similar in controls and patients with newly discovered hypertension, probably because of the very short duration of the hypertensive disease. These findings indicate that early signs of structural and functional abnormalities of the heart are already present in patients with recent mild hypertension, provided they are exposed to elevated BP levels over the 24-h period. These early changes may precede the development of left ventricular hypertrophy or systolic dysfunction, which may result in life-threatening cardiac failure. From the present findings it can be argued that the unfavorable consequences of nondipper status might be blunted by the duration of hypertension, as there is no difference between dippers and nondippers in the group with long-standing elevated blood pressure levels. However the clinical importance of nondipper status appears to be remarkable when high blood pressure does not act on end-organs for a long time; nondipper patients, possibly, need a shorter duration of exposure to high blood pressure levels than dippers to develop structural cardiovascular lesions. In a recent paper Glen and coworkers 31 have shown that even in white-coat hypertensives there is a subgroup with cardiovascular dysfunction that probably needs early antihypertensive treatment. 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