Original Article
Prognostic value of left ventricular mass normalized to different body size indexes: findings from the PAMELA population Cesare Cuspidi a,b, Rita Facchetti a, Michele Bombelli a, Carla Sala c, Marijana Tadic d, Guido Grassi a,e, and Giuseppe Mancia a,b
Aim: We estimated the risk of cardiovascular and all-cause mortality associated with left ventricular hypertrophy (LVH) as assessed by left ventricular mass (LVM), normalized by various indexation methods in 1716 representatives of the general population of Monza, enrolled in the Pressioni Arteriose Monitorate E Loro Associazioni study. Methods: LVH was defined according to four sex-specific criteria derived from the upper limits of normality for LVM index in the healthy normotensive fraction of the Pressioni Arteriose Monitorate E Loro Associazioni population. Death certificates were collected over an average 211 months of follow-up. Results: During follow-up, 89 fatal cardiovascular events and 264 all-cause deaths were observed. LVH prevalence rates in the whole population ranged from 14.2% [LVM/ body surface area (BSA)] to 18.0% (LVM/height2.7). Adjusted risk (for baseline covariates, including ambulatory blood pressure) of cardiovascular mortality was increased in patients with LVH, regardless of the indexation type: LVH/BSA [hazard ratio 3.19, 95% confidence interval (CI) 2.02–5.06, P < 0.0001], LVH/height1.7 (hazard ratio 2.39, 95% CI 1.51–3.78, P ¼ 0.0002), LVH/height2.7 (hazard ratio 2.38, 95% CI 1.50–3.76, P ¼ 0.0002), LVH/height (hazard ratio 2.28, 95% CI 1.44–3.60 P ¼ 0.0004). Similar findings were observed for all-cause mortality and when LVM was assessed as a continuous variable. The fraction of patients (5%) classified into the LVH group by height2.7, but not by BSA, had a mild increased LVM index and showed no increased risk. Conclusions: LVH, irrespective of indexation methods for LVM, confers an increased risk of cardiovascular and allcause mortality in the general population. LVH, detected by height-based indexes, but not by BSA-based criteria, was not associated with increased mortality; this finding, however, was based on a small group of patients and will deserve further investigations. Keywords: cardiovascular mortality, indexation methods, left ventricular hypertrophy Abbreviations: AUC, area under the curve; BP, Blood pressure; BSA, body surface area; CI, confidence interval; LVH, left ventricular hypertrophy; LVM, left ventricular
mass; PAMELA, Pressioni Arteriose Monitorate E Loro Associazioni study; ROC, receiver-operating characteristic
INTRODUCTION
C
ardiovascular disease represents the leading cause of mortality among noncommunicable chronic diseases and is responsible for 30% of deaths worldwide. Ischemic heart disease and cerebrovascular disease are responsible for the majority of cardiovascular mortality, accounting for about 13.0 million of deaths annually [1,2]. Control and management of cardiovascular risk factors is fundamental to reduce the impressive burden of cardiovascular complications. As subclinical alterations in cardiovascular structure reflect cumulative damages induced by risk factors and represent an intermediate stage between risks factor exposure and cardiovascular events, early detection of these damages may have important implications for prevention of cardiovascular morbidity and mortality [3]. Among the markers of target organ damage, increased left ventricular mass (LVM), as assessed by echocardiography or more accurately by MRI, is a powerful predictor of cardiovascular and all-cause mortality, independently of conventional risk factors [4–10]. In healthy children and adults, LVM is closely related to anthropometric parameters such as weight, height, and their derived measures body surface area (BSA) and BMI [11,12]. Although the strength of this relation is blunted by several conditions such as hypertension, diabetes mellitus, obesity, and aging,
Journal of Hypertension 2015, 33:1082–1089 a
Department of Health Science, University of Milano-Bicocca, bIstituto Auxologico Italiano IRCCS, cDepartment of Clinical Sciences and Community Health University of Milano and Fondazione Ospedale Maggiore Policlinico, Milan, Italy, dUniversity Clinical Hospital Centre ‘Dragisa Misovic’, Belgrade, Serbia and eIRCCS Multimedica, Sesto San Giovanni, Milan, Italy Correspondence to Professor Cesare Cuspidi, Istituto Auxologico Italiano, Clinical Research Unit, Viale della Resistenza 23, 20036 Meda, Italy. Tel: +39 0362/772433; fax: +39 0362/772416; e-mail: [email protected] Received 21 September 2014 Revised 18 December 2014 Accepted 18 December 2014 J Hypertens 33:1082–1089 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000527
1082
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Volume 33 Number 5 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Left ventricular hypertrophy and cardiovascular mortality
indexation of LVM to body size measures improves the clinical and prognostic value of this biomarker [13]. In the past three decades, different methods have been proposed for LVM normalization in the attempt to differentiate physiologic LVM adaptations from morbid conditions [14]. Among these methods, indexation BSA is the more common in clinical practice; this approach, however, has been criticized because: three-dimensional variable LVM is divided by two-dimensional variable BSA, and indexation to BSA tends to underestimate left ventricular hypertrophy (LVH) prevalence in obese individuals. Alternative LVM indexations to body height, or more properly, to height to the power of different exponents (i.e. 2.7, 1.9, and 1.7) were proposed. Height to the power of 2.7 (a value close to the power of 3 that regulates the relationship between three-dimensional LVM and mono-dimensional height) is the most used allometric signal for LVM normalization [15]. The ability of indexation to height2.7 to properly account for body size has been recently challenged by the findings of a study in 7528 participants from a multiethnic population-based adult sample [10]. In that study, only LVH defined by LVM/height1.7 demonstrated a consistent relationship with all fatal and nonfatal cardiovascular events. On the contrary, LVM/height2.7 or LVM/BSA failed to predict cardiovascular outcome and all-cause death. In the present study, we aimed to: validate the power of different echocardiographic LVH criteria, derived from sexspecific upper limits of normality, in a selected sample of healthy individuals belonging to the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) population, to predict cardiovascular and all-cause mortality; and compare the prognostic value of the different LVM indexes.
using a calibrated electronic scale, with the patients wearing indoor clothing without shoes. Height was recorded to the nearest 0.5 cm using a standardized wall-mounted height board. Data collection included ambulatory BP which was obtained by a monitoring device (Spacelabs 90207) set to obtain automated BP and heart rate oscillometric readings every 20 min over the 24 h. During the monitoring period, patients were asked to pursue their normal activities and to self-measure BP at home twice, namely at 0800 h and 2000 h using a semiautomatic oscillometric device (Philips, model HP 5331) on the arm contra-lateral to the one used for ambulatory BP monitoring.
METHODS
Follow-up
Population The PAMELA study was carried out in a sample of 3200 patients representative of the population of Monza (a town near Milan, Italy) for sex and age decades (25–74 years). Participation rate was 64%; thus data were collected in 2051 patients. Demographic characteristics of nonparticipants and participants were similar, and this was also the case for cardiovascular risk factors as assessed by data collected via phone interviews. Overall, 1716 patients out of 2051, without significant cardiac valve disease (>1þ valvular regurgitation, any degree of valvular stenosis or presence of prosthesis), had a valuable echocardiographic evaluation of LVM at baseline.
Entry data The methods employed in the PAMELA study have been previously described in detail [16]. Briefly, after an informed consent, patients were invited to undergo a comprehensive clinical evaluation at the out-patient clinic of the S. Gerardo University Hospital of Monza in the morning of a working day. Collected data included a full medical history, blood and urine samples, physical examination, standard 12-lead electrocardiogram, echocardiogram and three sphygmomanometric blood pressure (BP) measurements in the sitting position. Body weight was recorded to the nearest 0.1 kg Journal of Hypertension
Echocardiography Echocardiography was performed according to standardized procedures, as previously reported [17]. In brief, M-mode and two-dimensional echo examinations were carried out with a commercially available instrument (Acuson 128 CF; Computer Sonography). End-diastolic (d) and end-systolic (s) left ventricular internal diameters (LVIDs), interventricular septum (IVS) thickness and posterior wall thickness were measured off-line from two-dimensionallyguided M-mode tracings recorded at 50–100 cm/s speed, during at least three consecutive cycles. Relative wall thickness (RWT) was defined by the ratio of posterior wall and IVS thickness to LVIDd; LVM was estimated by using the corrected American Society of Echocardiography method: 0.8 {1.04 [(IVSd þ LVIDd þ PWTd) 3 LVIDd 3 ]} þ 0.6 [18] and normalized to BSA, height, height2.7, and height1.7. Echocardiographic tracings were obtained by two skilled operators and read by a third independent observer: intraobserver coefficient of variation was 0.6% for LVIDd, 3.1% for IVSd thickness, and 3.2% for PWd thickness. Participants were followed from the time of the initial medical visit (from 1990 to 1993) to 31 December 2008. Only 8 out of the 2051 participants of the PAMELA study were lost during the follow-up (0.39%). Death certificates were retrieved from the National Institute of Statistics database and coded using the International Classification of Diseases and Causes of Death, 10th revision (ICI-10) [19]. ICD-10 codes from I-0 to I-99 were considered as cardiovascular deaths. Each event was validated by Multinational Monitoring of Trends and Determinants in Cardiovascular Disease criteria (http://www.thl/publications/monica/ maual/index.htm).
Data analysis In each patient, three office BP measurements and two home BP measurements were obtained at the initial visit and separately averaged. Ambulatory BP readings were also averaged after editing for artifacts, based on preselected criteria [20]. The average of three measurements was used to define echocardiographic parameters. Cross-sectional analysis Partition values for LVH definition were derived from the distribution of LVM normalized to body size parameters (i.e. BSA, height, height2.7, and height1.7) using 1.96 SD above the mean from 675 healthy persons belonging to the www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1083
Cuspidi et al.
PAMELA study after excluding a total of 376 patients with isolated home or ambulatory hypertension, obesity, diabetes mellitus, and cardiovascular diseases. Values were expressed as means SD or as percentages. Means were compared by Student’s t test for independent samples and categorical data were analyzed by chi-square test or Fisher’s exact test when appropriate. A P value less than 0.05 was considered statistically significant. Follow-up analysis Baseline average LVM index and LVH prevalence rates, as detected by four indexation methods, were compared in patients with and without incident cardiovascular and all-cause mortality. Receiver-operating characteristic (ROC) curve analyses were performed in order to evaluate the diagnostic performance of echocardiographic LVH criteria in predicting cardiovascular mortality. The area under the curve (AUC), sensitivity, specificity, as well as negative and positive predictive values, were used to assess the discriminant power of echocardiographic cut-offs in predicting cardiovascular mortality. Agreement in diagnostic accuracy among LVH criteria were assessed using Kappa statistic (k). Crude and adjusted hazard ratios of fatal cardiovascular events and all-cause mortality were calculated by Cox’s proportional-hazard model [21]. Hazard ratio was calculated for each echocardiographic LVH criterion and for LVM index as a continuous variable. To this purpose, hazard ratio was determined for 1 SD increment of LVM index. Data were adjusted for age, sex, average 24-h SBP, previous cardiovascular disease, fasting blood glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL)-cholesterol, tobacco consumption, and antihypertensive drugs. All tests were two-sided and a P value less than 0.05 was considered as statistically significant. Statistical analysis was performed by SAS System (version 9.2; SAS Institute Inc., Cary, North Carolina, USA).
RESULTS A total of 1716 patients (50.4% men, mean age 50.3 13.7 years) with a good-quality echocardiographic examination were included in baseline analysis. Mean office BP was 132 21/84 10 mmHg and mean 24-h BP was 120 11/ 74 7 mmHg. Average BMI and waist circumference was 25.5 4.4 kg/m2 and 86 12 cm, respectively.
Left ventricular hypertrophy criteria and left ventricular hypertrophy prevalence rates Left ventricular hypertrophy was defined according to four sex-specific criteria as LVM index equal to or higher than: 114 g/m2 in men and 99 g/m2 in women; 123 g/height in men and 101 g/height in women; 51 g/height2.7 in men and 47 g/height2.7 in women; and 86 g/height1.7 in men and 74 g/height1.7 in women. These cut-offs, as described in the ‘Methods’ section, are derived from sex-specific upper limits of normality (mean þ 1.96 SD) for LVM index in 675 healthy individuals (284 men and 391 women) with sustained normotension. According to these partition values, prevalence rates of LVH in the study population ranged from 14.2% (LVM/BSA) 1084
www.jhypertension.com
to 18.0% (LVM/height2.7). The prevalence LVH was nonsignificantly higher in men than in women by LVM/BSA and LVM/height (14.5 vs. 13.8% and 17.6 vs. 17.0%, respectively; P ¼ 0.68 and P ¼ 0.74). The opposite trend was observed when LVH was diagnosed by LVM indexed to height2.7 and height1.7 (17.1 vs. 23.2% and 16.8 vs. 21.0%, respectively; P ¼ 034, and P ¼ 0.76). Table 1 reports demographic and clinical data of patients with and without LVH according to LVM/BSA (Table 1b) and LVM/height2.7 (Table 1b). Compared with patients with normal LVM, regardless of the index criterion, those with LVH were older, had higher BMI, office and ambulatory BP, glucose and triglyceride levels, and lower HDL-cholesterol. Furthermore, they were less frequently active smokers and had a higher prevalence of obesity and previous cardiovascular events. No difference was found in sex distribution between groups. Similar demographic and clinical findings were obtained when LVM was indexed by height and height1.7 (data not shown). Demographic and clinical characteristics of the four groups with LVH were superimposable, with the only exception of BMI, which was lower in patients defined by LVM/BSA as compared to the remaining three groups.
Left ventricular hypertrophy and cardiovascular mortality Over a follow-up of 211 months, a total of 109 fatal cardiovascular events were documented. Of these, 89 (78.8%) occurred in patients with reliable baseline echocardiographic data. Cardiovascular mortality rate per 100 patient-years and total mortality rate per 100 patient-years were 0.316 and 0.938, respectively. The relationship between LVH at baseline evaluation as assessed by four different criteria and incidence of cardiovascular events was investigated with four approaches: by comparing LVM index values and LVH prevalence in patients with and without incident cardiovascular mortality; by analyzing the performance of ROC curves; by calculating the risk of fatal cardiovascular events associated with the presence of LVH and 1 SD increment of LVM index in unadjusted and adjusted Cox models; and by classifying patients according to the presence or absence of LVH simultaneously defined by two more common criteria (LVM/BSA and LVM/height2.7) and examining the pattern of relative risk among those in the concordant and discordant cells. Patients who died from a cardiovascular event during follow-up had higher baseline LVM index than their alive counterparts (110 29 vs. 85 20 g/m2; 53 15 vs. 39 11 g/height2.7; 122 36 vs. 91 24 g/height; 87 25 vs. 64 17 g/height1.7; P < 0.0001 for all). The former group also exhibited a marked higher prevalence of LVH (LVH/BSA: 52.8 vs. 12.0%; LVH/height2.7: 55.1 vs. 16.0%; LVH/height: 52.8 vs. 15.4%; LVH/height1.7: 53.9 vs. 15.1%). A significant difference between groups persisted after adjusting for several covariates (data not shown). Diagnostic accuracy of each echocardiographic criterion in predicting cardiovascular mortality is shown in Table 2. The sensitivity was lowest for LVH/BSA and LVH/height, intermediate for LVH/height1.7 and highest for LVH/ height2.7. LVH/BSA provided the best specificity. Overall, Volume 33 Number 5 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Left ventricular hypertrophy and cardiovascular mortality TABLE 1. Demographic and clinical characteristics in patients without and with left ventricular hypertrophy (a) LVMI
Prognostic value of left ventricular mass normalized to different body size indexes: findings from the PAMELA population Cesare Cuspidi a,b, Rita Facchetti a, Michele Bombelli a, Carla Sala c, Marijana Tadic d, Guido Grassi a,e, and Giuseppe Mancia a,b
Aim: We estimated the risk of cardiovascular and all-cause mortality associated with left ventricular hypertrophy (LVH) as assessed by left ventricular mass (LVM), normalized by various indexation methods in 1716 representatives of the general population of Monza, enrolled in the Pressioni Arteriose Monitorate E Loro Associazioni study. Methods: LVH was defined according to four sex-specific criteria derived from the upper limits of normality for LVM index in the healthy normotensive fraction of the Pressioni Arteriose Monitorate E Loro Associazioni population. Death certificates were collected over an average 211 months of follow-up. Results: During follow-up, 89 fatal cardiovascular events and 264 all-cause deaths were observed. LVH prevalence rates in the whole population ranged from 14.2% [LVM/ body surface area (BSA)] to 18.0% (LVM/height2.7). Adjusted risk (for baseline covariates, including ambulatory blood pressure) of cardiovascular mortality was increased in patients with LVH, regardless of the indexation type: LVH/BSA [hazard ratio 3.19, 95% confidence interval (CI) 2.02–5.06, P < 0.0001], LVH/height1.7 (hazard ratio 2.39, 95% CI 1.51–3.78, P ¼ 0.0002), LVH/height2.7 (hazard ratio 2.38, 95% CI 1.50–3.76, P ¼ 0.0002), LVH/height (hazard ratio 2.28, 95% CI 1.44–3.60 P ¼ 0.0004). Similar findings were observed for all-cause mortality and when LVM was assessed as a continuous variable. The fraction of patients (5%) classified into the LVH group by height2.7, but not by BSA, had a mild increased LVM index and showed no increased risk. Conclusions: LVH, irrespective of indexation methods for LVM, confers an increased risk of cardiovascular and allcause mortality in the general population. LVH, detected by height-based indexes, but not by BSA-based criteria, was not associated with increased mortality; this finding, however, was based on a small group of patients and will deserve further investigations. Keywords: cardiovascular mortality, indexation methods, left ventricular hypertrophy Abbreviations: AUC, area under the curve; BP, Blood pressure; BSA, body surface area; CI, confidence interval; LVH, left ventricular hypertrophy; LVM, left ventricular
mass; PAMELA, Pressioni Arteriose Monitorate E Loro Associazioni study; ROC, receiver-operating characteristic
INTRODUCTION
C
ardiovascular disease represents the leading cause of mortality among noncommunicable chronic diseases and is responsible for 30% of deaths worldwide. Ischemic heart disease and cerebrovascular disease are responsible for the majority of cardiovascular mortality, accounting for about 13.0 million of deaths annually [1,2]. Control and management of cardiovascular risk factors is fundamental to reduce the impressive burden of cardiovascular complications. As subclinical alterations in cardiovascular structure reflect cumulative damages induced by risk factors and represent an intermediate stage between risks factor exposure and cardiovascular events, early detection of these damages may have important implications for prevention of cardiovascular morbidity and mortality [3]. Among the markers of target organ damage, increased left ventricular mass (LVM), as assessed by echocardiography or more accurately by MRI, is a powerful predictor of cardiovascular and all-cause mortality, independently of conventional risk factors [4–10]. In healthy children and adults, LVM is closely related to anthropometric parameters such as weight, height, and their derived measures body surface area (BSA) and BMI [11,12]. Although the strength of this relation is blunted by several conditions such as hypertension, diabetes mellitus, obesity, and aging,
Journal of Hypertension 2015, 33:1082–1089 a
Department of Health Science, University of Milano-Bicocca, bIstituto Auxologico Italiano IRCCS, cDepartment of Clinical Sciences and Community Health University of Milano and Fondazione Ospedale Maggiore Policlinico, Milan, Italy, dUniversity Clinical Hospital Centre ‘Dragisa Misovic’, Belgrade, Serbia and eIRCCS Multimedica, Sesto San Giovanni, Milan, Italy Correspondence to Professor Cesare Cuspidi, Istituto Auxologico Italiano, Clinical Research Unit, Viale della Resistenza 23, 20036 Meda, Italy. Tel: +39 0362/772433; fax: +39 0362/772416; e-mail: [email protected] Received 21 September 2014 Revised 18 December 2014 Accepted 18 December 2014 J Hypertens 33:1082–1089 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000527
1082
www.jhypertension.com
Volume 33 Number 5 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Left ventricular hypertrophy and cardiovascular mortality
indexation of LVM to body size measures improves the clinical and prognostic value of this biomarker [13]. In the past three decades, different methods have been proposed for LVM normalization in the attempt to differentiate physiologic LVM adaptations from morbid conditions [14]. Among these methods, indexation BSA is the more common in clinical practice; this approach, however, has been criticized because: three-dimensional variable LVM is divided by two-dimensional variable BSA, and indexation to BSA tends to underestimate left ventricular hypertrophy (LVH) prevalence in obese individuals. Alternative LVM indexations to body height, or more properly, to height to the power of different exponents (i.e. 2.7, 1.9, and 1.7) were proposed. Height to the power of 2.7 (a value close to the power of 3 that regulates the relationship between three-dimensional LVM and mono-dimensional height) is the most used allometric signal for LVM normalization [15]. The ability of indexation to height2.7 to properly account for body size has been recently challenged by the findings of a study in 7528 participants from a multiethnic population-based adult sample [10]. In that study, only LVH defined by LVM/height1.7 demonstrated a consistent relationship with all fatal and nonfatal cardiovascular events. On the contrary, LVM/height2.7 or LVM/BSA failed to predict cardiovascular outcome and all-cause death. In the present study, we aimed to: validate the power of different echocardiographic LVH criteria, derived from sexspecific upper limits of normality, in a selected sample of healthy individuals belonging to the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) population, to predict cardiovascular and all-cause mortality; and compare the prognostic value of the different LVM indexes.
using a calibrated electronic scale, with the patients wearing indoor clothing without shoes. Height was recorded to the nearest 0.5 cm using a standardized wall-mounted height board. Data collection included ambulatory BP which was obtained by a monitoring device (Spacelabs 90207) set to obtain automated BP and heart rate oscillometric readings every 20 min over the 24 h. During the monitoring period, patients were asked to pursue their normal activities and to self-measure BP at home twice, namely at 0800 h and 2000 h using a semiautomatic oscillometric device (Philips, model HP 5331) on the arm contra-lateral to the one used for ambulatory BP monitoring.
METHODS
Follow-up
Population The PAMELA study was carried out in a sample of 3200 patients representative of the population of Monza (a town near Milan, Italy) for sex and age decades (25–74 years). Participation rate was 64%; thus data were collected in 2051 patients. Demographic characteristics of nonparticipants and participants were similar, and this was also the case for cardiovascular risk factors as assessed by data collected via phone interviews. Overall, 1716 patients out of 2051, without significant cardiac valve disease (>1þ valvular regurgitation, any degree of valvular stenosis or presence of prosthesis), had a valuable echocardiographic evaluation of LVM at baseline.
Entry data The methods employed in the PAMELA study have been previously described in detail [16]. Briefly, after an informed consent, patients were invited to undergo a comprehensive clinical evaluation at the out-patient clinic of the S. Gerardo University Hospital of Monza in the morning of a working day. Collected data included a full medical history, blood and urine samples, physical examination, standard 12-lead electrocardiogram, echocardiogram and three sphygmomanometric blood pressure (BP) measurements in the sitting position. Body weight was recorded to the nearest 0.1 kg Journal of Hypertension
Echocardiography Echocardiography was performed according to standardized procedures, as previously reported [17]. In brief, M-mode and two-dimensional echo examinations were carried out with a commercially available instrument (Acuson 128 CF; Computer Sonography). End-diastolic (d) and end-systolic (s) left ventricular internal diameters (LVIDs), interventricular septum (IVS) thickness and posterior wall thickness were measured off-line from two-dimensionallyguided M-mode tracings recorded at 50–100 cm/s speed, during at least three consecutive cycles. Relative wall thickness (RWT) was defined by the ratio of posterior wall and IVS thickness to LVIDd; LVM was estimated by using the corrected American Society of Echocardiography method: 0.8 {1.04 [(IVSd þ LVIDd þ PWTd) 3 LVIDd 3 ]} þ 0.6 [18] and normalized to BSA, height, height2.7, and height1.7. Echocardiographic tracings were obtained by two skilled operators and read by a third independent observer: intraobserver coefficient of variation was 0.6% for LVIDd, 3.1% for IVSd thickness, and 3.2% for PWd thickness. Participants were followed from the time of the initial medical visit (from 1990 to 1993) to 31 December 2008. Only 8 out of the 2051 participants of the PAMELA study were lost during the follow-up (0.39%). Death certificates were retrieved from the National Institute of Statistics database and coded using the International Classification of Diseases and Causes of Death, 10th revision (ICI-10) [19]. ICD-10 codes from I-0 to I-99 were considered as cardiovascular deaths. Each event was validated by Multinational Monitoring of Trends and Determinants in Cardiovascular Disease criteria (http://www.thl/publications/monica/ maual/index.htm).
Data analysis In each patient, three office BP measurements and two home BP measurements were obtained at the initial visit and separately averaged. Ambulatory BP readings were also averaged after editing for artifacts, based on preselected criteria [20]. The average of three measurements was used to define echocardiographic parameters. Cross-sectional analysis Partition values for LVH definition were derived from the distribution of LVM normalized to body size parameters (i.e. BSA, height, height2.7, and height1.7) using 1.96 SD above the mean from 675 healthy persons belonging to the www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1083
Cuspidi et al.
PAMELA study after excluding a total of 376 patients with isolated home or ambulatory hypertension, obesity, diabetes mellitus, and cardiovascular diseases. Values were expressed as means SD or as percentages. Means were compared by Student’s t test for independent samples and categorical data were analyzed by chi-square test or Fisher’s exact test when appropriate. A P value less than 0.05 was considered statistically significant. Follow-up analysis Baseline average LVM index and LVH prevalence rates, as detected by four indexation methods, were compared in patients with and without incident cardiovascular and all-cause mortality. Receiver-operating characteristic (ROC) curve analyses were performed in order to evaluate the diagnostic performance of echocardiographic LVH criteria in predicting cardiovascular mortality. The area under the curve (AUC), sensitivity, specificity, as well as negative and positive predictive values, were used to assess the discriminant power of echocardiographic cut-offs in predicting cardiovascular mortality. Agreement in diagnostic accuracy among LVH criteria were assessed using Kappa statistic (k). Crude and adjusted hazard ratios of fatal cardiovascular events and all-cause mortality were calculated by Cox’s proportional-hazard model [21]. Hazard ratio was calculated for each echocardiographic LVH criterion and for LVM index as a continuous variable. To this purpose, hazard ratio was determined for 1 SD increment of LVM index. Data were adjusted for age, sex, average 24-h SBP, previous cardiovascular disease, fasting blood glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL)-cholesterol, tobacco consumption, and antihypertensive drugs. All tests were two-sided and a P value less than 0.05 was considered as statistically significant. Statistical analysis was performed by SAS System (version 9.2; SAS Institute Inc., Cary, North Carolina, USA).
RESULTS A total of 1716 patients (50.4% men, mean age 50.3 13.7 years) with a good-quality echocardiographic examination were included in baseline analysis. Mean office BP was 132 21/84 10 mmHg and mean 24-h BP was 120 11/ 74 7 mmHg. Average BMI and waist circumference was 25.5 4.4 kg/m2 and 86 12 cm, respectively.
Left ventricular hypertrophy criteria and left ventricular hypertrophy prevalence rates Left ventricular hypertrophy was defined according to four sex-specific criteria as LVM index equal to or higher than: 114 g/m2 in men and 99 g/m2 in women; 123 g/height in men and 101 g/height in women; 51 g/height2.7 in men and 47 g/height2.7 in women; and 86 g/height1.7 in men and 74 g/height1.7 in women. These cut-offs, as described in the ‘Methods’ section, are derived from sex-specific upper limits of normality (mean þ 1.96 SD) for LVM index in 675 healthy individuals (284 men and 391 women) with sustained normotension. According to these partition values, prevalence rates of LVH in the study population ranged from 14.2% (LVM/BSA) 1084
www.jhypertension.com
to 18.0% (LVM/height2.7). The prevalence LVH was nonsignificantly higher in men than in women by LVM/BSA and LVM/height (14.5 vs. 13.8% and 17.6 vs. 17.0%, respectively; P ¼ 0.68 and P ¼ 0.74). The opposite trend was observed when LVH was diagnosed by LVM indexed to height2.7 and height1.7 (17.1 vs. 23.2% and 16.8 vs. 21.0%, respectively; P ¼ 034, and P ¼ 0.76). Table 1 reports demographic and clinical data of patients with and without LVH according to LVM/BSA (Table 1b) and LVM/height2.7 (Table 1b). Compared with patients with normal LVM, regardless of the index criterion, those with LVH were older, had higher BMI, office and ambulatory BP, glucose and triglyceride levels, and lower HDL-cholesterol. Furthermore, they were less frequently active smokers and had a higher prevalence of obesity and previous cardiovascular events. No difference was found in sex distribution between groups. Similar demographic and clinical findings were obtained when LVM was indexed by height and height1.7 (data not shown). Demographic and clinical characteristics of the four groups with LVH were superimposable, with the only exception of BMI, which was lower in patients defined by LVM/BSA as compared to the remaining three groups.
Left ventricular hypertrophy and cardiovascular mortality Over a follow-up of 211 months, a total of 109 fatal cardiovascular events were documented. Of these, 89 (78.8%) occurred in patients with reliable baseline echocardiographic data. Cardiovascular mortality rate per 100 patient-years and total mortality rate per 100 patient-years were 0.316 and 0.938, respectively. The relationship between LVH at baseline evaluation as assessed by four different criteria and incidence of cardiovascular events was investigated with four approaches: by comparing LVM index values and LVH prevalence in patients with and without incident cardiovascular mortality; by analyzing the performance of ROC curves; by calculating the risk of fatal cardiovascular events associated with the presence of LVH and 1 SD increment of LVM index in unadjusted and adjusted Cox models; and by classifying patients according to the presence or absence of LVH simultaneously defined by two more common criteria (LVM/BSA and LVM/height2.7) and examining the pattern of relative risk among those in the concordant and discordant cells. Patients who died from a cardiovascular event during follow-up had higher baseline LVM index than their alive counterparts (110 29 vs. 85 20 g/m2; 53 15 vs. 39 11 g/height2.7; 122 36 vs. 91 24 g/height; 87 25 vs. 64 17 g/height1.7; P < 0.0001 for all). The former group also exhibited a marked higher prevalence of LVH (LVH/BSA: 52.8 vs. 12.0%; LVH/height2.7: 55.1 vs. 16.0%; LVH/height: 52.8 vs. 15.4%; LVH/height1.7: 53.9 vs. 15.1%). A significant difference between groups persisted after adjusting for several covariates (data not shown). Diagnostic accuracy of each echocardiographic criterion in predicting cardiovascular mortality is shown in Table 2. The sensitivity was lowest for LVH/BSA and LVH/height, intermediate for LVH/height1.7 and highest for LVH/ height2.7. LVH/BSA provided the best specificity. Overall, Volume 33 Number 5 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Left ventricular hypertrophy and cardiovascular mortality TABLE 1. Demographic and clinical characteristics in patients without and with left ventricular hypertrophy (a) LVMI
