Left Ventricular Hypertrophy in Autosomal Dominant Polycystic Kidney Disease

Transcription

1 Left Ventricular Hypertrophy in Autosomal Dominant Polycystic Kidney Disease ARLENE B. CHAPMAN,* ANN M. JOHNSON, SUSAN RAINGUET,* KENNETH HOSSACK,* PATRICIA GABOW,* and ROBERT W. SCHRIERt *De,,j,er Health Medical Center and tuniversitv of Colorado Healtit Sciences Center, Denier, Colorado. Abstract. Cardiovascular complications are the most common cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). To understand this relationship. known cardiovascular risk factors were examined in ADPKD. Left ventricular hypertrophy (LVH) is a known, important risk factor for premature cardiovascular death in patients with essential hypertension. Hypertension is known to occur frequently and early in ADPKD patients. The frequency of LVH in ADPKD patients and its relation with hypertension and other risk factors, however, is not known. In this study, echocardiographic tests were performed in 1 16 consecutive adult ADPKD patients and 77 healthy control subjects. There was a significantly higher frequency of LVH in ADPKD men (46 versus 20%, P < 0.05) and women (37 versus I 2%, P < 0.005) compared with control subjects. LVH in ADPKD patients was associated with higher systolic and diastolic arterial BP. There also was an association between LVH, diminished renal function, and increased renal volume. When comparing ADPKD patients with and without LVH, the former were older, weighed more, had a higher prevalence of hypertension, and had a lower hematocrit value and more renal impairment. LVH was also present in 23% of normotensive ADPKD patients and 16% of healthy control subjects (P = NS), but did not correlate with BP. The role of BP as a contributing factor to LVH in ADPKD patients may be due in part to earlier onset and inadequate treatment. (J Am Soc Nephrol 8: , 1997) Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1 in 400 to 1000 individuals in this country (1). With the advent of renal replacement therapy for those patients with end-stage renal disease, cardiovascular complications have emerged as the major cause of death in ADPKD (2,3). Hypertension is known to occur earlier and with increased frequency in those with ADPKD compared with unaffected family members (4,5), and thus is an important risk factor for cardiovascular complications in ADPKD. Importantly, hypertension occurs in ADPKD individuals approximately 10 yr earlier than essential hypertension occurs in the general population. Therefore, the potential for end-organ damage due to hypertension is increased in the ADPKD population. Left ventricular hypertrophy (LVH) is a cardiac response to elevated BP (6-8) and is an important known cardiovascular risk factor (6,7,9,10). It is not known how frequently LVH occurs in ADPKD patients and whether hypertension plays a significant role in any increases in left ventricular mass index (LVMI) found in ADPKD. Therefore, echocardiographic studies were undertaken in 1 16 consecutive ADPKD patients and 77 control subjects to determine LVMI and the relative presence of LVH. Variables potentially related to increases in LVMI were exammed. including the severity and duration of hypertension, age. Received April Accepted April 15, Correspondence to Dr. Arlene B. Chapman, C283, University of Colorado Health Sciences Center, 42(X East 9th Avenue, Denver. CO l() /0808- I 292$03.0()/0 Journal of the American Society of Nephrology Copyright I 997 by the American Society of Nephrology gender. renal function, renal volume, and hematocnit level in ADPKD patients. Materials and Methods Patients Subjects were studied at the General Clinical Research Center (GCRC) at the University of Colorado Health Sciences Center after signing informed consent. Subjects were considered to have ADPKD if five or more renal cysts were found bilaterally ( 1 1 ). Subjects were eligible for participation if they were more than I 8 yr of age. Hypertension was defined as a BP greater than 140/90 mmhg in the sitting position or a previous diagnosis of hypertension and presently taking antihypertensive medications. If patients were found to be hypertensive for the first time during their visit for the present study, this was considered the date of diagnosis of hypertension. ADPKD subjects were admitted to the GCRC for 2 d, during which time a complete history and physical examination. including height and weight measurements, were performed. BP were determined after sitting quietly for at least 20 mm. BP were determined by sphygmomanometer by a research nurse coordinator, trained and accredited in measuring BP. on the second morning of the study. BP were obtained in the morning before medication intake. Subjects did not discontinue antihypertensive medications before the study. Information was obtamed from each subject regarding class of antihypertensive agent taken and dosage level. Antihypertensive medications were classified as follows: diuretics. sympathetic blocking agents, converting enzyme inhibitors, calcium channel blockers, or vasodilators. Two, sequential, 24-h urine collections were obtained for the determination of sodium excretion and creatinine clearance. Subjects were provided with a selection of foods to choose from and were also allowed to have any preferred foods brought in from outside the GCRC. Subjects were also allowed to leave the GCRC with no dietary restraints. Blood samples

2 Left Ventricular Hypertrophy in ADPKD 1293 were obtained for the measurement of serum electrolyte and creatinine concentrations as well as hematocnit levels. Abdominal ultrasonography was performed to determine the presence of renal and liven cysts as well as for calculation of renal volume as described elsewhere (5). All ADPKD subjects underwent cardiac echocardiography for the determination of LVMI. During the same time period. healthy control subjects were also studied. Control subjects consisted of healthy volunteers from the hospital, medical, and nursing staff who worked at Denver Health Medical Center. Those with pre-existing pulmonary, renal, or cardiac disease or hypertension were excluded. Subjects taking any medication were also excluded from the study. Subjects were not recruited to specifically match the ADPKD subjects. Echocardiographic studies were performed with a Honeywell ultraimager with or 3.5-MHz mechanical sector scanners. Left ventricular end diastolic dimension, septal thickness, and posterior wall thickness were measured from M-mode traces. Two-dimensional images were used to direct the M-mode sweep. Measurements were made according to the conventions of the American Society of Echocardiography ( I 2). LVMI was calculated using the Penn equation and corrected for body surface area (I 3). LVH was defined as the upper limit of the mean LVMI of the control group plus two SD. LVH was considered present if LVMI was greater than I 25 g/m2 in men or greater than I I 0 g/m2 in women. Patterns of LVH were categorized as concentric or eccentric based on the end-diastolic relative wall thickness (14). End-diastolic relative wall thickness was calculated from the following formula: 2 x Posterior Wall Thickness/Left Ventricular End Diastolic Diameter. Elevated relative wall thickness above 0.41 with increased LVMI identified concentric as opposed to eccentric hypertrophy. Elevated relative wall thickness in the presence of normal LVMI identified concentric left ventricular remodeling. The presence of mitral valve prolapse was determined as reported elsewhere (15). Statistical Analyses Mean LVMI and the frequency of LVH were compared between ADPKD patients and healthy control subjects. Comparisons were made between ADPKD patients with and without hypertension and between ADPKD subjects with and without LVH. Subjects were separated based on gender. Standard statistical methods were used. Analysis of covariance was used to determine which variables, if any, were associated with LVM in ADPKD subjects. Significance was placed at P < 0.05, and all P values below 0.05 are reported. Means ± SEM are provided in the text. Results Characteristics of ADPKD versus Control Subjects The ADPKD and control subjects were similar with regard to gender distribution (Table 1). However, the control subjects were younger and had smaller body surface areas. The ADPKD patients had significantly higher systolic, diastolic, and mean arterial pressures (MAP), as well as an increased frequency of LVH. In addition, concentric hypertrophy or remodeling was present in 36% of ADPKD patients as opposed to 6% of control subjects (P < 0.001). In ADPKD patients, LVMI correlated with serum uric acid (r 0.42, P < ), serum creatinine concentration (r = 0.38, P < ), MAP (r 0.38, P < ), diastolic BP (r 0.35, P < ), systolic BP (r 0.34, P < ), body weight (r = 0.34, P < ), urinary sodium excretion (r 0.26, P < 0.01), duration of hypertension (r = 0.24, P < 0.01), age (r = 0.20, P < 0.05), and mean renal volume (r = Table 1. Characteristics of ADPKD and healthy control Characteristic subjects studied echocardiographically ADPKD Healthy Controls it Variable gender (M/F) 48/68 35/42 NS Value age 40.7 ± ± 1.0 P < BSA (m) 1.85 ± ± 0.02 P 0.05 SBP (mmhg) 135 ± ± 1 P < DBP (mmhg) 90 ± 1 74 ± 1 P < MAP (mmhg) 105 ± I 88 ± I P < UNaV (meq/d) 155 ± S NA LVMI (g/m2) 1 15 ± 3 96 ± 3 P < percentage with P < LVH a ADPKD. autosomal dominant polycystic kidney disease; BSA. body surface area; SBP, systolic BP; DBP, diastolic BP; MAP, mean arterial pressure; UNaV, urinary sodium excretion; NA, not applicable; LVMI, left ventricular mass index; LVH. left ventricular hypertrophy. 0.19, P < 0.05). LVMI was greater in males (P < 0.01), in those without mitral valve prolapse (P < 0.01), and in those diagnosed with high BP (P < ). When analysis of covaniance was performed using LVM not corrected for weight, weight (P < ), serum creatinine (P < 0.05), serum uric acid (P < 0.05), and diastolic BP (P < 0.05) accounted for 46% of the variation found in LVM in ADPKD subjects. A positive relationship between LVMI and MAP was found in ADPKD patients (Figure 1). This relationship was independent of age and gender. When ADPKD men and women were studied separately, LVMI correlated with serum uric acid (r = 0.38, P < 0.01), systolic BP (r = 0.38, P < 0.01), age (r = 0.35, P < 0.05), MAP (r = 0.34, P < 0.05), decreasing hematocrit (r = -0.28, P = 0.05), and serum creatinine concentration (r = 0.29, P < 0.05) in men. Analysis of covariance demonstrated that serum uric acid (P < 0.005), serum creatinine (P = 0.05), and absence of mitral valve prolapse (P = 0.07) accounted for 32% of the variation in LVM measured. In women, LVMI correlated with weight (r = 0.43, P < ), serum creatinine concentration (r = 0.39, P < 0.001), duration of hypertension (r = 0.36, P < 0.005), serum uric acid (r = 0.36, P < 0.005), diastolic BP (r = 0.29, P < 0.05), MAP (r = 0.28, P < 0.05), and decreasing hematocrit (r = -0.26, P < 0.05). Analysis of covaniance demonstrated that weight (P < ), duration of hypertension (P < 0.001), family history of aneurysm (P < 0.005), premenopausal state (P < 0.005), and lower hematocrit (P < 0.01) accounted for 60% of the variation in LVM measured. Characteristics of ADPKD Subjects with and without LVH The ADPKD patients with LVH were significantly older, heavier, and had a greater prevalence of hypertension (83

3 1294 Journal of the American Society of Nephrology 2 R = 0.38 P< E o0 S #{149}#{149} I MEAN ARTERIAL PRESSURE (mmhg) 150 Figure 1. Relationship between mean arterial pressure and left ventricular mass index (LVMI) in autosomal dominant polycystic kidney disease (ADPKD) patients. A positive correlation was found. versus 61%, P < 0.05) than the ADPKD patients without LVH (Table 2). Forty-eight percent of hypertensive ADPKD patients demonstrated LVH. Hypertensive ADPKD patients with LVH demonstrated concentric LVH 62% of the time. The serum creatinine concentration was also significantly higher in the ADPKD patients with LVH compared to those without LVH. Table 2. Characteristics of ADPKD subjects with and without LVHU Characteristic LVH No LVH P Value n Percentage male NS LVMI (g/m2) 147 ± 5 93 ± 2 P < Age 44±2 39±1 P< 0.05 Weight (kg) 77 ± 2 71 ± 2 P = 0.05 BSA (m2) 1.89 ± ± 0.03 P = 0.10 MAP (mmhg) 109 ± ± 1 P < Percentage HBP P < 0.05 Age-adjusted renal 787 ± ± 83 NS volume (cm3) Age-adjusted serum 2.0 ± ± 0.2 P < 0.05 creatinine (mg/dl) UNaV (meq/d) 164 ± ± 6 NS Hct (%) 41.6 ± ± 0.7 P 0.10 SUA 6.5 ± ± 0.2 P < 0.01 Duration of HBP (yr) 7.5 ± ± 0.7 P < 0.05 a HBP, high BP; Hct, hematocrit; SUA, serum uric acid. Other abbreviations as in Table I. Among hypertensive ADPKD patients, those with LVH weighed more (79 ± 2 versus 73 ± 2 kg, P < 0.05), had greater serum creatinine concentrations (2.3 ± 0.3 versus 1.6 ± 0.2 mg/dl, P < 0.05), lower hematocrit levels (41.2 ± 1. 1 versus 44.2 ± 0.9, P < 0.05), and tended to have greater MAP ( 1 13 ± 2 versus 108 ± 2 mmhg, P 0.06) than hypertensive patients without LVH. When normotensive and hypertensive ADPKD subjects without LVH were compared, concentric remodeling was more frequent in hypertensive ADPKD subjects (29 versus 7%, P < 0.05). Of the 8 1 hypertensive ADPKD subjects studied, 29 (36%) were not receiving medication. LVMI in those not receiving medication versus those receiving medication did not differ (Table 3). Thirty-nine of 52 (75%) were receiving sympathetic blocking agents, and 36 of 52 (69%) were receiving diuretics Table 3. LVMI of 8 1 hypertensive ADPKD on antihypertensive medicationa Table 1. b p NS between groups. subjects Drug Category it LVMIb based No medication ± 8 Sympathetic blocking agents ± 7 Diuretics ± 6 Vasodilators ± 21 Converting enzyme inhibitors ± 17 Calcium channel blockers ± 34 a Some overlap exists between groups. Abbreviations as in

4 Left Ventricular Hypertrophy in ADPKD 1295 either alone or in combination. Eight of 52 (15%) were receiving vasodilators, whereas only 2 of 52 (4%) were receiving calcium channel blockers and 2 of 52 (4%) were receiving angiotensin-converting enzyme inhibitors alone or in combination. Table 3 provides the LVMI of hypertensive ADPKD patients based on the type of antihypertensive medication. When ADPKD men and women with LVH were studied separately, different variables were related to the presence of LVH. Men with LVH were older (45 ± 3 versus 38 ± 2 yr. P < 0.05) and tended to have greater systolic BP (147 ± 4 versus 1 36 ± 3, P 0.05) with greater serum creatinine concentrations (2.6 ± 0.4 versus 1.6 ± 0.2 mg/dl, P = 0.06) and lower hematocrit levels (43.2 ± 1.6 versus 47.3 ± 0.8, P < 0.05), but demonstrated no difference in weight or duration of diagnosed hypertension compared with ADPKD men without LVH. ADPKD women with LVH had greater systolic BP (136 ± 3 versus 128 ± 2 mmhg, P < 0.05), diastolic BP (89 ± 2 versus 83 ± 1 mmhg, P < 0.05), and MAP (105 ± 2 versus 98 ± 1 mmhg, P < 0.01), a longer duration of diagnosed hypertension (6.8 ± 1.4 versus 3.0 ± 0.9 yr, P < 0.05), and were more frequently hypertensive (80 versus S 1 %, P < 0.05) compared with ADPKD women without LVH. Number of pregnancies or a history of maternal complications during pregnancy were not related to the presence of LVH in ADPKD women. The geometric pattern of LVH in ADPKD men and women with LVH was as follows: ADPKD men with LVH demonstrated concentric LVH 68% of the time compared with 52% of women with LVH. These differences did not reach statistical significance. In addition, ADPKD men without LVH demonstrated concentric remodeling 19% of the time compared with 21 % of women without LVH (P = NS). Characteristics of Normotensive ADPKD Subjects with and without LVH LVH was present in 23% of normotensive ADPKD patients (n 8 of 35) and in 16% of healthy control subjects (n = 12 of 77; P = NS). Normotensive ADPKD subjects with LVH compared to those without LVH did not differ with regard to age, weight, systolic or diastolic BP, urinary sodium excretion, renal function, or renal volume (Table 4). Normotensive ADPKD subjects with LVH demonstrated a concentric pattern 50% of the time compared with 7% of those without LVH (P < 0.005). Normotensive ADPKD subjects with LVH tended to come from families with a positive history of an intracranial aneurysm compared with normotensive ADPKD subjects without LVH (62 versus 26%, P 0.09). All normotensive ADPKD subjects with LVH were evaluated at a later date, and no patient has become hypertensive (mean time to follow-up, 7. 1 ± 0.7 yr; range, 4 to 9 yr). Discussion This study evaluated the frequency and correlates of LVH in a large number of ADPKD patients. Given the large number of subjects studied, modest but significant correlations were found with LVMI. There was an increased frequency of LVH Table 4. Characteristics of normotensive ADPKD subjects with and without LVH Characteristic LVH No LVII P Value n 8 27 LVMI (g/m2) 133 ± 4 90 ± 3 P < Age 35±4 35±2 NS Percentage male NS Weight (kg) 63 ± 4 68 ± 3 NS BSA (m2) 1.72 ± ± 0.05 NS SBP (mmhg) 125 ± ± 2 NS DBP (mmhg) 77 ± 2 80 ± 1 NS FH ICA (%) P = 0.09 Age-adjusted serum 0.9 ± ± 0.04 NS creatinine (mg/dl) Age-adjusted renal 355 ± ± 35 NS volume (cm3) UNaV (meq/d) 175 ± ± 10 NS Hct (%) 43.8 ± ± 1.0 NS LVEDD (mm) 50 ± 1 48 ± 1 NS IVS (mm) 10.2 ± ± 0.2 P < PWT (mm) 9.6 ± ± 0.2 P < a FH ICA, family history of intracranial aneurysm; LVEDD, left ventricular end diastolic diameter; IVS, intenventricular septal thickness; PWT, posterior wall thickness. Other abbreviations as in Tables I and 2. and concentric geometry in the I 16 ADPKD patients compared with a simultaneously studied control population. Although LVMI increases with age, changes usually occur later in life, making the age difference between ADPKD and control subjects (41 versus 33 yr in this study) an unlikely reason for the higher frequency of LVH in the ADPKD patients (16). The frequency of LVH in the male ADPKD patients was 46%, and in female ADPKD patients it was 37%; both values were significantly higher than the control group. LVMI correlated with both systolic and diastolic BP. This correlation of LVMI with BP in ADPKD is similar to that found in the general population and patients with essential hypertension. However, it was more significant than that found using casual outpatient BP measurements (7,8) or repeat outpatient clinical measurements (9). The improved correlation found in this ADPKD BP study may be due in part to the standardized conditions of BP measurement by trained personnel or greater end-organ sensitivity to BP in ADPKD patients than in the general population. LVH was present in 48% of hypertensive ADPKD subjects. This frequency of LVH is greater than that found in unselected essential hypertensive patients (12 to 30%) but similar to the frequency reported in hypertensive patients seen in referral centers (20 to 60%) (8-10). This increased frequency of LVH may be related to two important factors. First, hypertension occurs early in the course of ADPKD, being present in 59% of ADPKD patients at an average age of 3 1 yr (5). Second, only 28% of hypertensive ADPKD patients have their BP controlled to below 150/90 mmhg. This large gap between recognition and successful treatment of diagnosed hypertension in ADPKD

5 1296 Journal of the American Society of Nephrology may in part account for the high frequency of LVH found in hypertensive ADPKD patients. All hypertensive ADPKD subjects continued taking antihypertensive medications during this study. More than 70% of all treated hypertensive ADPKD subjects were receiving either diuretic or sympathetic blocking agents, and only 4 of 8 1 were receiving converting enzyme inhibitors or calcium channel blockers, both known to effectively reverse LVH (17). Given that activation of the renin-angiotensin-aldosterone system is important in the hypertension of ADPKD (I 8) and that angiotensin II has local, cardiac, growth-promoting effects independent of BP ( 19,20), the poverty of converting enzyme inhibitor use may also contribute to the high frequency of LVH that was found. However, no differences in LVMI based on drug classification were detected. Given that (1) the average age ofonset ofhypertension is 10 yr earlier in ADPKD patients compared to patients with essential hypertension (7); (2) a minority (28%) of hypertensive ADPKD patients have adequate BP control (5); (3) the selection of an antihypertensive agent may not be optimal (1 8); and (4) LVH is present in almost half of our hypertensive ADPKD study population, it is not surprising that the primary cause of death in ADPKD patients is due to cardiovascular disease (2,3). The importance of these findings is underscored further by two echocardiographic studies of young ADPKD individuals in which LVMI was increased compared with unaffected, age-matched controls and was correlated with systolic BP level (21) or 24-h ambulatory BP (22). In the general population and in unselected hypertensive patients. age. weight. and sodium intake also tend to be important determinants of LVMI (23-25), as was found in the study presented here. Increased LVMI was found in ADPKD patients with decreased renal function and greater BP. The increase in LVMI associated with decreased renal function in this study was similar to the LVMI found in patients with chronic renal failure before end-stage disease (26). Importantly, increased LVMI in dialysis patients is also associated with increased cardiac mortality (27). In the present study, factors contributing to increases in LVMI were different in ADPKD men and women. ADPKD men with LVH generally were older and had higher systolic BP, worse renal function, and lower hematocrit levels compared with men without LVH. Differences in hematocrit levels were not seen between ADPKD women with and without LVH. However, analysis of covariance indicated that premenopausal ADPKD women with lower hematocnit levels demonstrated greater LVMI. Lower hematocnit values have been consistently associated with LVH in predialysis and dialysis populations (26). The relationship between lower hematocrit levels and increased LVMI found in this study is surprising given the relatively increased erythropoietin concentrations found in polycystic kidneys (28). Nonetheless, these data indicate another potential treatment independent of BP control for the reversal of LVH in ADPKD patients as in other patients with chronic renal insufficiency (26). Importantly, in the study presented here and an earlier preliminary report (29). the prevalence of LVH in normotensive ADPKD patients was 23%. The appearance of LVH in this group was independent of BP level, age, weight, sodium intake (as assessed by excretion), or renal function, but was associated with an increased frequency of concentric geometry. LVH in the general normotensive population is a strong predictor of the future development of hypertension (30). Although the number of subjects studied was small, hypertension was not found in the present study after a 7-yr follow-up. Recent genetic studies suggest that modifying factors other than BP, such as the angiotensin-converting enzyme gene deletion polymorphism, are related to the occurrence of LVH in patients with normal BP (3 1). In the study presented here, the normotensive AD- PKD subjects with LVH also demonstrated a propensity for an increased family history of intracranial aneurysms, again suggesting that other genetic factors may be important in the LVH found in ADPKD patients. In summary, LVH was found in 46% of males and 37% of females in 1 16 consecutive ADPKD patients studied echocardiographically. LVMI correlated significantly with BP level. In hypertensive ADPKD patients, LVH was present in 48%. Because hypertension occurs earlier and with increased frequency in ADPKD patients, LVH may be a major treatable factor or marker for cardiovascular complications and mortality associated with ADPKD. Factors other than hypertension, including anemia, obesity, and sodium intake, as well as increased activity of the renin-angiotensin-aldosterone system and other genetic factors, may be involved in the LVH found in both hypertensive and normotensive ADPKD patients. Acknowledgments This research was supported by Grant 5 P01 DK34039, Human Polycystic Kidney Disease, awarded by the Department of Health and Human Services, Public Health Service, National Institute of Diabetes and Digestive and Kidney Diseases, and the Clinical Research Center. This work was also supported by Grant MORR from the General Clinical Research Centers Research Program of the Division of Research Resources, National Institutes of Health. References 1. Gabow PA: Autosomal dominant polycystic kidney disease: More than a renal disease [Reviewl. Aiiz J Kidney Dis 16: , Fick GM. 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