Abstract
Purpose: Left ventricular (LV) remodelling is observed in numerous patients with hypertension and is a principal cause of heart failure in elderly patients. The aim of this study was to determine the relationships between age and structural/functional LV remodelling observed in elderly hypertensive patients.
Methods: A total of 557 elderly hypertensive patients (mean age: 74.0 ± 8.6 years) with preserved LV systolic function underwent echocardiography and 24-hour blood pressure (BP) measurement.
Results: Overall, 41.1% of patients had LV hypertrophy, 77.9% had increased relative wall thickness (RWT) defined as RWT >0.42, and 31.8% had both. Logistic analysis of the entire study population showed that increased RWT was associated with both 24-hour systolic BP (odds ratio (OR) 1.38, 95% confidence interval (CI) 1.12 to 1.70) and age (OR 1.32, 95%CI 1.08 to 1.61), whereas increased RWT was associated only with age (OR 1.61, 95%CI 1.23 to 2.11) after excluding patients with LV hypertrophy. Univariate and multivariate linear regression analyses of all patients showed that LV diastolic echocardiographic parameters were consistently associated with age (p ≤ .001) alone, even considering LV structural changes.
Conclusions: Age was independently correlated with LV concentric/functional changes regardless of LV hypertrophy, suggesting that ageing is independently involved in the progression of LV remodelling.
Introduction
In the coming 10 years, the only increasing population in Japan is the very elderly. Therefore, adequate treatment of cardiovascular disease is required on the basis of the understanding of interactive physiological processes between aging and cardiovascular function.
Heart remodelling, especially left ventricular (LV) remodelling, consists of complex and diverse changes in cardiac structure and function that progress with increasing patient age [Citation1], and are known to be associated with increased cardiovascular morbidity and mortality [Citation2]. Thus, elucidating the mechanisms of LV remodelling is important for medical care of the elderly. While many studies have shown that ageing correlates with LV remodelling, it is not clear whether this is a direct or indirect relationship, because various diseases that affect structural/functional LV remodelling, such as hypertension, obesity, diabetes, chronic kidney disease, and hyperlipidemia, also develop and worsen with ageing.
Echocardiography has allowed the establishment of more precise criteria for LV remodelling. For example, LV remodelling is now evaluated by characterization of LV mass index (LVMI; hypertrophy) and relative wall thickness (RWT; the ratio of wall thickness to chamber diameter) and can be classified into four patterns: normal (normal LVMI and normal RWT), concentric remodelling (normal LVMI with increased RWT), eccentric hypertrophy (increased LVMI with normal RWT), and concentric hypertrophy (increased LVMI and increased RWT) [Citation3,Citation4]. Some studies have attempted to clarify the relationship between ageing and LV structural changes according to the above criteria [Citation5,Citation6], but the relationship between age and increased RWT which is interpreted as LV concentric change, remains unclear. Thus, the first aim of this study was to determine whether age is directly associated with structural LV remodelling, especially LV concentric change.
In addition, many studies have concluded that ageing is associated with functional LV remodelling [Citation7,Citation8]. However, some recent studies showed that LV structural changes and LV functional changes, especially LV diastolic dysfunction, are closely correlated [Citation9]. Therefore, it cannot yet be concluded that ageing itself is truly involved in LV functional change. Thus, the second aim of this study was to clarify the association of age and LV functional change, with consideration of LV structural change. Therefore, a retrospective, cross-sectional study targeting elderly hypertensive patients was performed.
Methods
Study design and participants
A retrospective review of the medical records of all 1500 hypertensive patients ≥60 years old who regularly attended the outpatient clinics of the Department of Cardiology and who had undergone 24-hour ambulatory BP measurements from January 2005 to June 2007 was conducted. Information on medical history, present medical conditions, and antihypertensive agents was obtained from their medical records. Patients with atrial fibrillation, mild to severe valvular heart disease, ischemic heart disease, dilated or hypertrophic cardiomyopathy, overt LV wall motion abnormalities, ejection fraction <50%, severe diastolic failure with a ratio of peak velocities of early (E) and late (A) diastolic flows (E/A) > 1.5, or early flow deceleration time (DecT) < 130 msec [Citation10,Citation11] based on cardiac ultrasonographic data were excluded from the study. The final study sample consisted of 557 patients after excluding those with incomplete ambulatory BP data. The Ethics Committee of Tokyo Metropolitan Geriatric Hospital approved all procedures, and each patient gave informed consent to participate.
24-Hour ambulatory BP measurement
Ambulatory blood pressure (BP) measurement (ABPM) was performed using a portable automatic manometer (ES-H531, Terumo Corp., Tokyo, Japan). Non-invasive BP measurements were obtained every 30 min. Subjects whose BP data were lost due to artefacts in >10% of the total recordings were not included in the study. In addition, controlled hypertension was defined as both average systolic BP <130 mmHg and average diastolic BP <80 mmHg under treatment, for statistical analysis.
Echocardiographic quantification of LV mass index and relative wall thickness
Echocardiographic assessment was carried out using a Vivid 7 Doppler echocardiograph with a 2.5-MHz transducer (GE Healthcare, Tokyo, Japan). In each patient, cardiac chamber quantification by two-dimensional echocardiography was performed according to the guidelines of the American Society of Echocardiography [Citation12]. LV end-diastolic and end-systolic dimensions, LV septal and posterior wall thicknesses, and LA anteroposterior diameter were measured just below the mitral leaflet tips in long- and short-axis views using M-mode echocardiography. LV mass was calculated using Devereux’s formula [Citation13], and LV mass index (LVMI) was obtained by normalization to body surface area. Relative wall thickness (RWT) was measured at end-diastole as: (2 × posterior wall thickness)/LV internal dimension. Patterns of abnormal LV structure were defined as follows in this study: (i) LV concentric remodelling (LVMI ≤104 g/m2 in females or ≤116 g/m2 in males combined with RWT >0.42); (ii) eccentric LVH (LVMI >104 g/m2 in females or >116 g/m2 in males combined with RWT ≤0.42); and (iii) concentric LVH (LVMI >104 in females or >116 g/m2 in males combined with RWT >0.42) [Citation12,Citation14].
Doppler echocardiography
To evaluate LV diastolic function, pulsed-wave Doppler examination of mitral inflow was performed as previously described [Citation15]. In this study, peak velocities of early (E) and late (A) diastolic flow (E/A), early flow deceleration time (DecT), and the ratio DecT/E were measured.
Evaluation of other clinical associated factors
Information on demographic characteristics and associated factors was collected from the medical records. Body mass index (BMI) was calculated by dividing weight (in kilograms) by the square of height (in meters). “Regular drinker” was defined as the patients with habitually drinking more than once a week. Blood samples were collected for determination of hemoglobin A1c (HbA1c), cholesterol, and serum creatinine (sCr). Diabetes mellitus was defined as HbA1c ≥ 6.5% or active use of anti-diabetes drugs. Hyperlipidemia was defined as low density cholesterol ≥140 mg/dl or active use of anti-hyperlipidemia drugs.
Statistical analysis
IBM SPSS Statistics Version 20 (IBM, New York, NY) was used for statistical analysis. All values are expressed as mean ± S.D (standard deviation) or percentage. Comparisons of continuous variables among the four subgroups categorized by LV structural change patterns were performed by analysis of variance (ANOVA) with post hoc test, and comparisons of categorical variables among the four subgroups were performed using Chi-squared test of independence with post hoc testing; pairwise comparisons with Bonferroni corrections of the P values. Variables for which significant differences (p < .05) were observed among the four subgroups were included in subsequent logistic or linear regression analyses. For LV structural remodelling, univariate and multivariate logistic regression analyses were performed. For LV functional remodelling, univariate and multivariate liner regression analyses were performed. A value of p < .05 was considered significant.
Results
Patients’ characteristics
The characteristics of the overall group of patients and the four subgroups categorized by LV geometric changes are shown in . Based on the established classification of LV structural changes, 557 patients were divided into four subgroups: normal subgroup composed of 71 patients (12.7%), concentric remodelling subgroup composed of 257 patients (46.1%), eccentric hypertrophy subgroup composed of 52 patients (9.3%), and concentric hypertrophy subgroup composed of 177 patients (31.8%). As shown, age, sex, BMI, sCr, 24-hour systolic BP, controlled hypertension, use of a calcium channel blocker (CCB), an angiotensin II receptor blocker (ARB), or a diuretic, and LV structural/functional echocardiographic parameters or indices (RWT, LVMI, E/A, DecT, E, Midwall FS, and DecT/E) were significantly different among the subgroups. The 24-hour systolic BP was higher in the concentric hypertrophy subgroup than in other subgroups (concentric hypertrophy, 138.9 ± 19.6 mmHg; normal, 123.2 ± 14.2 mmHg; concentric remodelling, 125.6 ± 16.7 mmHg; eccentric hypertrophy, 127.7 ± 15.8 mmHg; concentric hypertrophy versus normal, p < .001; concentric hypertrophy versus concentric remodelling, p < .001; concentric hypertrophy versus eccentric hypertrophy, p = .002).
Table 1A. Characteristics of entire study population and four subgroups categorized by LV structural changes.
Table 1B. Echocardiography data of entire study population and four subgroups categorized by LV structural changes.
Table 2. Univariate and multivariate correlation analyses between LV geometric change parameters and clinical data for entire study population.
Recently, Khouri et al. suggested the additional categorizations of eccentric and concentric LV hypertrophy based on with or without LV dilation, and clarified each subgroup’s characteristic [Citation16]. According to it, we additionally analyzed LV hypertrophy patients, and found the following results; (1) BNP and sCr were higher in subgroups with LV dilation but were not statistically significant (p > .05). (2) Midwall FS was significantly higher in subgroups with LV dilation (p < .01).
Logistic analysis of LV structural changes in entire study population
shows the logistic analysis between LV structural changes and clinical data for the entire study population. Multiple factors were significantly correlated (p < .05) with each LV structural change in univariate logistic analyses. Subsequent multivariate logistic analyses showed that 24-hour systolic BP was associated with LV structural changes (LV hypertrophy OR 2.08, 95%CI 1.52 to 2.83; LV concentricity OR 1.38, 95%CI 1.12 to 1.70), and age was associated with LV concentricity alone (OR 1.32, 95%CI 1.08 to 1.61).
Univariate and multivariate correlation analyses of LV functional changes
shows the univariate and subsequent multivariate correlation analyses between LV diastolic functional parameters and clinical/LV structural data for the entire study population. The left columns in show the results of univariate correlation analyses, and the right columns show the results of multivariate correlation analyses. All LV functional parameters were significantly associated with age (E/A p < .001, DecT p < .001, E p = .001, DecT/E p < .001). These data indicate that age itself was independently associated with LV diastolic dysfunction.
Table 3. Univariate and multivariate correlation analyses between LV functional parameters and clinical/LV structural data for entire study population.
Logistic analyses of increased RWT in patients without LV hypertrophy
Additional univariate and multivariate logistic analyses of increased RWT (RWT > 0.42) in patients without LV hypertrophy were performed (). Left columns show univariate analyses, middle columns show multivariate analyses of clinical data only, and right columns show multivariate analyses including LV functional echocardiographic indices for the normal and concentric remodelling subgroups, which were composed of 328 patients. Interestingly, age was the only clinical risk factor consistently associated with increased RWT in both multivariate analyses (multivariate (1) OR 1.61, 95%CI 1.23 to 2.11; multivariate (2) OR 1.44, 95%CI 1.06 to 1.95).
Table 4. Univariate and multivariate correlation analyses between increased relative wall thickness and clinical data for patients without hypertrophy.
Discussion
The main finding of this study was that age was independently associated with LV concentric change in elderly patients with treated hypertension, even considering the effects of LV functional changes. In addition, age was independently associated with diastolic dysfunction, even considering the effects of LV structural changes. These findings may be helpful to clarify the mechanisms of LV remodelling and to establish the optimal mode of medical treatment for elderly hypertensive patients.
Age is independently associated with LV concentric change
LV concentric change is known to involve major morphological LV remodelling [Citation17]. As shown in the present data, the most common LV structural remodelling pattern in elderly patients with treated hypertension was LV concentric remodelling, which is not accompanied by LV hypertrophy but by LV concentric changes (increased RWT). Patients with LV concentric remodelling have a worse prognosis than those with normal geometry [Citation18–20]. Furthermore, LV concentric change with hypertrophy (concentric hypertrophy pattern) is associated with an increase in mortality and the frequency of heart failure [Citation21]. Thus, LV concentric remodelling, either with or without LV hypertrophy, is thought to be harmful for elderly hypertensive patients [Citation22].
Several studies have investigated the relationship between ageing and LV concentric alteration but showed contradictory results. In studies of patients with hypertension, the association between increased RWT and age is not yet clear; some studies could show this association [Citation23,Citation24] but other studies could not [Citation25,Citation26]. On the other hand, in studies of healthy population, increased RWT was observed to be associated with age [Citation5,Citation27]. Considering together, LV hypertrophy might make it difficult to evaluate the independent effect of age to increased RWT in some reason; such as the interaction between LV hypertrophy and concentric change. With respect to this point, the present study clearly showed that age is the principal factor related to LV concentric change even in case of hypertensive patients. Thus, regardless of presence or absence of hypertension, increased RWT is consistently associated with age, and various clinical risk factors related to this geometrical change, such as hypertension, might only promote this structural change.
Age is independently associated with LV diastolic dysfunction
LV diastolic dysfunction is a serious condition in elderly hypertensive patients, because limitation of diastolic filling leads to various clinical features of heart failure that are caused by a decrease in cardiac output or left atrial pressure elevation [Citation28] despite normal systolic function and ejection fraction. The present study showed that age is independently associated with LV diastolic dysfunction in univariate and multivariate correlation analyses considering LV structural changes (LVMI and RWT). Therefore, this suggests that age itself is involved in the process of LV diastolic dysfunction. Although LV structural changes were not studied jointly, a correlation between age and LV functional change has been suggested [Citation7,Citation8,Citation27]. Thus, the present results may reinforce previous studies showing an association of age and LV diastolic dysfunction.
Clinical significance
Recent basic studies have begun to elucidate the molecular and cellular mechanisms of LV remodelling with ageing. All of these studies suggested that relaxation of cardiomyocytes and elasticity of the extracellular matrix deteriorate with ageing. When these abnormalities accumulate to a certain level in elderly patients, LV diastolic dysfunction is thought to manifest, as shown in the present study.
On the other hand, the way age affects LV concentric change remains unclear. However, recent basic studies reported the following changes of LV with ageing; (1) the number of cardiomyocytes decrease and residual cardiomyocytes excessively contract for compensation [Citation29,Citation30], (2) abnormal energy metabolisms of cardiomyocytes are caused [Citation31,Citation32], and (3) extracellular fibrosis and cardiomyocyte stiffening are caused [Citation33]. All of these changes theoretically cause LV wall thickness and cavity size reduction, which result to LV concentric remodelling.
LV concentric change and diastolic dysfunction are both related to cardiovascular morbidity and mortality; therefore, it is thought to be important to prevent the harmful LV remodelling progress. Thus, not only BP management, but also other new therapeutic strategies that can directly delay age-related cardiac remodelling, such as ω-3 PUFA supplementation, modulation of MMP or tissue inhibitor of MMP, and modulators of microRNA-34a [Citation34–36], are thought to be needed in the future.
Conclusions
Age is independently associated with structural/functional LV remodelling. This may directly lead to heart failure and may be indirectly associated with various geriatric syndromes in elderly hypertensive patients.
Limitations
This study was based on retrospective and cross-sectional data. Therefore, an independent association between age and structural/functional heart remodelling could be identified, but the causal relationships between them cannot be clarified. Thus, an additional longitudinal study will be needed. Second, in the present study, the frequency of eccentric hypertrophy was relatively low compared with that in previous studies. The difference may be due to the patients’ age of the present study (participants were older in the present study) and the strict criteria for valvular diseases. However, considering the region of interest, such differences may be helpful for clarifying the important effect of ageing on LV remodelling. Furthermore, the present study included only hypertensive patients; therefore, the case of normotensive patients remains unclear. However, considering that hypertension increases universally with ageing, it is likely that the same results will be obtained in healthy elderly subjects.
Acknowledgements
The authors would like to thank Dr. Iwao Kuwajima and Mrs. Azusa Ishikawa for helping to organize the database.
Disclosure statement
The authors declare that no conflict of interest exists.
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