Circ J 2005; 69: 1374 1379 Prospective Study of the Changes in Left Ventricular Mass and Geometry Patterns in Hypertensive Patients During 5 Years of Follow-up Alexandra O. Conrady, MD; Oleg G. Rudomanov, MD; Dmitriy V. Zaharov, MD; Olga I. Iakovleva, MD; Olga A. Ovchinnicova, MD; Natalya V. Vahrameeva, MD; Eugene V. Shlyakhto, MD Background Left ventricular hypertrophy (), as well as the geometry pattern of the left ventricle, is believed to be an independent risk factor for hypertension. The present study investigated the changes in left ventricular mass, diastolic function and geometry in hypertensive patients in a prospective 5-year follow-up in conjunction with an evaluation of the regularity and effectiveness of treatment. Methods and Results One hundred hypertensive patients older than 18 years were examined according to the study protocol, which included registration of weight, height, vital signs, and echocardiography. After 5 years a repeat examination was performed. Patients were divided into 3 groups according to blood pressure (BP) control: group 1 (n=32), no regular medication; group 2 (n=44), regular treatment but no target BP levels; group 3 (n=14), regular effective treatment. In group 1 an increase in and worsening of diastolic function were observed; in group 2 and isovolumetric relaxation time remained unchanged, while the early peak velocity/atrial peak velocity ratio decreased; in group 3 there was a significant decrease in. The geometry pattern only changed in 21 (23%) patients. Conclusions can be successfully reversed in only hypertensive with adequate BP control. The remodeling pattern appears to be a stable characteristic of the patient and transformation of one pattern into another is infrequent. (Circ J 2005; 69: 1374 1379) Key Words: Hypertension; Left ventricular hypertrophy; Remodeling Left ventricular hypertrophy () is generally believed to be an independent risk factor in hypertension, 1 5 and the possibility and beneficial effect of reversing during antihypertensive treatment have been well documented in clinical studies. 6 10 However, little is known about the evolution of left ventricular (LV) geometry in untreated subjects, because of the difficulties of long-term follow-up for humans and the ethical problems of organising a prospective study of untreated patients. There are 4 patterns of LV geometry in hypertension, classified according to the LV mass (LVM) index and relative wall thickness (RWT), 11 and it is now well established that the LV geometry pattern is closely related to LV function and the patient s prognosis. 12,13 Thus, concentric is associated with a higher risk of cardiac arrhythmias, and even sudden death, 12 and the literature is replete with evidence that concentric strongly predicts the development of heart failure. 13,14 In addition, the evidence is accumulating that eccentric is frequently observed in the early stages of hypertension, 15 17 but little is known whether the geometry patterns are necessary consequent stages in (Received February 28, 2005; revised manuscript received August 11, 2005; accepted August 17, 2005) Institute of Cardiovascular Diseases, Pavlov State Medical University, St Petersburg, Russia Mailing address: Alexandra Conrady, MD, PhD, Chief of the Laboratory of Hypertension Research in the Institute of Cardiovascular Diseases of St-Petersburg Pavlov State Medical University, St Petersburg, Lev Tolstoy str. 6/8 197089, St Petersburg, Russia. E-mail: podiatr @inbox.ru the development of the hypertensive heart from normal geometry through to LV dilatation and heart failure, or if every pattern is genetically and/or hemodynamically predisposed. Finally, the natural history of the transition from 1 pattern to another is still unknown, as are the changes in the geometry patterns during antihypertensive therapy. The present study investigated the changes in LVM, diastolic function, and geometry in hypertensive patients in a prospective 5-year follow-up in concordance with an evaluation of the regularity and effectiveness of treatment. Methods Patients Hypertensive patients older than 18 years from one of the city districts of St Petersburg who were in the patient database of the outpatient clinic, were screened for the study. Because no other option for outpatient care is available in this area, the vast majority of patients with essential hypertension are seen in the selected healthcare center. Patients were recruited for the study during their annual check-up from 1995 to 1998. The selection criteria were: (1) previously established diagnosis of essential hypertension (=1 year) based on the standard criteria (3 consecutive measurements of blood pressure (BP) in the right brachial artery while seated: >140 mmhg for systolic BP and/or >90 mmhg for diastolic BP); (2) no concomitant cardiovascular diseases and/or diabetes mellitus; and (3) no regular antihypertensive medication (>3 months of daily use). The
Hypertensive LV Remodeling 1375 Table 1 Clinical and Echocardiographic Characteristics of the Study Group Total group M F p (n=90) (n=38) (n=52) (F vs M) Age, years 49±3 51±6 49±4 NS Hypertension duration, years 8±3 8±2 9±3 NS Blood pressure, mmhg 168±19/101±7 170±20/101±9 168±20/101±9 NS Heart rate, beats/min 69±8 69±8 70±8 NS BMI, kg/m 2 29±4 29±4 30±5 NS Obesity 62 (69%) 27 (71%) 35 (67%) NS Smoking 19 (21%) 15 (39%) 4 (8%) <0.05 Menopausal mean duration, years 18 (31%)/42±2 PWd, cm 1.05±0.22 1.08±0.18 1.02±0.17 NS IVSd, cm 1.09±0.19 1.17±0.20 1.05±0.22 <0.05 LVDD, cm 5.04±0.39 5.14±0.37 4.89±0.44 <0.01 RWT 0.43±0.08 0.44±0.06 0.43±0.06 NS LA, cm 4.13±0.41 4.14±0.36 4.08±0.41 <0.01 LVMI, g/m 2 133±29 142±30 125±32 <0.01 IVRT, ms 105±21 111±23 101±18 <0.05 E, m/s 0.73±0.19 0.71±0.19 0.75±0.17 NS A, m/s 0.77±0.19 0.71±0.15 0.83±0.21 NS E/A ratio 1.04±0.25 1.07±0.22 1.01±0.23 0.06 NS, not significant; BMI, body mass index; PWd, diastolic left ventricular posterior wall thickness; IVSd, diastolic interventricular septum thickness; LVDD, left ventricular internal dimension at the end of diastole; RWT, relative wall thickness; LA, left atrium; LVMI, left ventricular mass index; IVRT, isovolumetric relaxation time; E, early peak velocity; A, atrial peak velocity. possible causes of secondary hypertension were also excluded (no clinical signs, normal results for serum urea nitrogen, creatinine, and electrolytes, normal urinary excretion of catecholamines, and normal renal imaging studies, including radionuclide renogram and/or intravenous urography and/or ultrasound scan). The patients were examined by the same investigator according to the study protocol, which included vital signs obtained (BP and heart rate in the morning, without medication), registration of weight, height, body mass index (BMI), and echocardiography. Patients who had poor quality images were excluded. Later, all patients were administrated antihypertensive medication according to the 1993 WHO/ISH Guidelines 18 and followed-up by their general physicians for 5 years. The study protocol was approved by the local Ethics Committee and informed consent was given by all the participants. After 5 years the patients were invited for a follow-up visit and repeat examination. The information concerning treatment regimen and BP control was obtained from the GPs case histories, comprehensive clinical history, or records of self-measurement of BP, where appropriate. Echocardiography Echocardiography was performed in M- and 2-dimensional mode with a Vingmed-CFM-800 machine (GE, USA) using a 3.25 MHz transducer. Echocardiographic studies were performed in the morning after a 30-min rest with the subject in a supine left lateral decubitus position. The interventricular septum and LV posterior wall were selected in the parasternal long-axis view. All measurements were made according to the Penn convention. 19 The LVM was calculated by the Devereux and Reicheck formula: LVM=1.04{(IVSd + PWd + LVDD) 3 LVDD 3 } 13.6g, where IVSd is the diastolic interventricular septum thickness (cm), PWd is the diastolic LV posterior wall thickness (cm), and LVDD is the LV internal dimension at the end of diastole (cm). 19 The LVM index (LVMI) was obtained by dividing the LVM by body surface area (BSA), according to the formula of Dubois and Dubois. 20 was diagnosed by indexation to BSA using the following criteria: LVMI >134 g/m 2 in men and 110g/m 2 in women. 16 The RWT was calculated as PWd + IVSd/LVDD. Values exceeding 0.45 were considered to be evidence of concentric remodelling. Patients were divided into 4 remodelling patterns according to the description by Ganau et al. 11 1. Normal geometry: no and RWT <0.45. 2. hypertrophy: with RWT=0.45. 3. Eccentric hypertrophy: and RWT <0.45. 4. remodeling: LVMI normal, RWT=0.45. Patients with asymmetric (IVSd/PWd >1.5) were analyzed together with those with concentric. Patients with regional wall movement abnormalities and depressed systolic function (<50%) were excluded from the study. A control echocardiographic study was performed 5 years ± 2 months after the first one by the same operator. The intraobserver and interobserver variability of LVMI measurements in the laboratory are good ( =0.94, p<0.01 and =0.92, p<0.001 respectively). Doppler Measurements Transmitral flow was assessed by continuous wave Doppler with the measurement of early peak velocity (E), atrial peak velocity (A) and their relation (E/A). Isovolumetric relaxation time (IVRT) was also determined. The flow in pulmonary veins was analyzed in order to distinguish different patterns of relaxation abnormalities. Statistical Analyses Data are presented as mean ± SD. Differences between groups were assessed by Mann-Whitney test for skewed distribution and discrepancies within the groups by Wilcoxon test. The chi-square statistic between the remodelling pattern distribution and status was calculated. Univariate relationships were assessed by Pearson s correlation coefficients. Relationships were also assessed by correlation and multiple regression analysis. All tests were two-sided and carried out to a significance level (p) of 0.05. The compu-
1376 CONRADY A O. et al. Table 2 Changes in the Clinical and Echocardiographic Parameters After 5 Years of Follow-up Parameter Group1 (n=32) Group 2 (n=44) Group 3 (n=14) Age, years 48±6 50±5 47±7 Hypertension duration, years 7±2 9±3 7±2 Baseline 5 years Baseline 5 years Baseline 5 years BMI, kg/m 2 28.2±5 28.4±5.1 27.9±3 28.1±7.2 27.5±5.0 27.9±6.1 SBP/DBP, mmhg 167±12/104±8 169±17/102±10 170±21/100±12 169±18/99±13 166±16/97±11 131±12*/83±9* PWT, cm 1.12±0.111 1.14±0.11 1.09±0.14 1.14±0.12 1.03±0.10 0.92±0.09* IVS, cm 1.17±0.13 1.23±0.14* 1.16±0.12 1.17±0.13 1.01±0.10 0.92±0.12* LVDD, cm 5.31±0.78 5.38±0.71 5.19±0.77 5.11±0.82 5.11±0.79 4.94±0.65* LA, cm 4.16±0.55 4.26±7.6* 4.13±0.62 4.07±0.48 3.99±0.44 3.77±0.39* RWT 0.43±0.09 0.42±0.08 0.43±0.08 0.42±0.06 0.42±0.0 0.41±0.06 LVMI, g/m 2 148±22 164±23* 151±24 147±18 138±21 112±19* E/A ratio 1.02±0.1 0.82±0.08* 0.98±0.09 0.75±0.10* 1.03±0.11 0.91±0.08 IVRT, ms 123±11 127±12* 123±8 126±11 112±8 108±9 *p<0.05 compared with baseline levels. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; PWT, relative wall thickness; IVS, diastolic interventricular septum; LVDD, left ventricular internal dimension at the end of diastole; LA, left atrium; RWT, relative wall thickness; LVMI, left ventricular mass index; E, early peak velocity; A, atrial peak velocity; IVRT, isovolumetric relaxation time. terized statistical program used was STATISTICA 5.0 for Windows. Results A total of 100 patients were included in the study; 5 patients were lost to follow-up, 4 patients had a myocardial infarction during the follow-up period and were excluded from the final analysis because of local contractility abnormalities, and 1 patient had new onset of diabetes mellitus was documented and was also excluded because of possible diabetic cardiomyopathy. Therefore, a final total of 90 patients who underwent the control echocardiography were analyzed. No cases of new onset atrial fibrillation were documented. Clinical characteristics and echocardiographic parameters are presented in Table 1. There were no differences between males and females. The prevalence of obesity was up to 70%. Male subjects had higher LVMI and septal thickness than females. The majority of patients had altered diastolic function (66%). Patients were divided into 3 groups according to BP control during the follow-up period. Those did not have regular antihypertensive therapy (poor compliance, other reasons), but continued to have stable hypertension were combined in group 1 (or untreated ) (n=32; 14 males, 18 females). The absence of regular medication was defined as no medication for more than 3 months per year. Patients who received regular antihypertensive therapy but did not achieve the goal BP (>140/90mmHg on repeated measurements) were combined into group 2 (or poorly controlled ) (n=44; 18 males, 26 females). Among these patients 24 were on single-drug therapy (angiotensin-converting enzyme inhibitors (ACEI) =14; calcium antagonists =5; -blockers (atenolol 50 100 mg/day) =2; thiazide diuretics (hydrochlorothiazide) =3). Of the ACEI the most frequently used was enalapril (12 patients, mean dose 20 mg/day; the other 2 patients received perindopril 4 mg/day). The calcium antagonist therapy was represented by nifedipine (retard forms) in a mean dose of 40 mg/day (4 patients) and amlodipine 5 mg/day in 1 patient. The remaining 20 patients were on combination therapy (16 were taking 2 drugs, and 4 were on 3-drug therapy); the most frequent combination being an ACEI (enalapril) and thiazide in 18 patients, 2 patients received a combination of -blocker and diuretic, plus the third drug was a calcium antagonist for the patients on 3-drug regimens. Only 14 patients (6 males, 8 females) were considered to be adequately treated (with goal BP achieved on visits to the clinic during the 5 years with at least 3 measurements per year) (group 3 or well controlled ). One patient was on losartan therapy (100 mg/day) and the other 13 received combination therapy of ACEI (enalapril (n=10), perindopril ), diuretics (hydrochlorothiazide (n=11), indapamide (n=2)) and/or -blockers (atenolol (n=7) or metoprolol (n=2)) or calcium antagonists (nifedipine; n=4). The changes in the hemodynamic and echocardiographic parameters after 5 years are presented in Table 2. There was a slight increase in BMI after the follow-up period in all groups. BP in the untreated and poorly controlled groups did not change significantly compared with the initial visits. In group 3 there was a significant reduction in BP, whereas at the inclusion visit BP was comparable with the other groups. In the group with no regular medication a progressive increase in LVMI and worsening of diastolic dysfunction was observed. In 18 of the 32 patients in the untreated group LVMI increased more than 10% during the 5 years. Only in 4 patients from this group did LVMI and wall thickness remain unchanged. A significant increase in IVRT was related to the increase in LVMI (r=0.71, p<0.05) whereas the E/A ratio decreased in all patients, which could be associated with the increase in age. Moreover, a marked increase in left atrial (LA) diameter was observed in this group, which was associated with the change in the E/A ratio (r= 0.44, p<0.05). In the poorly controlled group significant changes were only observed in diastolic function. LVMI and IVRT in the whole group remained unchanged, although the E/A ratio decreased significantly. In 12 patients the LVMI and IVRT increased more than 10%. In 23 patients the echoparameters remained unchanged compared with baseline, excluding the decrease in E/A, and in 9 patients there was a decrease in LVMI of more than 10% from baseline. No other features of BP, treatment regimen or clinical characteristics were observed in these subgroups. The control echocardiography study in the well controlled patients revealed a significant improvement in the structural and functional parameters of the heart, including
Hypertensive LV Remodeling 1377 Table 3 Changes in Left Ventricular Remodeling Patterns After 5 Years of Follow-up Group1 (n=32) Group 2 (n=44) Group 3 (n=14) Total group (n=90) Baseline 5 years Baseline 5 years Baseline 5 years Baseline 5 years Normal geometry 8 1 7 7 2 8 17 16 11 17 17 17 6 4 34 38 Eccentric 11 14 17 19 6 2 34 35 remodeling 2 0 3 1 0 0 5 1, left ventricular hypertrophy. Eccentric Normal geometry (n=17) (n=4) Eccentric (n=34) Normal geometry (n=1) Eccentric (n=34) Normal geometry (n=4) remodeling (n=5) Fig 1. Changes of remodeling patterns after 5 years in different remodeling groups., left ventricular hypertrophy. a decrease in, decrease in IVRT, improved diastolic filling and even a decrease in LA size. The correlation analysis revealed that the degree of LVMI reduction was associated with its initial value (r=0.46, p=0.03). However, normalization of LVMI was observed in 6 patients only (<134 g/m 2 in males and 110g/m 2 in females), and in 8 patients was still apparent despite effective treatment. A separate analysis of patients receiving or not receiving ACEI was performed for all groups (data not shown) and no significant discrepancies concerning the structural and functional echocardiographic parameters were observed. The data concerning the dynamics of the remodeling patterns after 5 years are presented in Table 3 and Fig 1. The geometry pattern changed in 21 patients only (23%). In 2 patients from group 1 concentric remodeling transformed into concentric because of the increase in LVMI and this same transformation occurred in 2 patients from the poorly controlled group. In 1 of them eccentric became concentric because of the increased wall thickness without changes in LVDD. Among the patients in the untreated group with normal geometry at the initial visit there was concentric in 4 and eccentric pattern in 3. In contrast, 6 patients from the well controlled group reverted to normal and the patients were transferred to the group with normal geometry. In group 2 there were only 3 cases of transformation from concentric to eccentric. In the majority of cases the remodeling pattern remained unchanged and the LVMI increased or decreased within the pattern. The changes in the distribution of the remodeling patterns in the total group and the 3 subgroups were not statistically significant. Patients ages and sex distribution among the 3 groups were comparable. No significant discrepancies between men and women concerning LV geometry changes were found. The relative number of patients with a changed remodeling pattern in men and women was low and comparable (10 males, 11 females). Discussion The present study has documented that a significant improvement in LV structure and function in patients with hypertension can be obtained only in those who are adequately treated. Not achieving target BP can result in either no decrease in or even progressive increase, the latter being a strong negative prognostic factor. It is worth mentioning that most patients in the group without adequate treatment regularly received ACEI and numerous metaanalyses have shown that ACEI have a stronger protective effect on the development of than other drug classes. 6,10,21 Our study shows that long-term treatment in humans, even with ACEI, has no significant effect on if BP is not lowered to the target level. This can be explained by the impact of different stimuli on development and progression in hypertensive patients, with particular importance of the hemodynamic load. 5 Study Limitations The study sample is not large enough to perform any comparisons between different treatment regimens and make final conclusions concerning efficacy of different drugs in regression. The second limitation is that the lack of an effect of ACEI therapy, in particular enalapril, on regression without adequate BP control was the
1378 CONRADY A O. et al. relatively low dose of the drug used (20 mg/day). Several experimental studies have previously documented regression of with administration of subhypotensive doses of ACEI, 22,23 although this effect has not been proven in clinical studies. Moreover, the efficacy of enalapril in reduction, even at moderate doses, is controversial. A single randomized trial 24 showed a lack of significant reduction during long-term enalapril administration at a daily dose of 20 mg, but the same dose effectively reduced LVM by 26 g in the PRESERVE trial. 7 Thus, despite our observation not being strong enough to deny the ability of ACEI to reverse without efficient BP control, it seems reasonable to conclude that BP reduction is more crucial for treatment than the drug regimen. The obvious limitation of the study is the lack of randomization and prospective systematic evaluation of BP, which is a result of ethical problem of conducting placebo studies in hypertensive patients. Another limitation is the lack of treatment standardization, which is a result of the observational design of the study. Therefore, we must interpret the results with caution. Other treatment regimens can produce some beneficial effects on the LV and its function, even without BP normalization. Promising results have been recently published by Nishikawa et al 25 concerning the effect of statins on, 25 but results from general practice, not clinical trials, of positive effects on target organ damage, in particular, show that target BP must be achieved. The study also investigated the dynamics of diastolic function in different groups. Passive relaxation measured by E/A ratio worsened in both the untreated and poorly controlled patients, whereas the parameters of diastolic function remained unchanged in the well controlled patients. This suggests that the E/A ratio is strongly influenced by pressure overload, compared with the LVMI, and that changes in diastolic function do not go absolutely in parallel with progression or regression. The problem of correcting diastolic dysfunction by different drugs has been previously reviewed and lack of sufficient evidence of the advantages of distinct drugs was stressed. 26 The parameters of diastolic filling were very sensitive to heart rate and BP during the echocardiographic study, and as these conditions were not standardized the results obtained are limited. Another important point about the results obtained concerns the data for the changes in the remodeling patterns. Our observations suggest that LV geometry is a rather conservative entity and transformation from one pattern to another is rarely observed. Moreover, the data also suggest that a previously postulated evolution from concentric to eccentric in hypertension could be a misunderstanding of the process. seemed to be a stable condition without any tendency to transform into eccentric pattern during the 5 years of follow-up. However, development of eccentric in patients with normal baseline geometry was documented, which is evidence in favor of independent determinants of eccentric geometry without necessarily evolving from the concentric pattern. Our study cannot provide a reasonable explanation of the development of different remodeling patterns and their evolution. No tendencies in the changes in LV remodeling according to treatment strategy were observed. It seems conclusive that concentric remodeling is a pre-stage of concentric hypertrophy, as the majority of patients develop this pattern without treatment. At the same time, concentric and eccentric remodeling patterns develop according to some intrinsic laws and further evolution is not predictable. In conclusion, may successfully regress in hypertensive patients in whom there is adequate BP control. Without medication LVM progressively increases, accompanied by worsening diastolic function. The LV remodeling pattern appears to be a stable characteristic of the patient and transformation from one pattern into another was infrequent during the 5-year period of observation. Acknowledgment The work was supported by the government program of hypertension management (contract N oo 921-D). References 1. Bikkina M, Levy D, Evans JC, Larson MG, Benjamin EJ, Wolf PA, et al. Left ventricular mass and risk of stroke in an elderly cohort: The Framingham study. JAMA 1994; 272: 33 36. 2. Kannel WB, Levy D, Balanger AJ. Prognostic significance of regression of left ventricular hypertrophy. Circulation 1988; 78: S89 S95. 3. Kannel WB. 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