Mitral deceleration index is associated with aortic root dilatation and not to biventricular structural changes in essential hypertension

Abstract

Background and aim. The ratio of deceleration time to early mitral wave velocity (mitral deceleration index, MDI) has been recently shown to predict cardiovascular events more precisely than deceleration time alone in human hypertension. Data, however, about the relationship of this parameter with cardiac structure are scant. In the present study, we investigated such an association in uncomplicated essential hypertensives. Methods. A total of 329 hypertensive subjects categorized in tertiles of MDI were considered for the analysis. All patients underwent the following procedures: (i) physical examination and clinic blood pressure measurement; (ii) routine laboratory investigations; (iii) M-mode, two-dimensional and Doppler echocardiography aimed at a comprehensive assessment of left- and right-sided chambers. Results. Unadjusted left ventricular (LV) mass, right ventricular (RV) and aortic root diameter were significantly higher in the upper MDI tertile, but only aortic root diameter remained significant after adjustment for covariates. A progressive, non-significant increase in biventricular hypertrophy occurred across the MDI tertiles. In a multivariate analysis, MDI was significantly associated with age (β = 0.229, p = 0.001) and aortic root diameter (β = 0.226, p = 0.001); this was not the case for deceleration time alone. No association between MDI and LV as well as RV structural parameters was found. Conclusion. Our findings indicate that MDI is unrelated to LV and RV structural changes. Altered LV diastolic function, as assessed by MDI but not by deceleration time alone, is independently associated with aortic root dilatation, a phenotype predictive of incident cardiovascular morbidity and mortality.

Key Words::

• Aortic root dilatation
• diastole
• echocardiography
• hypertension

Introduction

Subclinical cardiac damage related to human hypertension includes a wide spectrum of manifestations such as left ventricular (LV) hypertrophy (LVH), LV systolic/diastolic dysfunction, left atrial dilatation, aortic root enlargement and right ventricular (RV) hypertrophy (RVH) (1–4). These phenotypes result from the interaction of a variety of haemodynamic, humoral and genetic factors operating in hypertension and represent an intermediate stage in the temporal evolution of the cardiovascular disease (5,6).

Most attention has been focused on LVH and diastolic dysfunction, because of the high prevalence of these subclinical abnormalities and, more importantly, their robust association with an increased risk of cardiovascular morbidity and mortality (7–9). A consistent body of evidence points towards LVH as a key factor in the pathogenesis of diastolic dysfunction, whereas other observations indicate that an impairment of LV relaxation and filling may precede the development of LVH (10).

Among Doppler indexes assessing diastolic function, the ratio of the peak early (E) to peak late (A) mitral inflow velocity (E/A ratio), and deceleration time of the early mitral flow have been widely used in clinical research and current practice (11,12). The relation of both indexes with cardiovascular outcomes has a U-shaped form, the lowest and highest values being associated with a poor cardiovascular prognosis in different clinical settings (12,13). Normalization of deceleration time to peak E velocity, which is related to left atrial pressure and preload volume, has been recently proposed in order to correct for changes in cardiac load, which is unrelated to the intrinsic LV diastolic properties. The prognostic value of deceleration time/peak E velocity index (mitral deceleration index, MDI) (or the inverse ratio, deceleration slope), has been recently assessed in a large population-based sample and in hypertensive subjects with electrocardiographic LVH (14,15). In both studies, MDI predicted cardiovascular events, at difference from their individual components and other validated indexes of diastolic function.

To date, scant information is available on the relationship between MDI and cardiovascular hypertensive structural changes. Therefore, we investigated the association of this index with established markers of subclinical cardiac damage in a cohort of uncomplicated essential hypertensives.

Methods

Study population

Three hundred and forty-three treated and untreated essential hypertensive individuals, mostly referred to our outpatient hypertension clinic by their general practitioners, were included in the study.

High blood pressure (BP) was defined, according to guidelines (6), as systolic BP (SBP) ≥ 140 mmHg and/or diastolic BP (DBP) ≥ 90 mmHg in untreated subjects; treated hypertensives were included regardless of BP values and duration of treatment. Main exclusion criteria were poor echocardiographic window, history or evidence of congestive heart failure, atrial fibrillation, previous stroke, significant cardiac valve disease (> 1+ valvular regurgitation, any degree of valvular stenosis or presence of prosthesis), previous myocardial infarction or coronary bypass, secondary causes of hypertension, neoplastic disease, lung disease and pulmonary arterial hypertension.

After an informed consent had been obtained during the initial visit, all patients underwent the following procedures within a week interval: medical history and physical examination, clinic BP measurement, blood and urine sampling, standard 12-lead electrocardiogram, M-mode, two-dimensional and Doppler echocardiographic examination. In all subjects, laboratory tests for secondary hypertension were performed when considered appropriate on clinical grounds. The study protocol was approved by the Ethics Committee of one of the Institutions involved.

Clinic BP measurement

Blood pressure (BP) was measured by a physician during two visits at the outpatient clinic using a mercury sphygmomanometer. At each visit, three measurements were taken at 1-min interval after the subjects had rested for 5 min in the sitting position; values were averaged to define clinic SBP and DBP. Heart rate was assessed as pulse rate.

Echocardiography

Echocardiography was carried out according to standardized procedures as previously reported (16). M-mode, two-dimensional, Doppler echocardiographic examinations were made with commercially available instruments (Vivid 7, GE, Horten, Norvay).

Left ventricle. Briefly, end-diastolic and end-systolic LV internal diameter, interventricular septum thickness and posterior wall thickness were measured on two-dimensionally guided M-mode tracings during at least five cycles according to the Penn Convention and LV mass (LVM) was calculated by Devereux's formula (17) and normalized to body height^2.7. LV myocardial systolic performance was assessed as mid-wall fractional shortening and calculated by a two-shell cylindrical model (18).

LV filling was assessed by recording mitral flow by standard pulsed Doppler technique in apical four-chamber view; the following parameters were considered: early diastolic peak flow velocity (Em), late diastolic flow velocity (Am), their ratio (E/A)_M and Em wave deceleration time (from peak Em-wave to baseline). Deceleration time was divided by Em to obtain MDI (15).

Left atrium and aortic root. Left atrium size was determined in the parasternal long-axis view, using a leading edge-to-leading edge measurement of the maximal distance between end-systolic posterior aortic root wall and posterior LA wall. Aortic root size was measured at the level of Valsalva's sinuses by M-mode tracings, under two-dimensional control, as the maximal distance between the two leading edges of the anterior and posterior aortic root wall at end diastole (19).

Right ventricle. RV internal end-diastolic diameter and end-diastolic thickness were measured in parasternal long-axis view (anterior wall) at the outflow tract as well as in the sub-costal view at the tips of the tricuspid valve. RV filling was assessed by recording tricuspid flow by standard pulsed Doppler technique in apical four-chamber view; the following parameters were considered: early diastolic peak flow velocity (Et), late diastolic flow velocity (At), their ratio (E/A)_T and E_T wave deceleration time (from peak E_T wave to baseline). RV systolic function was assessed as the tricuspid annular plane systolic excursion (TAPSE).

Definition of LVH and RVH. LVH was defined by LVM index equal or greater than 51 g/m^2.7 in men and 47 g/m^2.7 in women (20), and RVH by RV anterior thickness ≥ 3.1 mm/m² in men and ≥ 3.0 mm/m² in women (16). Biventricular hypertrophy was defined when both criteria were fulfilled.

Details about reproducibility of LVM and RV anterior thickness measurements in our laboratory have been previously reported (16,21).

Statistical analysis

Statistical analysis was performed by the SAS system (version 6.12; SAS Institute Inc., Cary, NC, USA). Patients were categorized into tertiles according to MDI values. Data were expressed as means ± SD or as percentages. Means were compared by the Student's t-test for independent samples. Analysis of categorical data was carried out by χ² test or Fischer's exact test when appropriate. Differences between tertiles were tested by one-way analysis of variance (ANOVA). Univariate and multivariate regression analyses were performed in order to identify clinical and echocardiographic correlates of MDI. The limit of statistical significance was set at p < 0.05.

Results

A total of 329 out of 343 hypertensive subjects having completed clinical and echocardiographic records were included in the final analysis. Mean age was 58 ± 12 years (range 19–89), and mean SBP and DBP were 139 ± 13 and 88 ± 10 mmHg, respectively; 90% of the study sample were on antihypertensive treatment, 40% had the metabolic syndrome according to the amended National Cholesterol Education Program's (NCEP) Adult Treatment Panel III guidelines, 14% were smokers, and 11% had type 2 diabetes mellitus. Overall, 114 patients (35%) fulfilled the gender specific criteria for LVH (i.e. LVMI ≥ 51/47 g/m^2.7), 111 patients (33%) for RVH (i.e. RV anterior thickness ≥ 3.1/3.0 mm/m²), and 59 (18%) for biventricular hypertrophy.

Table I reports demographic and clinical characteristics of patients categorized according to MDI tertiles. Briefly, age, known duration of hypertension, body mass index, abdominal circumference and prevalence of obesity (i.e. BMI ≥ 30 kg/m²) progressively increased from the lowest to the highest tertile. No significant differences were found for clinic BP, heart rate, fasting blood glucose, lipids, Sokolow–Lyon voltage, current smoking, antihypertensive drugs and beta-blockers use. This also was the case for diuretics, calcium antagonists, angiotensin II converting enzyme inhibitors and angiotensin II receptor blockers (data not shown).

Table I. Clinical characteristics of the study population according to tertiles of mitral E wave deceleration time to peak E velocity ratio (MDI).

Variables	I MDI (1.3–2.7)	II MDI (2.7–3.6)	III MDI (>3.6)	p
n	110	109	110
Age (years)	54.1 ± 13.2	59.5 ± 11.0^d	61.6 ± 11.3^a	<0.01
Male gender (%)	58.7	57.3	69.3	NS
BSA (m^2)	1.84 + 018	1.85 + 018	1.91 + 0.19^c	0.01
BMI (kg/m^2)	26.1 ± 3.7	26.2 ± 3.7	26.7 + 3.8^b	<0.05
Abdominal circum. (cm)	92.5 ± 10.2	93.5 ± 10.8	96.0 ± 11.2^c	<0.01
Clinic SBP (mmHg)	139 ± 14	139 ± 13	139 ± 13	NS
Clinic DBP (mmHg)	87 ± 9	88 ± 9	88 + 10	NS
Clinic HR (b/min)	66 ± 9	67 ± 10	66 ± 10	NS
Duration of HTN (years)	8.3 ± 7.4	8.4 ± 6.4	10.5 ± 8.9^a	<0.01
Blood glucose (mg/dl)	101 ± 32.5	106 ± 25.2	103 ± 19.9	NS
HDL-cholesterol (mg/dl)	60.1 ± 14.7	59.1 ± 18.2	54.6 ± 15.2	NS
Triglycerides (mg/dl)	122 ± 65.1	133 ± 73.3	142 ± 116.0	NS
Creatinine (mg/dl)	1.02 ± 0.28	1.04 ± 0.25	1.06 ± 0.22	NS
Uric acid (mg/dl)	5.2 ± 1.6	5.6 ± 1.5	5.8 ± 1.3	NS
Obesity (%)	16.5	14.5	18.9^e	< 0.05
DM (%)	5.1	13.3	14.6	NS
Current smoking (%)	18.5	13.6	9.1	NS
Sokolow–Lyon (mm)	20.5 ± 6.0	19.9 ± 5.9	19.0 ± 5.4	NS
Untreated (%)	12.8	10.9	7.2	NS
Beta-blockers (%)	30.3	25.4	25.2	NS

Data are shown as means ±SD or %; BSA, body surface area; BMI, body mass index; SBP/DBP, systolic/diastolic blood pressure; HR, heart rate; HTN, hypertension; HDL, high-density lipoprotein; DM, diabetes mellitus; ^ap < 0.01 III vs I; ^bp < 0.05 III vs I; ^cp < 0.01 III vs II, I; ^dp < 0.05 II vs I; ^ep < 0.05 III vs II.

Echocardiographic data are shown in Table II. Several parameters such as end-diastolic diameter, interventricular septum, posterior wall thickness, absolute LVM, normalized LVM to height^2.7, and aortic root diameter showed a gradual increase across the groups, this was not the case for LV relative wall thickness and left atrium diameter; the E/A_m ratio displayed the opposite trend.

Table II. Echo-Doppler parameters of the study population according to tertiles of mitral deceleration index (MDI).

Variables	I MDI (1.3–2.7)	II MDI (2.7–3.6)	III MDI (>3.6)	p
n	110	109	110
LVIDd (mm)	48.3 ± 3.7	48.2 ± 4.1	49.6 ± 3.4^c	<0.01
IVSTd (mm)	9.9 ± 1.3	10.3 ± 1.3^d	10.5 ± 1.3^a	<0.01
PWTd (mm)	8.8 ± 1.0	9.0 ± 0.9	9.3 ± 0.9^a	<0.01
LV-RWT	0.39 ± 0.04	0.40 ± 0.05^d	0.40 ± 0.05	<0.05
LA long axis (mm)	46.8 ± 4.5	46.6.2 ± 4.4	47.6 ± 4.8	NS
Aortic root (mm)	32.8 ± 3.5	33.8 + 4.3	35.4 ± 4.1^c	<0.01
LV mass (g)	185 ± 49.9	194 ± 47.1	207 ± 45.3^c	<0.01
LV mass index (g/h^2.7)	45.1 ± 11.0	46.7 ± 10.1	48.4 ± 9.9^b	<0.05
MWS (%)	20.2 ± 1.9	19.5 + 2.1^d	19.3 ± 2.3^a	<0.01
(E/A)M ratio	1.2 ± 0.36	1.05 ± 0.33^d	0.85 ± 0.27^c	<0.001
DTm (ms)	181 ± 26.6	218 ± 32.9^d	268 ± 51^c	<0.001
RVDd outflow (mm)	25.9 ± 3.8	26.8 ± 4.2	27.8 ± 3.8^a	<0.01
RVTd outflow (mm)	5.3 ± 1.1	5.4 ± 1.0	5.5 ± 0.9	NS
RA long axis (mm)	44.9 ± 4.2	44.8 ± 3.9	45.5 ± 3.9	NS
TAPSE (cm)	2.6 ± 0.4	2.5 ± 0.5	2.5 ± 0.0.4	NS
(E/A)T ratio	1.39 ± 0.33	1.31 ± 0.33	1.18 ± 0.36^c	<0.01
DTt (ms)	212 ± 50.9	218 ± 64.9	238 ± 60.6^c	<0.01

LVIDd, left ventricular internal diastolic diameter; IVSTd, interventricular septum thickness in diastole; PWTd, posterior wall thickness in diastole; LV, left ventricular; RWT, relative wall thickness; LA, left atrium; LVM, left ventricular mass; MWS, mid-wall shortening fraction; Em, early diastolic mitral flow; Am, late diastolic mitral flow; DT, deceleration time; RVDd, right ventricular diastolic diameter; RVTd, right ventricular diastolic thickness; Et, early diastolic tricuspid flow; At, late diastolic tricuspid flow; RA, right atrium. TAPSE, tricuspid annular plane systolic excursion. ^ap < 0.01 III vs I; ^bp < 0.05 III vs I; ^cp < 0.01 III vs II, I; ^dp < 0.05 II vs I.

As for RV structural and functional indexes, end-diastolic diameter and tricuspid deceleration time progressively increased across MDI tertiles; no differences were observed in RV anterior thickness, right atrium and TAPSE; like E/A_m ratio, also E/A_t ratio decreased from the lowest to the highest tertile.

After adjustment for confounders such as age, gender, body mass index and abdominal circumference, LV (i.e. end-diastolic diameter, interventricular septum and posterior wall thickness, absolute and normalized LVM) as well as RV structural variables (i.e. end-diastolic diameter), the differences lost their statistical significance.

Moreover, when the echocardiographic data were analysed in a categorical way, as presence or absence of isolated LVH, isolated RVH or biventricular hypertrophy, a non-significant increase in these cardiac phenotypes occurred from the lowest to the highest tertile (i.e. biventricular hypertrophy : 14%, 18% and 21%, p = ns).

Correlation analyses

As listed in Table III, in a univariate regression analysis MDI was directly correlated with age, body surface area, duration of hypertension, LVM, aortic root diameter, left atrium diameter and end-diastolic RV diameter; an inverse correlation was found with heart rate, high-density lipoprotein (HDL)-cholesterol and E/A_t ratio. When these variables were tested in a multivariate analysis, age (β = 0.229, p = 0.001), aortic root diameter (β = 0.226, p = 0.001), E/A_t ratio (β = −0.168, p = 0.01) and HDL-cholesterol (β = −0.128, p = 0.03) turned out to be independent correlates of MDI.

Table III. Univariate and multivariate correlations between mitral deceleration index (MDI) and clinical and echocardiographic variables.

	Univariate analysis		Multivariate analysis
Variable	r	p	β	p
Age	0.31	<0.0001	0.229	0.001
BSA	0.12	0.03	0.033	NS
Clinic SBP	0.02	NS	–	–
Clinic DBP	0.03	NS	–	–
Clinic HR	−0.12	0.04	0.109	NS
Duration HTN	0.14	0.009	0.020	NS
Plasma glucose	0.09	NS	–	–
HDL-cholesterol	−0.14	0.02	−0.126	0.03
Serum creatinine	0.07	NS	–	–
LV mass	0.21	<0.0001	0.029	NS
LV-RWT	0.08	NS	–	–
Mid-wall shortening	0.09	NS	–	–
Aortic root	0.31	<0.0001	0.226	0.001
LA diameter	0.15	0.006	0.048	NS
RVTd (outflow)	0.15	0.005	0.021	NS
(E/A)T	0.19	<0.0001	−0.168	0.01

For abbreviations, see Tables I and II.

The analysis of the individual components of MDI showed that mitral deceleration time was independently correlated with heart rate (β = −0.228, p = 0.0001) and age (β = 0.166, p = 0.02) but not with aortic root diameter; this was also the case for mitral E-wave (data not shown).

Discussion

The present study in a cohort of cardiovascular disease free essential hypertensives with a high prevalence of LVH and metabolic syndrome demonstrates that MDI is independently associated with aortic root dilatation, an unfavourable phenotype of established adverse prognostic value, whereas the individuals components of the ratio, deceleration time and E-wave velocity, are not. Furthermore, we found that MDI is unrelated to LV and RV structural changes, supporting the hypothesis that alterations in diastolic function, also when assessed by a sensitive index accounting for variations in loading conditions (14,15), are not paralleled by proportional abnormalities in cardiac morphology.

Emerging evidence on clinical correlates and prognostic relevance of MDI comes from two recent studies conducted in different ethnic groups without overt cardiovascular disease.

In a large population-based sample of 3102 American Indians, Mishra et al. (14) documented that MDI and its inverse, deceleration slope, predicted fatal and non-fatal cardiovascular events, whereas deceleration time and E-wave individually did not. Similar findings have been provided by Chinali et al. (15) who investigated the value of this diastolic index in predicting cardiovascular morbidity and mortality in 770 hypertensives enrolled in the LIFE study. Dichotomizing the study population according to a prognostically validated MDI partition cut-off (14), they were able to demonstrate that baseline MDI > 4.25 ms/(cm/s) was associated with a twofold increase of incident cardiovascular events.

On the light of the aforementioned studies, some findings of our work deserve to be discussed. First, in healthy individuals, deceleration time increases and E-wave velocity decreases with age. As this trend is strongly enhanced in the hypertensive population because of the combined effect of the increased after-load and LVM, it is not unexpected that in our series age was the most important correlate of MDI. Second, our study extends previous findings provided by Chinali et al. (15) in demonstrating that in a hypertensive sample with a wide range of LVM, unbiased by pre-selection of patients with electrocardiographic LVH, in addition to age, aortic root diameter was a strong predictor of MDI. This result is in agreement with data reported in the Cardiovascular Health Study pointing toward an association between a decreased E-wave velocity and an increased aortic root diameter in a biracial sample of 3933 elderly subjects (22).

Aortic dilatation in hypertension may result from several mechanisms, which, in parallel, may contribute to impair diastolic function. Chronic pressure overload is thought to act as an important determinant of both aortic dilatation and alterations in LV relaxation and filling properties (23,24). Growth factors involved in cardiac remodelling, which leads to diastolic dysfunction, may be also invoked in aortic root dilatation. In addition, mild to moderate aortic regurgitation, often secondary to aortic dilatation, could also influence LV structure and diastolic function (25). It is worth noting that the relation between diastolic dysfunction and aortic root dilatation in our analysis was consistent only when the former was assessed by MDI but not by deceleration time per se.

Third, in accordance to the findings provided in hypertensive patients with electrocardiographic LVH (15), we failed to find an association between MDI and LVM. Notably, we were able to extend a such information to the setting of patients with biventricular hypertrophy (as defined by parallel increases in LVMI and RV wall thickness), a cardiac phenotype that reasonably reflects a more advanced subclinical involvement of the heart compared with isolated LVH (16).

The present study has several limitations. The majority of patients were on antihypertensive medication and the results may be partly influenced by the effects of various antihypertensive drugs on LVM and diastolic parameters. This hypothesis, however, is not supported by the observation that prevalence rates of treated patients and beta-blocker treatment were comparable across the MDI tertiles. The present analysis included only selected uncomplicated hypertensive subjects, without significant valve disease; therefore, our results may not be applicable to all hypertensive subjects. Colour flow mitral propagation velocity and tissue Doppler analysis were not part of our echocardiographic protocol; thus, the relations between MDI and newer indexes of diastolic function could not be investigated.

In conclusion, our findings indicate that: (i) MDI is unrelated to LV and RV structural changes; (ii) altered LV diastolic function, as assessed by MDI but not by deceleration time alone, is independently associated with aortic root dilatation, a phenotype predictive of incident cardiovascular morbidity and mortality (22). Thus, aortic root dilatation and not LVH or biventricular hypertrophy may be regarded as a correlate of LV diastolic dysfunction undetectable by the individual components of MDI, which are routinely used for the assessment of diastolic function.

Conflict of interest: None.