2 CAPÍTULO
4.4 Mapas de anomalías geoquímicas
4.4.6 Mapa Anomálico del Hierro (Fe)
STUDY DESIGN: The study was carried out as a cross sectional observational study.
LOCATIONS: Subjects were recruited into the study from the in-patient and out-patients unit of the Internal Medicine Department and the General Out-Patient Department of the University College Hospital Ibadan.
PATIENTS: Consecutive adults 18 years and above newly presenting with hypertension were recruited into the study. A second group consisted of normal men and women who had no clinical history of cardiovascular or any other medical condition. They were recruited from the medical and non-medical staff of the University College Hospital Ibadan and from patients’ relations. The 2 groups were comparable in their age and sex ratios.
EXCLUSION CRITERIA
1. Evidence of coronary heart disease.
2. Evidence of heart failure.
3. Valvular heart disease 4. Morbid obesity.
5. Co-existing cardiomyopathy
6. Arrhythmias like atrial arrhythmias, ventricular tachycardia, etc, that would make ECG guided left atrial area/volume measurement difficult.
7. Technically impossible or inadequate echocardiogram.
SAMPLE SIZE: The estimated minimum sample size was 100(Appendix I)66, 67. Consequently 100 patients newly presenting with hypertension and 50 normal subjects comparable by age and gender were recruited into the study.
CONSENT
Informed consent was obtained from all the study participants before enrolment into the study.
ETHICAL CLEARANCE
Ethical clearance was obtained from the joint University of Ibadan and University College Hospital ethical committee.
METHODOLOGY
Basic and clinical characteristics of all the subjects were collected. These included date of birth (age), gender, height and weight. The blood pressure was measured with an appropriate size cuff in the right arm of the patient after the subject had been sitting quietly for at least 5 minutes. Hypertension was diagnosed in subjects having a systolic BP ≥140mmHg or diastolic BP ≥90mmHg on at least 2 occasions 68. Ischemic heart disease was excluded in the absence of definite evidence of angina or myocardial infarction from history and electrocardiogram using established criteria 69, 70. Valvular heart disease was excluded using the echocardiogram and as well as by cardiac auscultation.
Electrocardiography (ECG): A 12 lead resting ECG was performed for the subjects.
A Spacelabs Burdick EclipseTM 850 machine (Spacelabs Burdick, Inc., U.S.A) was used for ECG recording with paper speed of 25mm/sec. All ECGs were recorded in
the supine position. For each recording, the stylus control was set at 10mm/mV (except in very high voltages when it was set at 5mm/mV)Electrocardiography was assessed for evidence of left ventricular hypertrophy. Left ventricular hypertrophy was defined by:
i. Sokolow-Lyon voltage criteria 54 (sum of the amplitude of the SV1 and RV5 or RV6 >35mm (3.5mV), RaVL >11mm (1.1mV).
Presence of any of the following was taken as evidence of left atrial abnormality 54 : i. Prolonged P wave duration (> 120msec) in lead II:
ii. Presence of P mitrale: prominent notching of the P wave usually most obvious in lead II with the interval between the notches >40msec.
iii. Ratio between P wave in lead II and duration of the PR segment >1.6.
iv. Leftward shift of the mean P wave axis to between +45 to -30 degrees.
Evidences for right atrial abnormality included 54 :
i. Presence of P pulmonale: peaked P wave with amplitude over 2.5 mm in lead II ii. Rightward shift of P wave axis to above 75 degrees.
Echocardiography: Echocardiography assessment was carried out with ALOKA SSD – 1700 echo machine which was equipped with a 3.5 MHz linear array transducer. 2-D guided M-mode echocardiography was performed on each subject in the left lateral decubitus position. All measurements were made according to the American Society of Echocardiography leading edge to leading edge criteria71(figures 2 and 3). Average of measurements in three cardiac cycles were taken with simultaneous ECG recording.
LV internal diameter and interventricular septal and posterior wall thickness were measured at end diastole and end systole. Left ventricular (LV) systolic
performance was assessed using the fractional shortening of the left ventricle and the ejection fraction.
LV ejection fraction was calculated using the Teichholz calculation formula72
100 EDV
ESV
-EDV
Fractional shortening was calculated from LV internal dimensions in diastole and
systole 100
LVIDd LVIDs -LVIDd
Each subject had 2-D and 2-D guided M-mode echocardiography. Only transthoracic echocardiography was carried out being the only form of echocardiography available at the site of study. The left atrial dimension was measured between the leading edge of the posterior aortic wall and the leading edge of the posterior wall of the left atrium at end systole. The areas of the left atrium was determined by tracing the endocardial border (figure 6) of the left atrium at end systole (ventricular) before the opening of the mitral valve in the apical 4 chamber view(maximal LA area or Amax), excluding the LA appendage and pulmonary vein confluences. The left atrial area was determined additionally at 2 other points-at the onset of the P wave on ECG (pre-atrial contraction area or Ap), and at mitral valve closure (minimal atrial area or Amin). The long axis length of the left atrium from the middle of the plane of the mitral annulus to the superior aspect of the left atrium, was also measured for each point in this view 2673 .
Measurements were according to the American society for echocardiography criteria 71. The left atrial volume was estimated by the single plane area-length method, a method that has been shown to compare well with reliable methods of estimating left atrial volume 26, using the formula 74:
Volume = 0.85 A²/L Where A = area of atrium
L = Long axis length of the atrium.
The corresponding volumes at each point of left atrial area assessment was estimated as maximal volume (Vmax), Pre-atrial contraction volume (Vp) and minimal LA volume (Vmin).
The following LA emptying function parameters were derived: LA passive emptying fraction = (Vmax-Vp)/Vmax; LA active emptying fraction = (Vp - Vmin)/Vp; LA total emptying fraction = (Vmax-Vmin)/Vmax. Left atrial dimensions were also indexed by height and body surface area for standardised comparison independent of differences in body size 75 . Body mass index (BMI) was calculated using the formula BMI = Weight (kg)/ (height)².. Body surface area was calculated using the formula of Dubois76.
Body Surface area (BSA) (in m²) = 0.0001× (71.84) × (weight in kilogram0.425× height in centimetre0.725).
Left ventricular mass was calculated using the Devereux modified ASE cube formula : 77
LVM= 0.8×{1.04×(VSTd+PWTd+LVIDd}³ -(LVID)³+0.6
Where VSTd is the ventricular septal thickness in diastole; PWTd is the posterior ventricular wall thickness in diastole and LVIDd is the left ventricular internal diameter in diastole. Left ventricular mass was indexed by height to minimise the contribution of body size to left ventricular hypertrophy. Relative wall thickness was calculated using:
RWT = VSTd + PWTd/LVIDd
4 patterns of left ventricular geometry were identified 78. LVH was defined by LV mass indexed by allometric signal 79 (Height2.7) >51g/m2.7 and increased relative wall thickness defined by relative wall thickness >0.45
1. Concentric hypertrophy is defined as increased LV mass and increased relative wall thickness.
2. Eccentric hypertrophy is defined as increased LV mass and normal relative wall thickness.
3. Concentric remodelling is defined as normal mass and increased relative wall thickness.
4. Normal geometry is defined as normal mass and normal relative wall thickness.
Left ventricular diastolic function was evaluated by studying the filling dynamics of the left ventricle (figure 5). This was quantified by measuring the transmitral ‘E’ wave velocity (peak early mitral inflow velocity) and the ‘A’ wave velocity (peak atrial inflow velocity), the E/A ratio and the deceleration time (DT):
time interval of peak E wave velocity to its extrapolation to the baseline.
Diastolic function was also assessed using the pulmonary venous flow velocities (figure 6):
(1) Forward flow during ventricular systole ( S-wave) (2) Forward flow during early diastole (D-wave)
(3) Reverse flow during atrial contraction ( reverse A wave) Evidences of diastolic dysfunction included:
(a) Ratio of peak early to peak early to peak atrial velocities (E/A) in subjects<50 years of age<1.0 and deceleration time (DT)>220ms or E/A in subjects >50 years of age<0.5 and DT>280ms.
(b) Ratio of pulmonary vein systolic and diastolic flow velocities (S/D) in subjects<50 years of age>1.5 or S/D in subjects>50 years of age >2.5.
These criteria were additive-the presence of any of these clinical settings was sufficient 8081.
DATA ANALYSIS
All data generated were collected in a standard proforma. Statistical analysis was performed using SPSS software version 11.0(SPSS, Inc. Chicago Illinois).
Means were expressed as means (standard deviation) while proportions were expressed as count (percentages). Categorical variables were compared using the chi square test, while continuous variables were compared using the t test. A Univariate correlation was calculated for variables potentially related to left atrial dimensions and the independent contributions of potential correlates were evaluated by multivariate regression analyses. A two tailed p value<0.05 was considered to be significant.
CHAPTER FIVE RESULTS
Table 1 shows the baseline characteristic of all 150 adult Nigerians comprising 100 subjects(Patients with hypertension) and 50 (apparently healthy) subjects in the control group, who were recruited into the study. The male to female ratio was the same in both groups. The mean age, weight and height were comparable between the two groups. Expectedly, the two groups differed in the blood pressure parameters.
Table 1: Baseline characteristics of the subjects
Characteristics Hypertensives Normal P value
Sex
Female 48(48) 24(48) 1.000
Male 52(52) 26(52)
Age(years) 52.9(12.72) 49.1(13.13) 0.100
Weight(Kg) 70.2(13.58) 67.6(11.57) 0.236
Height(cm) 162.4(9.21) 161.7(8.39) 0.672
Body mass index(Kg/m2)
26.6(4.67) 25.8(3.81) 0.281
Body surface area(m2)
1.75(0.19) 1.72(0.16) 0.302
Systolic blood pressure (mmHg)
153.2(17.11) 119.2(13.43) <0.0001
Diastolic blood pressure(mmHg)
97.6(13.29) 74.7(8.79) <0.0001
Pulse
pressure(mmHg)
55.7(18.53) 44.5(11.49) <0.0001
Mean arterial pressure(mmHg)
116.1(11.79) 89.5(9.07) <0.0001
Table 2 compares the left ventricular geometry and the systolic function between the two groups. The hypertensive group had a bigger interventricular septum, left ventricular mass and LV mass index and a higher relative wall thickness. The left ventricle ejection fraction and the other parameters were comparable between the two groups. Thirty seven(37%) of the hypertensives had left ventricular hypertrophy and 67(67%) had abnormal geometric pattern. The corresponding figures for the normal subjects were 8(16%) and 21(42%) respectively for the normal subjects. Subjects with eccentric hypertrophy had mean left atrial dimension of 3.67cm which was the highest among of all the left ventricular geometry patterns. The corresponding values for normal, concentric remodelling and concentric hypertrophy patterns are 3.27cm, 3.21cm and 3.58cm respectively. The differences were statistically significant (p=0.0004).
Table 2: Echocardiographic M-mode measurements
Variables Hypertensives Normal P value
Aortic root diameter(cm)
2.8(0.33) 2.8(0.32) 0.471
Left atrial diameter 3.5(0.48) 3.1(0.47) <0.0001
Aortic valve opening(cm)
1.8(0.25) 1.8(0.24) 0.483 Left ventricular end
diastolic diameter(cm)
4.5(0.69) 4.5(0.68) 0.9646 Left ventricular end
systolic diameter(cm)
2.8(0.68) 2.8(0.62) 0.780 Inter ventricular septal
diameter in diastole(cm)
1.2(0.27) 1.0(0.16) <0.0001
Posterior wall thickness in diastole(cm)
0.92(0.26) 0.85(0.15) 0.079
Left ventricular mass(LVM)(g)
177.5(72.70) 147.3(45.35) 0.008 LVM/BSA(g/m2)
LVM/Height(g/m) 108.8(42.15) 90.9(26.91) 0.007
LVM/Height2.7(g/m2.7) 47.4(17.6) 40.2(11.91) 0.007 Relative wall
thickness(cm)
0.48(0.14) 0.42(0.08) 0.005 Left ventricular
fractional shortening
38.1(9.41) 38.1(8.60) 0.987 Left ventricular
ejection fraction
73.2(14.13) 74.3(9.91) 0.597 Left ventricular
geometry
Normal 33(33) 29(58)
Concentric remodelling
30(30) 1(26)
Concentric Hypertrophy
26(26) 1(2)
Eccentric Hypertrophy
11(11) 7(14)
Table 3 shows echocardiographic assessment of left atrial size and functions of the subjects and control. Those with hypertension had a bigger left atrial linear dimension than the control group. The group with hypertension also had greater left atrial length just before left atrial contraction. The other parameters were comparable between the two groups.
Table 3: Left atrial dimension and functions in the subjects
Variables Hypertensives Normal P value
M-mode left atrial dimension(cm)
3.5(0.48) 3.1(0.47) <0.0001
Maximum atrial area(cm2)
13.6(3.19) 13.1(2.84) 0.309
Minimum atrial area(cm2)
8.4(2.43) 8.1(2.57) 0.568
Pre atrial
contraction atrial area(cm2)
11.0(2.94) 10.3(2.85) 0.199
Maximum left atrial length(cm)
4.3(0.58) 4.2(0.50) 0.266
Minimum left atrial length(cm)
3.4(0.60) 3.3(0.52) 0.132
Pre atrial contraction left atrial length(cm)
3.8(0.56) 3.6(0.45) 0.02
Maximum left atrial volume(cm3)
37.8(13.40) 35.9(13.98) 0.45
Minimum left atrial volume(cm3)
18.2(8.47) 18.0(9.73) 0.906
Atrial reservoir volume(cm3)
19.4(9.38) 19.9(8.03) 0.263
Pre atrial contraction left atrial volume(cm3)
27.6(11.59) 26.1(12.80) 0.475
Passive atrial emptying fraction
0.27(0.14) 0.27(0.17) 0.804
Active atrial emptying fraction
0.34(0.13) 0.31(0.16) 0.227
Total atrial emptying fraction
0.51(0.14) 0.51(0.16) 0.694
Table 4 shows a comparison of echocardiographic Doppler parameters between the two groups. Only the Peak atrial mitral inflow velocity was significantly different between the two groups. It was higher in the hypertensive group. The other parameters were comparable between the two groups.
Table 4: Echocardiographic Doppler parameters of the subjects
Variables Hypertensives Normal P value
Peak early mitral inflow velocity(E)(m.s-1)
0.63(0.18) 0.64(0.17) 0.613
Peak atrial mitral inflow velocity(A) (m.s-1)
0.64(0.19) 0.56(0.15) 0.010
E/A ratio 1.1(0.53) 1.3(0.46) 0.096
Deceleration time of E(ms)
191.5(53.3) 182.84(45.16) 0.329
Pulmonary vein systolic forward flow velocity(S) (m.s-1)
0.45(0.16) 0.44(0.16) 0.771
Pulmonary vein diastolic forward flow velocity(D) (m.s-1)
0.39(0.14) 0.34(0.11) 0.60
S/D ratio 1.2(0.44) 1.4(0.45) 0.129
Pulmonary atrial flow reversal velocity(AR) (m.s-1)
0.27(0.11) 0.24(0.08) 0.093
Table 5 shows the correlation of the patients variables and characteristics with left atrial size using the linear LA diameter which was found to be significantly different between the group with hypertension and the normal controls. Weight, body mass index, left ventricular end diastolic diameter and left ventricular mass were all significantly correlated with left atrial size.
Table 5: Correlates of left atrial size
Variables Correlation
coefficient
Z value P value 95%
confidence interval
Age 0.105 1.038 0.2994
(-0.93)-(0.925)
Sex -0.072 -0.713 0.4762
(-0.265)-(0.585)
Weight 0.270 2.726 0.0064 0.078-0.433
Height 0.016 0.156 0.8757
(-0.181)-0.212
Body mass index 0.308 3.134 0.0017 0.119-0.476
Systolic blood pressure 0.144 1.428 0.1533
(-0.54)-0.331 Diastolic blood pressure -0.019 -0.188 0.8512
(-0.215)-0.178
Pulse pressure 0.147 1.454 0.1460 (-0.51)-0.33
Left ventricular end diastolic diameter
0.284 2.881 0.0040 0.093-0.455
Interventricular septal diameter in diastole
0.162 1.607 0.1081
(-0.036)-0.37 Left ventricular posterior wall
thickness in diastole
0.133 1.115 0.2648
(-0.086)-0.302
Left ventricular mass 0.263 2.648 0.0081 0.070-0.473
Relative wall thickness -0.010 -0.097 0.9224 (-0.206)-0.187
Fractional shortening -0.017 -0.168 0.8664
(-0.213)-0.180
Ejection fraction 0.046 0.456 0.6483
(-0.152)-0.241
Table 6 shows the multivariate regression model for the variables potentially related to left atrial size. Only weight was found to be independently related to LA size.
Table 6: Multivariate regression analysis of variables related to left atrial size
Left atrial size coefficient P value Confidence interval
Lower limit Upper limit
Weight 0.0082614 0.018 0.0014373 0.0150856
Log LVM/HT2.7 0.3182939 0.055 -0.0067007 0.6432884
Left ventricular internal diameter in diastole
0.0538652 0.526 -0.1141213 0.2218518
Systolic blood pressure
0.0046992 0.979 -0.0005567 0.0099552
Adjusted R2=0.1528 F=5.46 P=0.0005
CHAPTER SIX DISCUSSION
The study showed that patients with hypertension tended to have a bigger left atrium, bigger interventricular septum, higher left ventricular mass and relative wall thickness when compared with normal subjects. It also showed that left atrial length just before atrial contraction is higher in the hypertensives and that subjects with hypertension had accentuated atrial systolic activity.
Left atrial size and function
Atrial dimension by M-mode echocardiography was found to be .higher in the subjects with hypertension. This finding is similar to findings in previous studies by Dunn et al 8 and Miller et al 9. Okeahialam et al 28 found no significant difference between the left atrial size of hypertensives and normal subjects in their own study.
The higher pre atrial contraction length in the group with hypertension is in keeping with what is known about atrial function in hypertension in which left atrial reservoir function is expected to increase with consequent increased left atrial contractility 29 . Dernellis et al 82 in a study on subjects newly diagnosed with hypertension found that the atrial reservoir volume and left atrial ejection force were significantly higher, but the conduit function decreased in the group with hypertension compared with the normal subjects. On the contrary the seemingly higher reservoir volume in the hypertensive group in this present study did not reach statistical significance and the conduit function was not assessed. The similarity of the other left atrial parameters between the group with hypertension and the normal subjects in this present study may be due to the fact that the patients were recruited into this study quite early in
the natural history of hypertension and the changes observed may be the earliest changes in the left atrium in hypertension..
Left ventricular geometry and systolic function
The findings of thicker interventricular septum, higher left ventricular mass, left ventricular mass indices, and a higher relative wall thickness are similar to the findings of Platini et al 84 early in hypertension, Muscholl et al 85 in patients with white coat hypertension, Mayet et al 86 in blacks and whites, the changes being more prominent in blacks, and Adebiyi et al 87 in unselected Nigerian hypertensives. Some of the normal controls in this study had abnormal left ventricular geometry. Krumholz et al 78 had found in a population without cardiovascular disease 24% of the men and 28% of women having abnormal geometry and also found that prognosis in this group of patients is related mainly to the left ventricular mass and the known cardiovascular risk factors. The number in this study is however higher(42%). The difference may be due to the difference in the races studied as left ventricular mass and geometry differ between different races78.
Left ventricular diastolic function
The significantly higher peak atrial mitral inflow velocity in the subjects with hypertension indicates an accentuated atrial systolic function. Palatini et al 84 found that the peak atrial mitral inflow velocity was higher in subjects with sustained or white coat hypertension when compared with normal subjects. The other parameters of mitral inflow was not significantly different between the subjects with hypertension and the normal subjects. They did not look at parameters of pulmonary venous flow.
They proposed that the earliest changes of cardiac involvement in hypertension are left ventricular abnormalities. It is therefore very likely that the marginal changes in
left ventricular diastolic function are as a result of increased left ventricular mass and consequent impaired ventricular filling. Rizzo et al 88 however found that in their own series of untreated hypertensives that the peak early mitral inflow velocity , peak atrial inflow velocity and deceleration time were significantly smaller in the hypertensive group compared with normal.
Correlates of left atrial size
The correlates of left atrial(LA) size identified in this study were weight and body mass index, left ventricular mass and left ventricular end diastolic diameter. Vaziri et al 25 in the Framingham heart study found that measures of body size such as weight and body mass index correlated significantly to left atrial size. They also found that LA size correlated with blood pressure variables especially systolic and pulse pressure, left ventricular mass and age. The findings by Gerdts et al 89 in the Losartan Intervention For End point reduction in hypertension(LIFE) study was similar but additionally gender and ventricular geometry were found to also influence left atrial size. Adebiyi et al 87 also documented findings similar to the first two studies mentioned but found no relationship between blood pressure parameters and left atrial size. Neither age nor gender was found to correlate significantly with left atrial size in this study. In multivariate regression analysis only weight was independently related to left atrial size. This is similar to the findings by Gottdiener et al21 who identified obesity as the strongest predictor of left atrial size.
Left ventricular geometry and left atrial size
This study showed that left atrial size was higher for patients with eccentric pattern of LV hypertrophy. Giovanni et al90, 91 in studies among patients with hypertension and in patients with aortic valve disease found that the concentric pattern of hypertrophy was associated with a higher left atrial size than the eccentric pattern. Gerdts et al89 however found a pattern of relationship similar to the pattern described in this study with the highest in subjects with eccentric LV geometry followed by concentric LVH, Normal geometry and concentric remodelling in descending order.
IMPLICATIONS OF THE STUDY
The findings from this study show that left ventricular hypertrophy occurs early in hypertension and the change in the left atrium is just the marginal at this stage. These suggest that the early changes in hypertension occur as a result of pressure overload and the further changes from neurohormonal contributions probably occur later.. It would therefore be useful to identify subjects with hypertension early and institute appropriate management before overt left ventricular or left atrial dysfunction develops. It would also be useful to determine the effects of the currently available antihypertensive medications on left atrial function.
LIMITATIONS OF THE STUDY
The study being an hospital based one may not be representative of what obtains in the community or in other parts of the country. A multicentred and/or community based study would be desirable.
Inability to obtain the pulmonary venous flow in many of the patients due to
technical difficulties (obtained in only 87(58%) of the subjects) might have reduced the strength of the deductions that can be made from the interpretation of the pulmonary venous flow parameters results.
CONCLUSION
Changes in left ventricular size and structure such as increased left ventricular mass, increase in the size of the interventricular septum and increased relative wall thickness occur early in patients with hypertension. The systolic function may still be well preserved at this stage. Changes in left atrial size and function are marginal early in hypertensions and manifest as increased pre atrial contraction length and increased left atrial systolic function. The correlates of left atrial size were body weight and body mass index, left ventricular end diastolic diameter and left ventricular mass.
Weight has the strongest influence on left atrial size