Download Left ventricular hypertrophy and the insulin resistance

Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine 992
_____________________________
_____________________________
Left Ventricular Hypertrophy and the
Insulin Resistance Syndrome
BY
JOHAN SUNDSTRÖM
ACTA UNIVERSITATIS UPSALIENSIS
UPPSALA 2001
Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) in
Geriatrics presented at Uppsala University in 2001
Abstract
Sundström, J. 2001. Left ventricular hypertrophy and the insulin resistance
syndrome. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala
Dissertations from the Faculty of Medicine 992. 68 pp. Uppsala. ISBN 91-554-4919-0.
Left ventricular hypertrophy (LVH) and the insulin resistance syndrome are common
conditions associated with a markedly increased cardiovascular risk. In a fairly large
prospective longitudinal study of men from the general population, we found that an
unfavorable serum fatty acid profile and components of the insulin resistance
syndrome such as dyslipidemia, obesity and hypertension at age 50 predicted the
prevalence of LVH at age 70. In cross-sectional analyses at age 70, several
components of the insulin resistance syndrome were significantly related to left
ventricular relative wall thickness and concentric remodeling, but less to LVH. Left
ventricular relative wall thickness was inversely related to insulin sensitivity in
skeletal muscle and borderline significantly directly related to insulin sensitivity in
the myocardium in a healthy, normotensive sample of the cohort investigated with
positron emission tomography, whereas left ventricular mass index was not related
to myocardial or skeletal muscle insulin sensitivity. At age 70, echocardiographic
LVH was related to a variety of common electrocardiographic diagnoses. In a
prospective mortality analysis with baseline at age 70 and a median follow-up time
of five years, echocardiographic and electrocardiographic LVH predicted mortality
independently of each other and of other cardiovascular risk factors, implying that
echocardiographic and electrocardiographic LVH in part carry different prognostic
information.
In summary, components of the insulin resistance syndrome predicted LVH twenty
years later, but were cross-sectionally more related to increased left ventricular
relative wall thickness and concentric remodeling. Echocardiographic and
electrocardiographic LVH predicted mortality independently of each other and of
components of the insulin resistance syndrome.
Key words: Left ventricular hypertrophy, insulin, glucose, lipids, mortality.
Johan Sundström, Department of Public Health & Caring Sciences, Section for Geriatrics,
Box 609, SE-751 25 Uppsala, Sweden
© Johan Sundström 2001
ISSN 0282-7476
ISBN 91-554-4919-0
Printed in Sweden by Uppsala University, Tryck & Medier, Uppsala 2001
to Anna
Left ventricular hypertrophy and the insulin
resistance syndrome
This thesis is based on the following investigations, which will be referred to by their
Roman numerals:
I.
Sundström J, Lind L, Vessby B, Andrén B, Aro A, Lithell H. Dyslipidemia and
an unfavorable fatty acid profile predict left ventricular hypertrophy 20 years
later. Circulation 2001; in press.
II.
Sundström J, Lind L, Nyström N, Zethelius B, Andrén B, Hales CN, Lithell H.
Left ventricular concentric remodeling rather than left ventricular hypertrophy
is related to the insulin resistance syndrome in elderly men. Circulation
2000;101:2595-600.
III.
Sundström J, Lind L, Valind S, Holmäng A, Björntorp P, Andrén B,
Waldenström A, Lithell H. Myocardial insulin-mediated glucose uptake and
left ventricular geometry. Blood Pressure 2001; in press.
IV.
Sundström J, Lind L, Andrén B, Lithell H. Left ventricular geometry and
function are related to electrocardiographic characteristics and diagnoses. Clin
Physiol 1998;18:463-470.
V.
Sundström J, Lind L, Ärnlöv J, Zethelius B, Andrén B, Lithell H.
Echocardiographic and electrocardiographic left ventricular hypertrophy
predict mortality independently of each other in a population of elderly men.
Submitted for publication.
The original articles were reprinted with permission from the publishers.
Contents
ABBREVIATIONS _________________________________________________________________________ 6
INTRODUCTION _________________________________________________________________________ 7
THE ETIOLOGY OF LEFT VENTRICULAR HYPERTROPHY ______________________________________________ 8
LEFT VENTRICULAR HYPERTROPHY AND THE INSULIN RESISTANCE SYNDROME ____________________________ 9
ELECTROPHYSIOLOGIC CO-MORBIDITY OF LEFT VENTRICULAR HYPERTROPHY __________________________ 12
PROGNOSTIC SIGNIFICANCE OF LEFT VENTRICULAR HYPERTROPHY __________________________________ 12
AIMS OF THE STUDY_____________________________________________________________________ 13
METHODS______________________________________________________________________________ 14
THE COHORT __________________________________________________________________________ 14
Study populations _________________________________________________________________ 15
INVESTIGATIONS AT AGE 50 _______________________________________________________________ 15
INVESTIGATIONS AT AGE 70 _______________________________________________________________ 16
Echocardiography ________________________________________________________________ 16
Electrocardiography ______________________________________________________________ 17
Blood pressure measurements _____________________________________________________ 19
Hyperinsulinemic euglycemic clamp _______________________________________________ 19
Oral glucose tolerance test ________________________________________________________ 20
Lipid measurements_______________________________________________________________ 20
Positron emission tomography _____________________________________________________ 20
FOLLOW-UP AFTER AGE 70________________________________________________________________ 21
STATISTICAL ANALYSIS ____________________________________________________________________ 21
RESULTS _______________________________________________________________________________ 23
STUDY I ______________________________________________________________________________ 23
STUDY II ______________________________________________________________________________ 25
STUDY III______________________________________________________________________________ 26
STUDY IV _____________________________________________________________________________ 28
STUDY V______________________________________________________________________________ 30
DISCUSSION ___________________________________________________________________________ 34
LEFT VENTRICULAR HYPERTROPHY AND THE INSULIN RESISTANCE SYNDROME ___________________________ 34
Components of the insulin resistance syndrome are risk factors for later left ventricular
hypertrophy ______________________________________________________________________ 34
Fatty acids and left ventricular hypertrophy ________________________________________ 34
Relative wall thickness is related to components of the insulin resistance syndrome ___ 36
Relative wall thickness is related to skeletal muscle insulin resistance _________________ 38
INSULIN RESISTANCE AND LEFT VENTRICULAR HYPERTROPHY: CAUSE OR CONSEQUENCE? ________________ 39
Potential mechanisms whereby insulin resistance or hyperinsulinemia may cause left
ventricular hypertrophy____________________________________________________________ 39
Insulin resistance and left ventricular hypertrophy as parallel phenomena ____________ 42
Left ventricular hypertrophy as a causal factor for hypertension and insulin resistance_ 42
THE CLINICAL IMPORTANCE OF LEFT VENTRICULAR HYPERTROPHY ___________________________________ 43
Electrophysiologic co-morbidity of left ventricular hypertrophy_______________________ 43
Prognostic significance of echocardiographic and electrocardiographic left ventricular
hypertrophy ______________________________________________________________________ 44
STRENGTHS AND LIMITATIONS OF THE STUDY ___________________________________________________ 45
CONCLUSIONS_________________________________________________________________________ 47
FUTURE PERSPECTIVES ___________________________________________________________________ 48
ACKNOWLEDGEMENTS _________________________________________________________________ 51
SUMMARY IN SWEDISH / SAMMANFATTNING PÅ SVENSKA _________________________________ 52
REFERENCES ___________________________________________________________________________ 53
Abbreviations
LVH
ECG
RWT
LVMI
SD
CE
PET
OGTT
CV
ICD
HDL
LDL
LA
IVS
PW
LVEDD
LVESD
ASE
LVEDV
LVESV
LVOT
FVI
IVRT
SBP
DBP
AUC
NEFA
18FDG
ROI
PYAR
ANOVA
CI
HR
ROC
BMI
PPAR
IGF-I
GLUT
PKC
ET-1
ACE
AT1
left ventricular hypertrophy
electrocardiography
left ventricular relative wall thickness
left ventricular mass index
standard deviation
cholesteryl ester
positron emission tomography
oral glucose tolerance test
intra-individual coefficient of variation
International Classification of Diseases
high-density lipoprotein
low-density lipoprotein
left atrial diameter
interventricular septal thickness
posterior wall thickness
left ventricular end-diastolic diameter
left ventricular end-systolic diameter
American Society of Echocardiography
left ventricular end-diastolic volume
left ventricular end-systolic volume
left ventricular outflow tract
flow velocity integral
isovolumetric relaxation time
systolic blood pressure
diastolic blood pressure
area under the curve
nonesterified fatty acids
2-[18F]-fluoro-deoxyglucose
region of interest
person-years at risk
analysis of variance
confidence interval
Cox proportional hazard ratio
receiver operating characteristic
body mass index
peroxisome proliferator-activated receptor
insulin-like growth factor-I
glucose transporter
protein kinase C
endothelin-1
angiotensin-converting enzyme
angiotensin II type-1 receptor
6
Introduction
Under some circumstances, of which we today only know a handful, the mass of the
left ventricle of the heart increases. A too large left ventricular mass is known as left
ventricular hypertrophy (LVH). LVH is a very common condition. The prevalence of
echocardiographic LVH in the general population ranges from 10-20% in young and
middle-aged subjects to 30-50% in elderly subjects1-3, and LVH is also more common
in the settings of obesity, hypertension, valvular disease or previous myocardial
infarction3,4. Irrespective of the underlying cause of LVH and diagnostic method, LVH
imposes a great risk for cardiovascular and all-cause mortality and morbidity5-21.
The only way of accurately determining the weight of the left ventricle is by autopsy,
but several diagnostic methods give reasonable assessments of left ventricular mass
in living subjects. Electrocardiography (ECG) was one of the first methods, and is still
the most extensively used because of its low cost, widespread accessibility and
proven prognostic value17-21. In the last decades, the introduction of cardiac
ultrasound (echocardiography) has made direct assessment of cardiac geometry and
calculation of left ventricular mass possible. Other aspects of the left ventricle than
the mass, such as the ratio between the thickness of the left ventricular walls and the
diameter of the left ventricular cavity (the relative wall thickness, RWT), have been
possible to assess. The grouping of subjects into four left ventricular geometric
groups according to left ventricular mass indexed for body size (left ventricular mass
index, LVMI) and RWT (figure 1) has been shown to be relevant and to give
prognostic information7,11-13. A hypertrophic left ventricle (increased LVMI) is
denoted eccentric LVH if RWT is normal, and concentric LVH if RWT is increased. A
normal LVMI with increased RWT is denoted concentric remodeling22. Recently,
measuring left ventricular mass by nuclear magnetic resonance tomography has been
found to have a high precision23, but is yet expensive and time-consuming.
There are several ways of determining the clinical importance of an exposure, such as
LVMI or RWT, and establishing limits for what should be regarded as healthy and
unhealthy levels of this exposure. One way is to investigate the levels of the exposure
in a healthy population, and simply regard the highest 5% of the values of the
exposure (or >2 standard deviations (SD) above the mean exposure) as pathological.
This is the way the definitions of echocardiographic LVH were originally derived24.
Another way is to investigate if the exposure is cross-sectionally related to other
pathological conditions, and if that is the case, determine at which level of the
exposure the relation to pathological conditions appears. A third, and more
appropriate, way is to investigate at which level of the exposure an increased risk for
subsequent morbid or mortal events appears. In this study, a combination of these
approaches were used in the investigation of left ventricular mass and geometry.
Evaluation of the impact of prospectively determined risk factors on subsequent
LVH, as well as evaluation of echocardiographic and ECG-LVH as predictors of later
total and cardiovascular mortality and morbidity was made. Cross-sectional relations
between left ventricular geometry and ECG abnormalities and glucose metabolism in
the heart, skeletal muscle and the whole body were also investigated.
7
Fig. 1: Distribution of left ventricular geometric patterns in the study population
Relative wall thickness
Concentric remodeling, n=79
Concentric LVH, n= 40
Normal, n= 262
Eccentric LVH, n= 94
0.44
LVH = left ventricular hypertrophy
150 g/m2
Left ventricular mass index
The etiology of left ventricular hypertrophy
An increased mass of the left ventricle has generally been thought to be the
consequence of a compensation by the ventricle for a hemodynamic stimulus, such as
an increased demand for cardiac work. If the heart is challenged with a higher
afterload, such as an aortic valve stenosis or an increased peripheral arterial
resistance with arterial hypertension, the left ventricle is believed to respond with
thickening of the ventricular walls and, ultimately, concentric LVH. If the heart is
challenged with a higher preload, as in the case of a larger circulating blood volume
in obesity or a regurgitating valve, the left ventricle is believed to respond with
dilatation and, ultimately, eccentric LVH. Both wall thickening and dilatation may
initially serve as relevant compensation for the increased hemodynamic stress and
improve cardiac function, but also increase the weight of the heart. This increased
mass is due to cardiomyocyte hypertrophy, rather than hyperplasia, because
cardiomyocytes are probably terminally differentiated shortly after birth25. The
myocyte hypertrophy is accompanied by a variable degree of non-myocyte
proliferation and fibrosis26. Eventually, the structure of the myocardium is altered
and the risk of subsequent morbidity and mortality increases, and the hypertrophy is
no longer considered compensatory or physiologic, but pathologic27. However, the
repertoire of stimuli that may cause LVH stretches far beyond hemodynamic ones,
and is yet largely unknown.
8
Previous cross-sectional studies of correlates of LVH3,4,28-31 have shown age
(although not in healthy elderly32), hypertension, obesity, certain valvular diseases,
alcohol use, heredity, blood viscosity and previous myocardial infarction to be
related to LVH or left ventricular mass. In one prospective study33, average blood
pressure over 30 years was associated with LVMI at follow-up. Hypertension is
generally regarded as the worst culprit, indicated by the large number of clinical
trials on the subject (overviews in references34-36) showing that antihypertensive
therapy lowers left ventricular mass and RWT. However, the correlation between
degree of blood pressure lowering and degree of LVH reduction in previous studies
is not always impressive34, and the variation in 24-h blood pressure explains only 2530% of the variation in left ventricular mass37, although findings are conflicting38.
Thus, other factors must be of importance in the etiology of LVH. Body size is a
powerful determinant of left ventricular mass39, and may explain part of the gender
difference regarding left ventricular mass40. It is therefore common to index left
ventricular mass for a measurement of body size, such as lean body mass, body
surface area, height or height2.7, to obtain LVMI. Weight reduction has been shown to
decrease RWT, left ventricular mass41 and LVMI in overweight hypertensive patients
even more than pharmacological antihypertensive treatment42. Lifestyle intervention
aimed at reducing weight, dietary salt intake, alcohol consumption and increasing
physical activity in sedentary subjects has been found to be as effective in decreasing
left ventricular mass by itself as in combination with antihypertensive medication43,
suggesting that lifestyle factors may account for part of the hitherto unexplained
LVH.
Numerous intervention studies aiming at determining causal factors or possible
treatments for LVH exist, but very few longitudinal studies of predictors of LVH33
have been made. Therefore, we have undertaken such a study aimed at identifying
hemodynamic, metabolic, dietary and psychosocial predictors in men aged 50 for the
prevalence of echocardiographic LVH and left ventricular geometric subtypes twenty
years later (study I). As a proxy for dietary fat quality, we investigated the fatty acid
composition of serum cholesteryl esters (CE), which mainly reflects dietary fat
quality over the past couple of weeks44,45. Serum CE fatty acid composition has been
shown to predict myocardial infarction46, but relation to LVH is not known. Neither
have relations between smoking or other psychosocial factors and later LVH been
investigated.
Left ventricular hypertrophy and the insulin resistance syndrome
It is well known that important cardiovascular risk factors, such as hypertension,
glucose intolerance, hyperinsulinemia, dyslipidemia, and obesity, often cluster in the
same individuals. The existence of a syndrome involving some of these disorders was
proposed nearly 80 years ago by the Swede Eskil Kylin47, among others. Insulin
resistance to glucose uptake, as assessed by the hyperinsulinemic euglycemic
clamp48, has been proposed to be of pathogenetic importance in the syndrome,
particularly by Gerald Reaven49-51. Consequently, the term ”insulin resistance
syndrome” has, among other terms50,52,53, been proposed49. There is no
internationally agreed definition of the insulin resistance syndrome at present, but
9
the most accepted definitions54,55 include the presence of insulin resistance or glucose
intolerance together with two or more other components of the syndrome: insulin
resistance, glucose intolerance, hypertension, abdominal obesity, raised plasma
triglycerides, decreased HDL-cholesterol or microalbuminuria. The insulin resistance
syndrome is a highly prevalent condition, present in 12.5% of the present cohort at
age 50 and 18.8% at age 7056, in 20% of another general Swedish population57 and in
22-27% of a general American population58. In the present study, the mentioned
definitions of the insulin resistance syndrome have not been used, but the relations
between individual components of the insulin resistance syndrome and LVH have
been investigated.
The associations between LVH and components of the insulin resistance syndrome,
mainly insulin levels, have recently gained interest (table 1). The left ventricular
geometric correlates of insulin resistance are not yet clear, since some studies have
found relations between insulin resistance variables and RWT59-61 whereas others
have not62, and some studies have found relations between insulin resistance
variables and the sum of left ventricular wall thickness62-64, LVH or left ventricular
mass (with or without indexation for body size by various methods), whereas others
have not. We used a fairly large sample of elderly men from the general population
for a study of the relations between several important variables of the insulin
resistance syndrome and RWT, LVMI and left ventricular geometric subgroups
(study II).
Pathogenetic processes linking the insulin resistance syndrome and LVH or
increased RWT also remain to be elucidated. Although relations between wholebody insulin resistance and LVH or increased RWT have been investigated
previously, the relations between insulin sensitivity in the myocardium and RWT or
LVMI are not yet fully understood. Insulin-mediated glucose uptake, as measured
with 18F-fluorodeoxyglucose and positron emission tomography (PET), has been
found to be increased in the myocardium of hypertensives in one study65, but
reduced in the myocardium in subjects with LVH in other studies66,67. As the
increased work imposed on the left ventricle by hypertension is a powerful
denominator of myocardial glucose uptake65, we investigated the relations between
myocardial and skeletal muscle insulin sensitivity and RWT and LVMI in a
homogenous sample of healthy, normotensive men with wide ranges of RWT and
LVMI (study III).
10
Table 1: Previous studies of relations between left ventricular geometric properties
and insulin resistance
Study
Study population
LVM
indexation
Findings
229 (111 ♂), 107 DM type-2
Insulin
resistance
method
OGTT
Uusitupa, 198768
/BSA
Sharp, 199269
102 (51 ♂), 51 HT, 2 LVH
f-Ins
/height
Sasson, 199370
40 (18 ♂) healthy obese NT
IVGTT
/height
Marcus, 19941
851 (439 ♂) healthy general
population, age 18-42
89 (42 ♂) general population,
age 36-37
f-Ins
/BSA
f-Ins
/height
/weight
50 HT
clamp, f-Ins
-
in ♀: LVMI ➸ f-Ins, OGTT-Ins
in ♂: LVMI ✗ f-Ins, OGTT-Ins
in HT: LVMI ➸ f-Ins, f-Glu
in NT: LVMI ✗ f-Ins, f-Glu
LVMI ➸ IVGTT-f-Ins, -90min-Ins, -AUC-Ins and kvalue
LVMI ➸ f-Glu, TG, stress-NE and -E
in men: LVH ➸ f-Ins➹
➹, TG➹
➹, stress-NE and –E➹
➹
LVM ➸ f-Ins
LVM/height ➸ f-Ins
LVM/weight ✗ f-Ins
LVWT ➸ f-Ins (-)➸
➸WBGD
36, 26 HT, 14 LVH
?
Kupari, 199471
Lind, 199563
Paolisso, 199572
Paolisso, 199573
37 (19 ♂) HT, 25 LVH
Souza, 199574
14 HT, 6 LVH
clamp,
OGTT, IC
clamp,
OGTT
ITT
?
LVH ➸ KITT➷
29 (14 ♂) healthy lean HT
OGTT
/BSA
LVMI ✗ OGTT-peak-Ins, IRI
OGTT
Kamide, 199676
390 ♂, 180 HT, work-site
population
40 (17 ♂) healthy lean HT
/BSA
/height2.7
/BSA
LVMI ✗ f-Ins, OGTT-Ins, f-Glu, OGTT-Glu
RWT ➸ OGTT-Ins, f-Glu, OGTT-Glu ✗ f-Ins
LVMI (-)➸
➸ WBGD
Rabkin, 199677
23 (13 ♂) DM type-2
LVMI ✗ f-Ins, IGF-I, IGF-II, GH
Paolisso, 199762
26 ♂ healthy HT
/BSA
/height
/height
Avignon, 199778
24 ♀ healthy obese NT
Tomiyama,
52 ♂ healthy HT
Vetta, 199879
Jelenc, 199880
49 ♂ healthy NT, 29 obese,
mean age 69
30 ♂ HT, 21 dippers
Phillips, 199864
29 (21 ♂) healthy lean HT
Chen, 199881
Verdecchia,
Costa, 199575
Ohya, 199659
199760
199961
Watanabe,
199982
Rheeder, 199983
Galvan, 200084
clamp,
OGTT
f-Ins, IGF-I,
IGF-II, GH
clamp, IC
?
in HT: LVMI ➸ f-Ins (-)➸
➸WBGD, NOGM
LVH ➸ WBGD➷
➷, NOGM➷
➷, f-Ins➹
➹
LVH ➸ f-Ins➹
➹, WBGD➷
➷
LVMI (-)➸
➸WBGD, NOGM
LVWT ➸ f-Ins, (-)➸
➸WBGD, NOGM
RWT ✗ f-Ins, WBGD, NOGM
LVM ➸basal metabolism, f-Glu, TG
LVM ✗ SI
frequently
sampled
IVGTT, IC
24h-u-Cpeptide
-
/height2.7
LVMI, RWT ➸ 24h-u-C-peptide
OGTT
/height2.7
LVMI ➸ f-Ins, OGTT-AUC-Ins, (-)➸
➸Glu/Ins-ratio
/height2
in dippers: LVM ➸ f-Glu, f-s-C-peptide ✗ f-Ins
in non-dippers: LVM ✗ f-Glu, f-C-peptide, f-Ins
LVMI, LVWT (-)➸
➸ SI
1315 (698 ♂) healthy
OGTT, s-Cpeptide
frequently
sampled
IVGTT
s-C-peptide
-
LVM ➸ f-s-C-peptide
101 (58 ♂) healthy HT
OGTT
-
LVM ➸ f-Ins, OGTT-2h-Ins, HOMAIR, IGF-I
RWT ➸ IGF-I
83 (47 ♂) healthy, 65 HT
IST, OGTT
/BSA
LVMI ➸ f-Ins, SSPG, HbA1c
1655 (749 ♂) general
population, mean age 65
50 (32 ♂) healthy, 21 HT
OGTT
/BSA
LVMI ➸ OGTT-2h-Ins
clamp,
/height2.7
LVMI, PW, IVS ✗ f-Ins, OGTT-Ins, AUC-Ins, WBGD
OGTT
LVM = left ventricular mass; ♂ = male; HT = hypertensive; LVH = left ventricular hypertrophy; LVMI = left ventricular mass index; ➸ =
relation; Ins = insulin; Glu = glucose; NT = normotensive; ✗ = no relation; IVGTT = intravenous glucose tolerance test; AUC = area under
curve; BSA = body surface area; TG = triglycerides; NE = norepinephrine; E = epinephrine; ➹ = increased; clamp = hyperinsulinemic
euglycemic clamp; LVWT = sum of left ventricular wall thicknesses; (-)➸
➸ = inverse relation; WBGD = clamp whole-body glucose
disposal; OGTT = oral glucose tolerance test; NOGM = non-oxidative glucose metabolism; IC = indirect calorimetry; ➷ = decreased; ITT
= intravenous insulin tolerance test; KITT = glucose disappearance rate at ITT; IRI = insulin resistance index (OGTT peak plasma insulin *
corresponding plasma glucose * 10-4); RWT = relative wall thickness; IGF-I, IGF-II = insulin-like growth factor-I and –II; GH = growth
hormone; ♀ = female; SI = insulin sensitivity by frequently sampled IVGTT and the Bergman minimal model; HOMAIR = f-Ins * f-Glu / 22.5;
IST = insulin suppression test; SSPG = steady-state plasma glucose at 2h-IST; PW = left ventricular posterior wall thickness; IVS =
intraventricular septum thickness
11
Electrophysiologic co-morbidity of left ventricular hypertrophy
Cross-sectional analyses cannot determine causal relations between variables, but are
relevant for the study of co-existence of conditions or diseases. In this study, we have
investigated the co-existence of ECG aberrations and echocardiographic LVH or left
ventricular geometric and functional abnormalities, in order to assess the associations
between these two ways (ECG and echocardiography) of measuring cardiac functions
(study IV). Previously, LVH has been shown to be related to premature ventricular
beats85, and to a wide variety of ECG aberrations, including Q-waves, S-T segment
and T-wave aberrations, in patients with hypertrophic cardiomyopathy86.
Prognostic significance of left ventricular hypertrophy
LVH has previously been shown to be a strong risk factor for mortality and morbidity
whether diagnosed by echocardiography5-16 or ECG17-21. Echocardiographically
determined LVH has been shown to be a major risk factor for cardiovascular
morbidity and mortality (including cerebrovascular stroke9 and sudden death14) in the
general population5,6 and in patients with hypertension15, coronary artery disease8,10
or left ventricular dysfunction16. In some studies7,11-13, an increased RWT has also
been shown to be of adverse prognostic value, with a worse prognosis in subjects with
concentric LVH than in subjects with eccentric LVH, and a worse prognosis in subjects
with concentric remodeling than in subjects with a normal left ventricular geometry
(table 2). However, in one of these studies11, the geometric pattern gave little
additional information when taking left ventricular mass into account.
Although many studies of the prognostic value of LVH and geometric subtypes have
been made, it is not known if subjects with echocardiographic LVH who later suffer
morbid events or die also have ECG-LVH or vice versa, or if the methods provide
complementary prognostic information. It is not fully known if the increased
cardiovascular risk associated with echocardiographic or ECG-LVH or an increased
RWT is independent of associated metabolic disturbances (such as insulin resistance
measured with the clamp technique) and hypertension. We therefore studied these
prognostic aspects using a fairly large cohort of elderly men from the general
population, followed for a maximum of 6.4 years (study V).
Table 2: Previous studies of the prognostic importance of left ventricular geometric
patterns
Rate (endpoints / 100 patient-years)
Study
Study population
253 (167 ♂) HT
Krumholz, 199511
3216 (1400 ♂)
general population,
age >40
694 (305 ♂) HT
274 (195 ♂) HT
Koren, 19917
Verdecchia,
199512
Verdecchia,
199613
Follow-up
duration
(years)
10.2
Endpoint
CV mortality
CV morbidity
total mortality
CV morbidity
Normal
geometry
0
1.1
0.7
1.2
Concentric
remodeling
0.3
1.5
1.6
2.0
Concentric
LVH
2.1
3.1
2.7
3.6
Eccentric
LVH
1.0
2.3
1.4
2.1
2.7
CV morbidity
1.1
2.4
-
-
3.2
CV morbidity
-
-
3.3
2.2
7.7
LVH = left ventricular hypertrophy; ♂ = male; HT = hypertensive; CV = cardiovascular. Adapted from reference87 with permission.
12
Aims of the study
I.
To investigate prospectively determined hemodynamic, metabolic, dietary and
psychosocial factors at age 50 as predictors for the prevalence of
echocardiographic LVH and left ventricular geometric subtypes at age 70, by
using a fairly large, regionally determined sample of men from the general
population, followed-up for twenty years.
II.
To cross-sectionally investigate the relations between echocardiographic left
ventricular mass and geometry and components of the insulin resistance
syndrome.
III.
To investigate the relations between myocardial and skeletal muscle insulin
sensitivity and RWT and LVMI, by measuring glucose uptake in myocardium
and skeletal muscle during hyperinsulinemic euglycemic clamp using 18Ffluorodeoxyglucose and PET in a homogenous sample of healthy, normotensive
men with wide ranges of RWT and LVMI.
IV.
To cross-sectionally investigate the relations between echocardiographic indices
of left ventricular geometry and function and ECG characteristics and
diagnoses, with special emphasis to the role of echocardiographically
determined LVH.
V.
To investigate if prospectively determined echocardiographic and ECG-LVH
predict subsequent total and cardiovascular mortality and morbidity
independently of each other and of components of the insulin resistance
syndrome, and if any additional prognostic information was provided by an
echocardiographic examination if the subject’s ECG-LVH and hypertension
status was known.
13
Methods
The cohort
In 1970-73, all men born in 1920-24 and resident in the municipality of Uppsala were
invited to a health survey aimed at identifying risk factors for cardiovascular disease
in ≈50 year-old men and selecting high-risk individuals for treatment88. Of the
invited subjects, 2322 participated (82%). The cohort was reinvestigated 20 years later
(in 1991-95, at age ≈70) with echocardiographic and Doppler examinations,
ambulatory blood pressure monitoring, hyperinsulinemic euglycemic clamp and oral
glucose tolerance test (OGTT) in addition to the previous study protocol. All
investigations in the same subject were performed within 1 month. In the latter
investigation, 1221 subjects participated. A reproducibility study was made of all
investigations in 22 subjects ≈1 month after the original investigations. The intraindividual coefficients of variation (CVs) presented are from this reproducibility
study. Echocardiographic examinations were performed in the first 583 consecutive
men in the investigation at age 702, and determination of left ventricular geometry
was possible in 475 of these (figure 2).
Fig. 2: The Uppsala Longitudinal Study of Adult Men
1970-73
422 died
219 moved
2841 men born 1920-24 (≈ 50
year old) and living in Uppsala
municipality were invited,
2322 (82%) participated
1991-95
44 died
1681 eligible participants of
the 1970-73 study (≈ 70
year old) were invited,
1221 (73%) participated
583 first
consecutive
men had echocardiography
475 men had left
ventricular geometry
determinations
PET = positron emission tomography
14
9 in PET
study
Study populations
The population of studies I, II and V consisted of 475 of the first 583 consecutive men
of the investigation at age 70 in which determination of left ventricular geometry was
possible2. The men included in the study did not differ significantly from the
excluded men in any of the investigated variables. Fifty-four subjects had been
hospitalized due to ischemic heart disease (ICD-9 codes 410-414) between the
investigations at 50 and 70 years of age. At age 70, 167 subjects were regularly using
antihypertensive medication, of which 6 were using α-receptor blockers, 60 calcium
antagonists, 24 angiotensin-converting enzyme (ACE) inhibitors, 57 diuretics, and 88
β-receptor blockers, as monotherapy or in combination. At age 70, 38 subjects used
lipid lowering drugs, of which 16 used statins, 15 fibrates, 6 resins and 2 used
nicotinic acid, as monotherapy or in combination. Only 17 subjects had significant
echocardiographic valvular disease (aortic or mitral stenosis or regurgitation grades 3
or 4). According to the criteria proposed by the World Health Organization in 198589,
66 subjects had diabetes mellitus type-2 and 115 had impaired glucose tolerance at
age 70. In study I, all analyses were also made on a subset (n=421) without ischemic
heart disease during follow-up, and in study II, all analyses were also made on a
subset (n=458) without valvular disease.
The population of study III consisted of 9 subjects, chosen from the investigation at
age 70 by echocardiographic left ventricular geometry to have wide ranges of RWT
and LVMI. The subjects all had supine office blood pressures <160/95 mm Hg at a
single office visit, were free from regular medication, history of heart disease,
significant echocardiographic valvular disease and signs of coronary heart disease on
resting ECG, exercise testing and 24-h ambulatory ECG monitoring.
The population of study IV consisted of 540 of the first 583 consecutive men of the
investigation at age 70 who had both an ECG and an echocardiographic examination.
Investigations at age 50
These investigations were used in study I and have been described extensively
previously88. Blood pressure in the recumbent position was measured with a
mercury manometer and radial pulse rate was counted. All blood samples were
drawn in the morning after an overnight fast. Blood glucose, serum insulin,
cholesterol, triglycerides and HDL-cholesterol were measured, and LDL-cholesterol
was calculated using Friedewald’s formula: LDL = serum cholesterol – HDL – (0.45 *
serum triglycerides). The serum CE proportions of several fatty acids (14:0, 16:0, 16:1,
18:0, 18:1, 18:2 ω6, 18:3 ω6, 18:3 ω3, 20:3 ω6, 20:4 ω6, 20:5 ω3, 22:6 ω3) were determined
by gas chromatography46. No dietary records were obtained, but in other population
studies in middle-aged men in the 1970s in Sweden, intake of fat corresponded to
about 40%, carbohydrates 45-50% and protein 13-15% of energy intake. The
estimated intake of saturated fats corresponded to 17-18% of energy intake90.
15
A questionnaire covered level of physical activity (four categories) and education
(five categories). Coding of smoking (smoker, non-smoker, ex-smoker), civil status
and socioeconomic status (three social classes, Central Bureau of Statistics) was based
on interview reports88.
Investigations at age 70
Seven-day dietary records in 444 of the 475 subjects in studies I, II and V showed an
intake of fat corresponding to 35%, carbohydrates 48% and protein 16% of energy
intake, which was comparable to other contemporary Swedish populations of the
same age90. Coding of smoking (smoker, non-smoker) was based on an interview
question also at age 70.
Echocardiography
A comprehensive two-dimensional and Doppler echocardiography was performed
with a Hewlett Packard Sonos 1500 cardiac ultrasound unit (Hewlett Packard,
Andover, MA) as described previously2. A 2.5 MHz transducer was used for the
majority of the examinations. Dimensions were measured in M-mode using the
leading-edge to leading-edge convention. The measurements included left atrial
diameter (LA), interventricular septal thickness (IVS), posterior wall thickness (PW)
and left ventricular diameter at the end of diastole and the end of systole (LVEDD
and LVESD) (figure 3). Left ventricular mass was determined using the Troy formula
according to the recommendations of the American Society of Echocardiography
(ASE)24: left ventricular mass (grams) = 1.05 * ((LVEDD + IVS + PW)3 – LVEDD3). To
correct for differences in body constitution, left ventricular mass was divided with
body surface area to obtain LVMI. LVH was defined as LVMI ≥150 g/m2 according
to data from the Framingham Heart Study24, corresponding to 131 g/m2 for LVMI
measured with the Penn convention and the modified cube formula24. Left
ventricular mass by both conventions correlate well with necropsy left ventricular
mass91, but slightly overestimate it (6% by the Penn convention and 25% by the ASE
convention). Thus, LVMI measured with the leading-edge to leading-edge
convention and the Troy formula can easily be transformed to reflect anatomic
measurements91: left ventricular mass = 0.80 * (ASE mass) + 0.6g. RWT was
calculated as (IVS + PW) / LVEDD, and a partition value of 0.44 was used. Thus, left
ventricular geometry was considered normal if RWT was <0.44 and LVMI <150
g/m2. A normal LVMI with increased RWT was denoted concentric remodeling, and
a hypertrophic left ventricle was denoted eccentric if RWT was normal and
concentric if RWT was increased (figure 1)22.
Left ventricular volumes (LVEDV, LVESV) were calculated according to the
Teichholz formula: Vol = 7 * D3 / (2.4 + D). From these volumes ejection fraction was
calculated. Stroke volume was calculated from Doppler measurements of left
ventricular outflow tract diameter (LVOT) and the flow velocity integral (FVI) as
π * LVOT2 / 4 * FVI and was divided by body surface area to obtain stroke index. The
left ventricular filling pattern in diastole was examined by measuring mitral blood
16
flow velocities with the transducer in the apical position. The peak velocities of the
early rapid filling phase (E-wave) and the atrial systolic phase (A-wave) were
recorded and E/A ratio calculated. Left ventricular isovolumetric relaxation time
(IVRT) was measured as the time between the aortic valve closure and the start of the
mitral flow using the Doppler signal from the area between the LVOT and mitral
flow.
All examinations were performed with the subjects in the standard left lateral
position in expiratory apnea or quiet breathing. The best five cardiac beats were
chosen and the average of these was calculated. All examinations and readings of the
images were done by one experienced physician (Bertil Andrén) who was unaware of
other data of the subjects. The CVs were for dimensional measurements LA 6.5%, IVS
8.8%, PW 6.7%, LVEDD 3.5%, LVMI 12.5% and RWT 6.9% and for Doppler
measurements IVRT 6.8%, E-wave 10.0%, A-wave 9.4% and E/A-ratio 16.9%.
Fig. 3: Echocardiographic left ventricular geometric measurements
IVS
LVEDD
PW
Relative wall thickness = (IVS+PW)/LVEDD
Left ventricular mass = 1.05((IVS+LVEDD+PW )3-LVEDD3)
Electrocardiography
A standard 12-lead ECG was recorded at 50 mm/s and 10 mm/mV and evaluated
according to the Minnesota code92 by one experienced physician (Lars Lind) who
was unaware of other data of the subjects. In study IV, the analyzed diagnoses were:
Q-wave (Minnesota codes 1-1 or 1-2), S-T segment depression (4-1 or 4-2), T-wave
items (5-1, 5-2 or 5-3), left bundle-branch block (7-1), frequent premature beats (10%
17
or more of recorded beats, 8-1), atrial flutter or fibrillation (8-3), bradycardia (less
than 50 beats per minute, 8-8), atrioventricular block type 1 (6-3) and left anterior
hemiblock (7-7). All analyses of S-T segment depression, T-wave items and left
bundle-branch block were carried out in a subset without Q-wave. All analyses of
frequent premature beats, atrial flutter or fibrillation, bradycardia, atrioventricular
block type 1 and left anterior hemiblock were carried out in a subset without Q-, S-Tor T-wave abnormalities or left bundle-branch block (figure 4).
In study IV, ECGs of a subset of 107 consecutive subjects without ECG abnormalities
defined in the Minnesota code system were also analyzed for linear relations
between echocardiographic and ECG measurements. The Sokolow-Lyon Voltage was
determined as the amplitude of SV1 + RV5 or RV6, the Cornell Voltage as SV3 + RaVL
and the Cornell Product as SV3 + RaVL * QRS duration. The direction of the QRS axis
in the frontal plane was calculated from the QRS amplitudes in the extremity leads
and expressed as degrees in a 360° circle, with 0° defined as the direction of extremity
lead I, increasing clockwise. The early diastolic phase at ECG was defined as the time
between the end of the T-wave and the beginning of the P-wave. All intervals were
corrected for heart rate according to Bazette93.
Fig. 4: Distribution of electrocardiographic diagnoses in the study population
Total
n=540
No Q-, ST- or T-wave abnormalities
or left bundle-branch block, n=364
Frequent
premature
beats
n=9
Q-wave
n=77
Normal electrocardiogram
n=273
No Q-wave
n=463
Left bundlebranch block
n=9
Atrial
flutter /
fibrillation
n=12
n=22
Bradycardia
n=18
Atrioventricular
block type 1
n=12
18
T-wave items
n=58
ST-segment
depression
n=54
In study V, we analyzed the predictive value of several ECG criteria for LVH:
Sokolow-Lyon Voltage (SV1 + RV5 or RV6) ≥3.5 mV, Cornell Voltage (SV3 + RaVL) >2.8
mV, left ventricular strain (down-sloping ST-segment depression >0.1 mV with Twave flattening or inversion in leads V4-V5) (which have previously been validated
in prospective studies17,19,21) and Cornell Product (SV3 + RaVL * QRS duration) >244
µVs (not validated in a prospective study before, but used as inclusion criterion in
the LIFE study94). Sensitivities/specificities (%) for detection of echocardiographic
LVH were 27/88 for Sokolow-Lyon Voltage ≥3.5 mV; 17/91 for Cornell Voltage >2.8
mV; 28/88 for Cornell Product >244 µVs; and 21/92 for left ventricular strain, in the
present population.
Blood pressure measurements
The ambulatory blood pressure measuring device Accutracker II (Suntech Medical
Instruments) was attached to the subject’s nondominant arm. Systolic and diastolic
blood pressures (SBP, DBP) and heart rate were measured over 24 hours, every 30
minutes during daytime (6 AM to 11 PM) and every hour during nighttime. Data
were edited to a limited extent, omitting all readings of 0, all heart rate readings <30
beats per minute, DBP readings >170 mm Hg, SBP readings >270 and <80 mm Hg,
and all readings for which the difference between SBP and DBP was <10 mm Hg. The
CV for 24-h mean arterial blood pressure (DBP + (SBP - DBP) / 3) was 5.5%.
Office supine SBP, DBP and heart rate were also measured. Blood pressures were
measured twice in the right arm after 10 minutes rest, and means were calculated.
The rate-pressure product (an index of cardiac work) was calculated as office
SBP*office heart rate.
Hyperinsulinemic euglycemic clamp
Whole-body glucose uptake and insulin sensitivity index were determined with the
hyperinsulinemic euglycemic clamp, performed according to the method of
DeFronzo et al48 with a slight modification. After a priming dose of insulin given
during 10 minutes, insulin (Actrapid Human®, Novo) was infused at a constant rate
of 56 (instead of 4048) mU/(min * m2 body surface area). Such a high concentration of
insulin has been shown to inhibit hepatic glucose output by 88-95% also in
diabetics95. The arterialized plasma glucose concentration was determined every fifth
minute (Beckman Glucose Analyzer II®, Beckman instruments) and the rate of a 20%
dextrose solution was thereafter adjusted every fifth minute to keep plasma glucose
at the target level of 5.1 mmol/l. The whole-body glucose uptake was calculated as
the amount of glucose infused during the last 60 minutes of the 2-h clamp (mg/kg
body weight/min), and the insulin sensitivity index (studies II and V) was calculated
by dividing whole-body glucose uptake by the mean plasma insulin concentration
times 100 (mU/L) during the last 60 minutes of the 2-h clamp. In study III, wholebody glucose uptake was calculated immediately before the PET measurements were
done. The CV for whole-body glucose uptake was 9.2%, and for insulin sensitivity
index, it was 13.9%.
19
Oral glucose tolerance test
Blood samples for determining fasting concentrations were drawn in the morning
after an overnight fast. An OGTT was performed by measuring the concentrations of
plasma glucose and ”immunoreactive insulin” immediately before and 30, 60, 90, and
120 minutes after 75 g anhydrous dextrose was ingested. Fasting, 2-h levels and the
incremental areas under the curves (AUC) of glucose and immunoreactive insulin
were analyzed. Glucose was measured by the glucose dehydrogenase method (GlucDH, Merck), and immunoreactive insulin was analyzed by use of an enzymaticimmunological assay (Enzymun, Boehringer Mannheim) performed in an ES300
automatic analyzer (Boehringer Mannheim). Fasting specific insulin and 32-33 split
and intact proinsulin concentrations were measured with a specific 2-site
immunoradiometric assay technique96 in Cambridge, UK, on a Nuclear Enterprises
1600 gamma counter of 125I. The CV for fasting plasma glucose was 5.8%, and for
immunoreactive insulin, it was 15.4%.
Lipid measurements
HDL was separated by precipitation with magnesium chloride/phosphotungstate.
Cholesterol and triglyceride concentrations in serum and HDL were assayed by
enzymatic techniques (Instrumentation Laboratories) in a Monarch 2000 centrifugal
analyzer. LDL-cholesterol was calculated with Friedewald’s formula. Serum
nonesterified fatty acids (NEFA) were measured by an enzymatic colorimetric
method (Wako Chemical GmbH) applied for use in the Monarch 2000. The CVs were
for serum total cholesterol 5.7%, HDL-cholesterol 11.1%, LDL-cholesterol 6.6%,
serum triglycerides 14.8%, and NEFA 24.2%.
Positron emission tomography
In study III, myocardial and skeletal muscle glucose uptake were determined by
means of the radiolabelled tracer 2-[18F]-fluoro-deoxyglucose (18FDG) and PET. PET
investigations were performed during hyperinsulinemic euglycemic clamp with the
subject in supine position, using a GEMS 4096-15WB scanner (General Electric
Medical Systems) with a spatial resolution of 6 mm (full width at half maximum)
covering 100 mm (15 tomographic slices) with a 6.5 mm slice spacing. Attenuation of
photons was corrected for using a 10 minutes transmission scan obtained with a
rotating 68Ga/68Ge pin radiation source. Emission tomograms were reconstructed to
a 128*128 matrix with 2 mm pixel size using a 4.2 mm Hanning filter.
18FDG
is a glucose analogue, transported across the cell membrane by the same
transport proteins as glucose and phosphorylated by hexokinase. However, 18FDG is
not further metabolized, but the phosphorylated moiety is trapped in the cytosol.
Starting at the time of an intravenous bolus injection of some 6 MBq/kg body weight
of 18FDG, the accumulation of tracer in the studied tissue was followed for 60
minutes. Venous blood, arterialized by heating of the hand, was collected from a vein
on the back of the hand for measurements of the plasma concentration of
radioactivity and of plasma glucose levels. Altogether 15 samples were taken to
20
outline the variation of 18FDG in plasma during the study. The glucose uptake
(metabolic rate of glucose), expressed in µmol/min/100cm3 tissue, was calculated by
the graphical method97, using a value of the ”lumped constant” equal to 1.0 for
myocardium98, and 1.2 for skeletal muscle. Partial volume or spill-over effects in
18FDG time-activity curves were corrected for corresponding 15O-water
measurements from assessments of myocardial perfusion.
Images acquired during peak myocardial concentration of 18F (40-60 minutes after
injection of the tracer) were used for the definition of regions of interest (ROI) in the
short axis view. ROIs defining the left ventricular wall were 10 mm in the radial
direction, symmetrically placed from the endo- to the epicardial surface in sections 10
mm apart, covering the left ventricular wall from apex to base. All ROIs were
lumped together to provide a volume, representing the entire left ventricular
myocardium. ROIs representing skeletal muscle were defined in the soft tissues of
the left upper arm in six adjacent image slices which were joined together. Bone was
identified in the transmission measurement and excluded from the ROIs.
Follow-up after age 70
The subjects had a median follow-up time of 5.2 years (range 0.7-6.4 years) after the
investigation at age 70, contributing to 2415.6 person-years at risk (PYAR). Endpoints
were defined using the Swedish national cause-of-death and hospital discharge
registers. During follow-up, 44 subjects died (rate 1.82/100 PYAR), 18 from
cardiovascular disease (ICD codes 390-459, rate 0.75/100 PYAR) (of which 7 died
from acute myocardial infarction and 4 from stroke). Morbidity was defined as first
hospitalization or death from cardiovascular disease or any cause, and was evaluated
only for subjects who had not previously been hospitalized for cardiovascular
disease or any cause, respectively. During follow-up, 48/122 (39%, rate 9.50/100
PYAR) had a morbid event of any cause, and 64/338 (19%, rate 4.09/100 PYAR) had
a cardiovascular morbid event.
Statistical analysis
Variables with a skewed distribution (fasting serum insulin, triglycerides,
LDL/HDL-cholesterol, CE proportion of palmitoleic, stearic, γ-linolenic, α-linolenic,
eicosapentaenoic and docosahexaenoic acids at age 50; and fasting plasma glucose,
immunoreactive insulin, specific insulin, proinsulin, 32-33 split proinsulin, serum
triglycerides and NEFA, 2-h glucose and immunoreactive insulin levels, and the
AUC of immunoreactive insulin at the OGTT at age 70) were logarithmically
transformed to achieve normal distribution, and these transformed variables were
used in all analyses. One-way and multi-way ANOVA (adjusted for possible
confounders) was used to calculate differences in means between subgroups. Posthoc comparisons between subgroups were only performed if overall ANOVA was
significant. Chi2-test was used to evaluate differences in nominal variables between
subgroups. Pearson’s correlation coefficients and partial correlation coefficients
(adjusted for possible confounders) were used to evaluate relations between pairs of
21
continuous variables. Two-tailed 95% confidence intervals (CI) and significance
values were given, with P<0.05 regarded as significant. In study I, logistic regression
was used with LVH or increased RWT at age 70 as outcome variables and
standardized continuous variables (mean=0, SD=1) or indicator variables for multilevel nominal variables at age 50 as explanatory variables. Multiple logistic
regression was used to adjust for possible confounders, treated as dichotomous
variables. Squared terms and interaction terms were tested in all regressions. In
study II, relations to LVMI but not to RWT were adjusted for use of antihypertensive
medication, because subjects using antihypertensive medication had significantly
higher LVMIs but did not differ in RWT. Squared variables and interaction terms
between independent variables were tested in all regression models. Scatter plots
were visually examined for other nonlinear associations. In study V, the prognostic
value of transfer from one level of a dichotomous variable to another, or a one SD
increase in a continuous variable, was investigated with Cox proportional hazard
ratios (HR). Proportionality of hazards was confirmed with Kaplan-Meier plots.
Multiple Cox proportional hazards analyses were used to adjust for either LVMI,
previous ischemic heart disease or nine cardiovascular risk factors. Other cut-off
levels for LVMI than 150 g/m2 were sought using histograms of quartiles of LVMI
for cardiovascular and total mortality, and by performing logistic regression and
receiver operating characteristic (ROC)-curves. JMP 3.2 (SAS Institute Inc.) and Stata
6.0 (Stata Corporation) software were used.
22
Results
Prospectively defined predictors at age 50 for left ventricular hypertrophy or
increased relative wall thickness at age 70 (I)
The prevalence of LVH at age 70 was 28% in the present cohort. Among the variables
associated with the insulin resistance syndrome, a one SD increase in any of body
mass index (BMI), SBP, DBP, fasting LDL/HDL-cholesterol or serum triglycerides at
age 50 resulted in a 27-41% increased odds of having LVH at age 70 (figure 5). A one
SD increase in the serum CE proportion of any of myristic (14:0), palmitic (16:0),
stearic (18:0), oleic (18:1) or eicosapentaenoic acid (20:5 ω3) at age 50 increased the
odds of having LVH at age 70 by 29-37%, whereas a one SD increase in the
proportion of linoleic acid (18:2 ω6) at age 50 reduced the odds of having LVH at age
70 by 24%. No studied psychosocial factors at age 50, crude or adjusted, predicted
later LVH.
The prevalence of an increased RWT at age 70 was 25% in the present cohort. A one
SD increase in serum CE proportion of oleic acid (18:1), γ-linolenic acid (18:3 ω6) or
dihomo-γ-linolenic acid (20:3 ω6) at age 50 increased the odds of having increased
RWT at age 70 by 28-32%, whereas a one SD increase in the proportion of linoleic
acid (18:2 ω6) at age 50 reduced the odds of having increased RWT at age 70 by 26%.
The studied psychosocial issues were not associated with an increased RWT.
Fig. 5: Odds-ratios and 95% confidence intervals for having left ventricular hypertrophy
at age 70 for a one standard deviation increase in a variable at age 50
Body mass index
Systolic blood pressure
Diastolic blood pressure
Pulse rate
Total cholesterol
LDL/HDL-cholesterol
Triglycerides
Glucose
Insulin
Myristic acid (14:0)
Palmitic acid (16:0)
Palmitoleic acid (16:1)
Stearic acid (18:0)
Oleic acid (18:1)
Linoleic acid (18:2ω6)
0.6
0.8
1.0
1.2
23
1.4
1.6
Approximately the same results were obtained when: 1, adjusting all the above
analyses for ischemic heart disease (ICD-9 codes 410 to 414) during follow-up and
valvular disease and use of antihypertensive medication at age 70; 2, adjusting for
these three variables and BMI at age 50; 3, adjusting for the first three variables and
use of lipid lowering drugs at age 70; and 4, analyzing a subsample of 421 subjects
without ischemic heart disease during follow-up, adjusted for valvular disease and
use of antihypertensive medication at age 70.
Characteristics at age 50 according to left ventricular geometric patterns at age 70
(I)
The levels of several variables associated with the insulin resistance syndrome and
serum CE proportions of several fatty acids determined at age 50 varied significantly
between the four left ventricular geometry groups determined at age 70 (figure 6). In
the concentric remodeling group, serum CE proportions of oleic (18:1) and γ-linolenic
acid (18:3 ω6) were significantly higher, and linoleic acid (18:2 ω6) significantly lower
than in the normal geometry group. In the concentric LVH group, DBP and serum
CE proportions of myristic (14:0), palmitic (16:0), oleic (18:1) and eicosapentaenoic
acid (20:5 ω3) were significantly higher, and linoleic acid (18:2 ω6) significantly lower
than in the normal geometry group. In the eccentric LVH group, BMI, SBP, DBP,
fasting serum triglycerides and CE proportions of oleic (18:1) and eicosapentaenoic
acid (20:5 ω3) were significantly higher, and linoleic acid (18:2 ω6) significantly lower
than in the normal geometry group. Adjusting for ischemic heart disease during
follow-up and valvular disease and use of antihypertensive medication at age 70, or
adjusting for these three variables and BMI at age 50, gave similar results.
Fig. 6: Significant predictors at age 50 for left ventricular geometric subtypes at age 70
18:1 ↑
18:2 ω6 ↓
DBP ↑
14:0 ↑
16:0 ↑
18:1 ↑
18:2 ω6 ↓
Concentric remodeling
LVH = left ventricular hypertrophy
14:0 = myristic acid
16:0 = palmitic acid
18:1 = oleic acid
18:2 ω6 = linoleic acid
BMI = body mass index
SBP = systolic blood pressure
DBP = diastolic blood pressure
TG = triglycerides
Normal
Concentric LVH
Eccentric LVH
24
BMI ↑
SBP ↑
DBP ↑
TG ↑
18:1 ↑
18:2 ω6 ↓
Relations between components of the insulin resistance syndrome and left
ventricular geometric parameters at age 70 (II)
Several components of the insulin resistance syndrome were significantly and
directly related to RWT, such as 24-h SBP and DBP, 24-h heart rate, 2-h glucose level
and the AUC of glucose at the OGTT, fasting specific insulin and 32-33 split
proinsulin, waist-to-hip ratio, BMI, serum triglycerides, and NEFA, whereas clamp
insulin sensitivity index was inversely related to RWT (figure 7). On the other hand,
of the measured variables, only 24-h SBP (directly), 24-h heart rate, and 2-h
immunoreactive insulin level at the OGTT (inversely) were significantly related to
LVMI. In a subsample of 458 subjects without valvular disease, controlling for
previous ischemic heart disease, results were essentially the same as in the original
analyses. There was no relation between RWT and LVMI.
Fig. 7: Significant correlations between left ventricular geometric determinants
and components of the insulin resistance syndrome at age 70
Left ventricular mass index
Relative wall thickness
24-h SBP
24-h DBP
24-h heart rate
Insulin sensitivity index
OGTT 2-h glucose
OGTT AUC glucose
Fasting specific insulin
Fasting 32-33 split proinsulin
W aist-to-hip ratio
Body mass index
Serum triglycerides
Serum NEFA
SBP = systolic blood pressure
DBP = diastolic blood pressure
OGTT = oral glucose tolerance test
AUC = area under the curve
NEFA = non-esterified fatty acids
-0.1
0
Correlation coefficient
0.1
0.2
Metabolic and other characteristics of subjects with various left ventricular
geometries (II)
The levels of several components of the insulin resistance syndrome — 24-h SBP and
DBP, 24-h heart rate, clamp insulin sensitivity index, 2-h glucose level and the AUC
of glucose at the OGTT, waist-to-hip ratio, and BMI — differed significantly between
the 4 left ventricular geometric groups (figure 8). The values of 24-h heart rate, waistto-hip ratio, 2-h glucose level, and the AUC of glucose at the OGTT were significantly
25
higher and clamp insulin sensitivity index was significantly lower in the concentric
remodeling geometry group compared with the group with normal left ventricular
geometry. The 24-h SBP and DBP were significantly higher in the concentric LVH
group compared with the group with normal left ventricular geometry.
The difference in 24-h heart rate between the groups (higher in the concentric
remodeling geometry group and lower in the eccentric LVH group than in the
normal geometry group) remained significant when adjusting simultaneously for the
possible confounders ischemic heart disease, stroke index and use of β-receptor
blockers and any other antihypertensive medication. In a subsample without
valvular disease, controlling for previous ischemic heart disease, differences between
the groups were essentially the same as in the original analyses.
Fig. 8: Metabolic and other characteristics of left ventricular geometric subtypes at age 70
24-h HR ↑
Insulin sensitivity index ↓
OGTT glucose ↑
Waist-to-hip ratio ↑
24-h SBP ↑
24-h DBP ↑
Concentric remodeling
Concentric LVH
24-h HR ↓
LVH = left ventricular hypertrophy
HR = heart rate
OGTT = oral glucose tolerance test
SBP = systolic blood pressure
DBP = diastolic blood pressure
Normal
Eccentric LVH
Myocardial and skeletal muscle insulin-mediated glucose uptake and left
ventricular geometry (III)
In a homogenous group of 9 subjects, insulin-mediated glucose uptake in the skeletal
muscle was inversely correlated to RWT (figure 9) whereas there was a borderline
significant positive correlation between insulin-mediated myocardial glucose uptake
and RWT (figure 10). The myocardial to skeletal muscle glucose uptake ratio showed
a positive correlation to RWT (figure 11). We found no relations between LVMI and
insulin-mediated glucose uptake in the myocardium, skeletal muscle or the ratio
between myocardial and skeletal muscle glucose uptake.
26
Fig. 9: Insulin-mediated skeletal muscle glucose uptake
in relation to left ventricular relative wall thickness
Skeletal muscle glucose uptake
(µmol/min/100cm3)
10
8
6
4
2
0.35
0.40
0.45
0.50
Relative wall thickness
Fig. 10: Insulin-mediated myocardial glucose uptake
in relation to left ventricular relative wall thickness
120
Myocardial glucose uptake
(µmol/min/100cm3)
100
80
60
40
20
0.35
0.40
0.45
Relative wall thickness
27
0.50
Myocardial / skeletal muscle glucose uptake
(µmol/min/100cm3)
Fig. 11: Ratio between insulin-mediated myocardial and skeletal muscle glucose
uptake in relation to left ventricular relative wall thickness
40
30
20
10
0
0.35
0.40
0.45
0.50
Relative wall thickness
Insulin-mediated whole-body glucose uptake (measured with hyperinsulinemic
euglycemic clamp) was directly related to the insulin-mediated glucose uptake in the
skeletal muscle, and tended to be inversely related to the insulin-mediated
myocardial glucose uptake (the latter two measured with 18FDG- PET). There was no
significant relation between insulin-mediated myocardial and skeletal muscle
glucose uptake or between insulin-mediated myocardial muscle glucose uptake and
fasting plasma glucose, 24-h systolic, diastolic or mean arterial blood pressure or the
rate-pressure product.
Echocardiographic characteristics of various electrocardiographic diagnoses at age
70 (IV)
For distribution of ECG diagnoses in the study population at age 70, see figure 4. An
increased LVMI was the most common echocardiographic finding in the analyzed
ECG diagnoses (figure 12). Subjects with a Q-wave had significantly higher LVEDD
and LVMI and lower ejection fraction than subjects without a Q-wave. Subjects with
ST- or T-wave abnormalities had significantly larger LA, IVS, PW and LVMI than
subjects without ST- or T-wave abnormalities. Subjects with left bundle-branch block
had significantly higher LVEDD and LVMI and lower ejection fraction than subjects
without left bundle-branch block. Subjects with atrial flutter or fibrillation had a
significantly larger LA than subjects without atrial flutter/fibrillation. Subjects with
atrioventricular block type 1 had significantly larger IVS, PW, IVRT and LVMI than
subjects without atrioventricular block type 1. Subjects with frequent premature
28
beats had significantly larger LA, IVS, PW and LVMI than subjects without
premature beats. Subjects with bradycardia had a significantly higher E/A ratio than
subjects without bradycardia.
The prevalences of several ECG diagnoses differed significantly between the four
echocardiographically determined left ventricular geometric groups (figure 13); the
prevalence of Q-waves was highest in the eccentric LVH group, whereas the
prevalences of ST- or T-wave abnormalities and atrioventricular block type 1 were
highest in the concentric LVH group.
Fig. 12: Left ventricular mass index in various electrocardiographic diagnoses
Atrioventricular block type 1
Frequent premature beats
Left bundle-branch block
ST- or T-wave abnormalities
Q-wave
Normal electrocardiogram
100
110 120 130 140 150 160
Left ventricular mass index (g/m2)
170
Fig. 13: Prevalences (%) of various electrocardiographic
diagnoses in the left ventricular geometric subgroups
Any electrocardiographic abnormality
70
ST- or T-wave abnormalities
Q-wave
60
Atrioventricular block type 1
Left bundle-branch block
50
40
30
20
10
0
Normal
Concentric
remodeling
LVH = left ventricular hypertrophy
29
Concentric
LVH
Eccentric
LVH
Relations between echocardiographic and electrocardiographic measurements (IV)
Left ventricular systolic function, as measured by the ejection fraction, was inversely
related to the Sokolow-Lyon Voltage. Left ventricular diastolic function, as measured
by the E/A ratio, was related to the duration of the early diastolic phase at the ECG
and inversely related to the Sokolow-Lyon Voltage. The IVRT was inversely related
to the clockwise deviation of the QRS axis from the direction of extremity lead I.
Sokolow-Lyon Voltage was also significantly related to LVMI.
Prognostic value of prospectively determined echocardiographic left ventricular
hypertrophy (V)
Echocardiographic LVH was a significant predictor of cardiovascular morbidity and
mortality. Dividing the population into geometric subgroups provided some
additional information (figure 14): concentric remodeling and eccentric LVH were
significant predictors of cardiovascular mortality compared to subjects with a normal
geometry. Concentric LVH had a similar but non-significant hazard ratio as
concentric remodeling. Also LVMI as a continuous variable was a significant
predictor of morbidity and mortality from cardiovascular disease and total mortality.
Other cut-off levels for LVMI than the proposed24 150 g/m2 were sought using
quartiles of LVMI and logistic regressions and ROC-curves with total and
cardiovascular mortality as dependent variables. Total mortality seemed to increase
rather linearly with increasing LVMI, and no obvious cut-off level for prediction of
total mortality was found. In contrast, the risk for cardiovascular mortality was
markedly increased only in the fourth quartile of LVMI (figure 15). This information
combined with the ROC-curve for LVMI regarding cardiovascular mortality (figure
16) indicated that 150 g/m2 was a cut-off level that provided a reasonable
combination of sensitivity and specificity for detection of this increased risk.
Nine cardiovascular risk factors (clamp insulin sensitivity index, proinsulin, total and
HDL-cholesterol, triglycerides, waist circumference, smoking, hypertension and
previous ischemic heart disease) were also evaluated as risk factors for mortality and
morbidity. Smoking or a 1 SD increase in proinsulin increased the risk, and a 1 SD
increase in HDL-cholesterol decreased the risk for mortality from cardiovascular
disease. Smoking also predicted total morbidity. When adjusting for these nine
cardiovascular risk factors, concentric remodeling and eccentric LVH remained
significant predictors of cardiovascular mortality, and the predictive value of LVMI
as a continuous variable for total and cardiovascular mortality remained significant.
30
Fig. 14: Cox proportional hazard ratios for cardiovascular mortality
in various categories of left ventricular geometry
Hazard ratio for cardiovascular mortality
P=0.002
9
8
7
6
5
4
3
2
1
0
P=0.04
LVMI ≥ 150 g/m2
LVMI < 150 g/m2
RWT ≥ 0.44
RWT < 0.44
RW T = relative wall thickness
LVMI = left ventricular mass index
Hazard in the normal geometry group was set to 1.0
A
B
34
61
Total mortality (%)
Cardiovascular mortality (%)
Fig. 15: Total (A) and cardiovascular (B) mortality in quartiles of left ventricular mass index
0
0
71 <117
117 <135
135 <154
71 <117
154 250
117 <135
135 <154
154 250
Left ventricular mass index (g/m2)
Left ventricular mass index (g/m2)
31
Fig. 16: Receiver operating characteristics-curve for left ventricular
mass index (g/m2) regarding cardiovascular mortality
100
130 120 110
140
Sensitivity (%)
75
150
160
50
170
25
0
25
50
75
100
100 - Specificity (%)
Area under left ventricular mass index curve = 76 %
0
Prognostic value of prospectively determined electrocardiographic left ventricular
hypertrophy (V)
LVH as defined by Sokolow-Lyon Voltage ≥3.5 mV was a significant predictor of
total mortality. LVH as defined by Cornell Voltage >2.8 mV was a significant
predictor of total mortality, also after adjustment for LVMI. LVH as defined by
Cornell Product >244 µVs was a strong predictor of both cardiovascular and total
mortality, also after adjustment for nine other cardiovascular risk factors.
Adjustment for LVMI made prediction of cardiovascular, but not total mortality, lose
in significance. The left ventricular strain pattern only predicted morbidity from
cardiovascular disease.
Comparison between the prognostic values of echocardiographic and
electrocardiographic left ventricular hypertrophy (V)
In multivariate Cox proportional hazards analyses with LVMI, Cornell Product >244
µVs, Sokolow-Lyon Voltage ≥3.5 mV and nine other cardiovascular risk factors as
independent variables, LVMI and Cornell Product >244 µVs were significant
predictors of total mortality. LVMI, previous ischemic heart disease, HDLcholesterol, smoking and proinsulin were significant predictors of cardiovascular
mortality.
32
By assessing echocardiographic LVH if ECG Cornell Product ≤244 µVs, another 7 of
the 44 total deaths (another 6 of the 18 cardiovascular deaths) could be predicted. By
assessing ECG Cornell Product if echocardiography showed no LVH, another 8 of
the 44 total deaths (another 2 of the 18 cardiovascular deaths) could be predicted
(figure 17). We also stratified for hypertension. In 263 normotensive subjects, no
more total or cardiovascular deaths could be predicted by assessing
echocardiographic LVH if ECG Cornell Product ≤244 µVs. In 212 hypertensive
subjects, another 7 of the 19 total deaths (another 6 of the 12 cardiovascular deaths)
could be predicted by assessing echocardiographic LVH if ECG Cornell Product ≤244
µVs.
Fig. 17: Total (A) and cardiovascular (B) mortality rates and Kaplan-Meier survival plots in
groups with/without LVH as defined by Cornell Product and echocardiography
B
100
6
5
4
3
50
Echo+
2
1
0
EchoCP+
CP -
PYAR = person-years at risk
CP+/- = Cornell Product >244 µVs +/Echo+/- = left ventricular mass index ≥150 g/m2 +/LVH = left ventricular hypertrophy
33
Analysis time (years)
0
2
4
6
3
2
75
Echo+
1
0
100
Survival (%)
Analysis time (years)
2
4
6
Survival (%)
Total mortality rate (/100 PYAR)
0
Cardiovascular mortality rate (/100 PYAR)
A
EchoCP+
CP -
Discussion
In this prospective longitudinal study, we found that an unfavorable serum fatty acid
profile and components of the insulin resistance syndrome at age 50 predicted the
prevalence of LVH at age 70 in a twenty-year follow-up of a fairly large, regionally
determined sample of men from the general population. In cross-sectional analyses at
age 70, several components of the insulin resistance syndrome were significantly
related to RWT and concentric remodeling, but less to LVH. More specifically, RWT
was inversely related to insulin sensitivity in skeletal muscle and borderline
significantly directly related to insulin sensitivity in the myocardium in a small,
healthy and normotensive sample of the cohort, whereas LVMI was not related to
myocardial or skeletal muscle insulin sensitivity. At age 70, echocardiographic LVH
was related to a variety of common ECG diagnoses. In a prospective mortality study
with baseline at age 70, echocardiographic and ECG-LVH were found to predict
mortality independently of each other and of other cardiovascular risk factors,
implying that echocardiographic and ECG-LVH in part carry different prognostic
information.
Left ventricular hypertrophy and the insulin resistance syndrome
Components of the insulin resistance syndrome are risk factors for later left
ventricular hypertrophy
In the twenty-year prospective study (I), dyslipidemia and a serum CE fatty acid
composition with a high proportion of saturated fatty acids and low proportion of
linoleic acid at age 50 predicted the prevalence of LVH at age 70 to a similar degree
as hypertension and obesity. The impact of obesity, dyslipidemia and an unfavorable
fatty acid profile on LVH was independent of history of ischemic heart disease,
valvular disease and use of antihypertensive medication at age 70. The relations
between dyslipidemia and an unfavorable fatty acid profile and later LVH were also
independent of obesity at age 50. Hypertension has previously been related to the
development of LVH in a prospective study33, but the predictive value of obesity,
dyslipidemia and an unfavorable fatty acid profile for LVH has not been shown
before.
No psychosocial variables were associated with later development of LVH, in
accordance with a cross-sectional population study1 where exercise physical activity
and smoking were not related to LVH.
Fatty acids and left ventricular hypertrophy
The relation in study I between an unfavorable serum CE fatty acid composition and
later LVH is important since the fatty acid composition mainly reflects dietary fat
quality over the past couple of weeks44,45 and thus is a modifiable risk factor. A diet
with a high proportion of saturated fatty acids has recently been shown to impair
34
insulin sensitivity in humans99, supported by the experimental finding that nonesterified palmitate has been shown to decrease insulin-mediated as well as basal
glucose uptake100. The effects of dietary fat quality on insulin sensitivity may in part
be explained by the observation that long-chain unsaturated fatty acids have a higher
affinity than shorter saturated fatty acids for peroxisome proliferator-activated
receptors (PPARs)101, which have an important role in regulating glucose and fatty
acid metabolism101,102. Previous studies of the present cohort have shown an
unfavorable fatty acid profile to be related to insulin resistance103 and to predict
myocardial infarction over 19 years46. Also the impact of other traditional risk factors
on myocardial infarction46 was similar to their impact on LVH in the present study,
which suggests that LVH might be regarded as an intermediary risk factor on the
pathway between the described risk factor profile and myocardial infarction. The
apparently opposite effects of linoleic acid (which comprises more than 50% of all
serum CE fatty acids) and the saturated fatty acids may be due to passive
redistribution of the less abundant acids following changes in linoleic acid
proportion, but may also reflect true pathophysiological effects of the saturated fatty
acids. Oleic acid is a major component in olive oil and the cardioprotective
Mediterranean diet, but in the present study, a high serum CE oleic acid proportion
was related to later LVH and increased RWT. The serum CE oleic acid proportion is a
poor marker for dietary oleic acid intake45, but the serum CE linoleic-to-oleic acid
ratio has been shown to be a good indicator of dietary polyunsaturated-to-saturated
fatty acids ratio104. In men of the present study, the dietary source of oleic acid was
not olive oil (which was not used by middle-aged men in Sweden in the early 1970s)
but food groups containing a high proportion of saturated fatty acids, such as dairy
products, solid margarines and meat products. The low impact of ω3polyunsaturated fatty acids, which are generally regarded as favorable, and the at a
first glance surprising relation between eicosapentaenoic acid (20:5 ω3) levels and
later LVH may be due to the fact that a high intake of linoleic-acid-rich vegetable fats
reduces ω3-acid levels in serum44 by a decreased conversion of α-linolenic acid (18:3
ω3) to eicosapentaenoic acid, through competition for the same enzyme systems.
Furthermore, of the two major ω3 fish fatty acids eicosapentaenoic acid and
docosahexaenoic acid (22:6 ω3), the latter seems to have the most beneficial effects on
blood pressure and heart rate105. Other factors than dietary fat intake may affect
serum CE fatty acid profile, but the relations between LDL/HDL-cholesterol and
triglycerides and later LVH support the adverse role of a diet rich in saturated fats.
Fatty acids are the major oxidative fuel for the heart under fasting circumstances106,
and myocardial substrate uptake is determined by the glucose-free fatty acid cycle107.
Cardiac fatty acid β-oxidation is under the control of PPAR-α101,108, in such a way
that high levels of fatty acids activate PPAR-α, which up-regulates transcription of
genes coding for proteins involved in cardiac fatty acid transport and metabolism108.
During development of LVH, cardiac substrate utilization changes towards more use
of exogenous glucose109, which is preferentially metabolized through
glycolysis110,111. Furthermore, cardiac expression of PPAR-α and fatty acid βoxidation falls112, which may lead to myocardial fibrosis113, contractile dysfunction
and rhythm disturbances112.
35
Intervention trials in animals have shown that administration of ω3-polyunsaturated
fatty acids affects cardiac lipid profile114 and reduces or prevents LVH115, whereas
inhibition of long-chain fatty acid β-oxidation increases left ventricular mass116. In
controlled trials in humans with recent myocardial infarction, treatment with ω3polyunsaturated fatty acids reduced left ventricular enlargement117 and
cardiovascular events118. Long-chain unsaturated fatty acids have been suggested to
be the natural ligands for the PPARs101. A possible interpretation of these findings
may be that the beneficial effect of long-chain unsaturated fatty acids in LVH may, at
least in part, be mediated through an improvement of the disturbed PPAR-α activity
seen in LVH.
Relative wall thickness is related to components of the insulin resistance syndrome
In study II, several components of the insulin resistance syndrome were found to be
related to an increased left ventricular RWT and left ventricular concentric
remodeling but less to LVH, at age 70.
Several attempts have been made to investigate the relations between components of
the insulin resistance syndrome and echocardiographic left ventricular mass, mass
index, sum of wall thicknesses or relative wall thickness (table 1). The previous
studies show a wide variety of results, and are difficult to compare because of
different methods of assessing left ventricular parameters and the insulin resistance
syndrome and the use of different populations. The method of determining left
ventricular parameters seems to influence the results, as investigators who have not
indexed left ventricular mass for body size, or have not clearly stated the method of
indexation, have more often found significant relations between left ventricular mass
and signs of insulin resistance than investigators who have indexed left ventricular
mass for height or height raised to any power, followed by investigators who have
indexed left ventricular mass for body surface area. The characteristics of the
investigated populations also seem to influence the results, as more significant
relations between left ventricular mass and signs of insulin resistance were found in
hypertensive populations than in the general population, followed by normotensive
populations. Most of the previous studies in table 1 have comprised a limited
number of middle-aged, hypertensive subjects. Because hypertension is a part of the
insulin resistance syndrome, the relations found in hypertensive populations
between components of the insulin resistance syndrome and left ventricular mass
and geometry may not easily be generalized to normotensive or general populations.
We therefore used a sample of men from the general population in study II. When
investigating relations between LVH and components of the insulin resistance
syndrome, it is important to take into account that both phenomena are related to an
increased body size. Therefore, simple correlations between left ventricular mass and
for instance insulin are, not surprisingly, often positive. Indexation for body size of
some kind should be made for this kind of investigation to be meaningful. The best
body size determinant of left ventricular mass is probably lean body mass119, which
is most closely matched by the surrogate measurement body surface area120.
Indexation methods based solely on height tend to overestimate the influence of
obesity on left ventricular mass, whereas indexation for body surface area (which has
36
been criticized for disregarding the effect of obesity on left ventricular mass3,39) gives
relations between left ventricular mass and obesity of similar magnitude as
indexation for lean body mass119. This suggests that relations found between
components of the insulin resistance syndrome and left ventricular mass indexed for
body surface area are relatively independent of obesity. In study II, waist-to-hip ratio
and BMI were related to RWT and not to LVMI and were highest in the concentric
remodeling group. In another population study, left ventricular mass indexed to
body surface area was not correlated to BMI in men1, suggesting that indexation for
body surface area effectively takes care of the relation between left ventricular mass
and obesity.
In study II, insulin sensitivity index derived from the hyperinsulinemic euglycemic
clamp, glucose tolerance at an OGTT, and fasting levels of specific insulin and 32-33
split proinsulin were all related to left ventricular RWT but not to LVMI in the
present study, and subjects with left ventricular concentric remodeling had lower
insulin sensitivity index and impaired glucose tolerance compared with subjects with
normal left ventricular geometry. These findings are in accordance with another
population study of men59 in which the insulin levels tended to be higher in subjects
with concentric remodeling and concentric LVH and glucose and insulin levels
correlated with RWT but not with LVMI. The values of several insulin sensitivity
variables were similar for concentric remodeling and concentric LVH, although
significant only for the former. This may be due to a small group of men with
concentric LVH, but may also reflect a real difference.
Heart rate was significantly increased in the concentric remodeling group, in
accordance with previous research59. Tachycardia is proposed to be a reliable marker
for an increased sympathetic activity in population studies121. The inverse relation
between LVMI and heart rate reflects the increased heart rate in the concentric
remodeling group and decreased heart rate in the eccentric LVH group, the latter
probably made up of both subjects with heart failure and subjects with a
physiological LVH caused by exercise, with low sympathetic activity and normal
metabolic status. An inverse relation between LVMI and heart rate in men has been
found in another population-based study1.
In study I, lipid derangements, unfavorable fatty acid profile and obesity seemed to
be powerful longitudinal predictors of LVH development, in contrast to study II, in
which the main finding was that several measures of glucose intolerance and insulin
resistance were related to an increased RWT and concentric remodeling, but less to
LVH. The reason for these differences is not clear, but the metabolic associations may
be affected by the normal age-related increase in RWT32. A possible sequence of
events may be that the insulin resistance syndrome is cross-sectionally related to an
increased RWT, which later develops to LVH. This may be a reason for the finding
that factors of the insulin resistance syndrome at 50 are related to later LVH, but that
(other) factors of the insulin resistance syndrome at 70 are cross-sectionally related to
increased RWT, but not to LVH.
37
Relative wall thickness is related to skeletal muscle insulin resistance
In study III, left ventricular RWT was inversely related to insulin sensitivity in
skeletal muscle and borderline significantly directly related to insulin sensitivity in
the myocardium. LVMI was not related to insulin sensitivity in the myocardium or
skeletal muscle. Because skeletal muscle is the most important determinant of wholebody glucose uptake, this correlates well with the findings of study II, in which RWT,
but not LVH, was related to whole-body insulin resistance.
The relation between RWT and the ratio between myocardial and skeletal muscle
glucose uptake indicates that myocardial and skeletal muscle insulin sensitivity are
separate qualities, in accordance with some previous studies65,67 but in contrast to
other122,123. Thus, the term ”insulin sensitivity”, frequently used to describe insulinmediated glucose uptake in skeletal muscle, might have different determinants and
implications in the heart. For instance, cardiac work load is one of the most powerful
denominators of myocardial glucose uptake65,67. Comparisons between study III and
a recent similar study by Paternostro et al66 are difficult, since LVH patients of that
study were more whole-body insulin resistant, older and had more
pharmacotherapy than controls.
Whether changes in myocardial glucose uptake are involved in the pathogenesis of
the growth of left ventricular walls or merely reflect adaptive changes in oxygen
demand has to be further evaluated. Supporting the former theory is the finding that
induced hyperinsulinemia in the rat was followed by marked ventricular
hypertrophy without hypertension124. In favor of the latter theory is the fact that
oxidizing glucose yields more ATP per oxygen atom than oxidizing palmitate, which
may be important in a situation with a decreased coronary reserve such as LVH.
Induction of LVH in rats has been found to be associated with a shift in myocardial
myosin isoenzymes from a faster to a slower form together with a decrease in
ATPase activity and oxygen consumption125, although this mechanism is possibly of
less importance in humans126. Increased myocardial glucose uptake and increased
RWT may also be non-causally related parallel findings. The insulin resistance
syndrome may be causally related to increased RWT due to other mechanisms, and
the observed increased myocardial glucose uptake may be due to an increased
availability of circulating glucose associated with the insulin resistance syndrome,
since cardiac substrate utilization is largely dependent of substrate availability.
In study III, we defined the study population from a thoroughly investigated cohort
study, which enabled us to make the sample homogenous in all variables except the
left ventricular geometry variables under study. As a result, too few subjects with
LVH were eligible to make a meaningful division of the population into two groups,
with and without LVH. Furthermore, no medication-free normotensive subjects with
concentric LVH could be found in the health survey population from which the
present study population was drawn, so only subjects with eccentric LVH were
included. Although eccentric LVH is proposed to be associated with a lower risk for
coronary heart disease than concentric LVH (table 2), the risk is still higher than that
of normal left ventricular geometry. The findings may not have been the same if
subjects with concentric LVH were included.
38
Insulin resistance and left ventricular hypertrophy: Cause or
consequence?
Potential mechanisms whereby insulin resistance or hyperinsulinemia may cause left
ventricular hypertrophy
Several lines of evidence indicate that insulin resistance or hyperinsulinemia may be
causal factors in the development of thick left ventricular walls and LVH:
i.
Insulin at high concentrations is capable of inducing hypertrophic effects via the
insulin-like growth factor (IGF)-I receptor (which are abundant in the heart), but
also at low concentrations via the insulin receptor127,128. Stimulation of the IGF-I
receptor by IGF-I causes myocyte hypertrophy in vitro129, and the effect on
cardiac hypertrophy in vivo is probably mainly due to local rather than
circulating IGF-I130,131. Cardiomyocytes produce IGF-I during development of
hypertrophy132-134, a process suggested to be independent of the systemic reninangiotensin system132. Administration of growth hormone to humans (which
mainly exerts its cardiac effect via cardiac IGF-I) leads to left ventricular wall
thickening and an increased utilization of carbohydrates and lower oxygen
consumption135. Long-term exposition to increased cardiac IGF-I levels result in
myocardial fibrosis130.
ii.
Glucose uptake may in itself have an effect on LVH. Type-2 diabetic American
Indians have been shown to have an increased RWT and LVMI136, and changes
in blood glucose levels in type-2 diabetics during one year of follow-up have
been shown to correlate to changes in LVMI137. The main glucose transporters
(GLUT) in the heart are GLUT-1 and GLUT-4, of which GLUT-1 is the most
important for basal glucose uptake138. Several findings indicate that increased
basal cardiac glucose uptake may lead to cardiac hypertrophy. Conventionally
used therapeutic doses of the thiazolidinedione troglitazone lead to a 3-4-fold
increase in cardiac GLUT-1 and a <2-fold increase in GLUT-4138, and much
higher doses lead to LVH139. Selective knock-out of the cardiac GLUT-4-receptor
in mice leads to increased GLUT-1 levels and a 3-fold increase in cardiac basal
glucose uptake and LVH140. In a study in humans66, cardiac GLUT-1 levels were
increased in patients with LVH and whole-body insulin resistance.
Hyperglycemia induces activation of protein kinase C (PKC)-β in the heart141,
which is capable of enhancing angiotensin effects and macrovascular
contractility, among other things142. Transgenic mice which overexpress PKC-β2
in the heart develop LVH and myocardial fibrosis143.
iii. Hyperinsulinemia leads to renal sodium and water retention, an increased blood
volume144,145 and a higher preload, which is a known trigger of LVH.
iv. Hyperinsulinemia inhibits myocardial protein degradation in insulin resistant
subjects. Myocardial protein undergoes continual turnover with a half-life of
approximately 10 days, and acute insulin administration has been shown to
decrease myocardial protein degradation by 80%146, which might lead to LVH.
39
v. Insulin resistance and hyperinsulinemia have been shown to cause systemic147,148
and cardiac149 sympathetic activation, which has been related to cardiac
hypertrophy in experimental studies150,151. In dogs, repeated pressor episodes
with elevated plasma norepinephrine levels152 or chronic infusion of
norepinephrine153 resulted in LVH, but did not induce a sustained elevation of
blood pressure. In humans, raised plasma catecholamine levels1,72 and an
increased cardiac norepinephrine release154 have been found in subjects with
LVH, and in the present study II and one other study59, heart rate (a marker for
an increased sympathetic activity 121) was related to left ventricular concentric
remodeling. In other studies, sympathetic activity has not been convincingly
shown to be related to LVH151. Heart rate variability, an index of cardiac
autonomic function, has been shown to be abnormal in subjects with the insulin
resistance syndrome155,156 and in subjects with LVH157,158, suggesting that
abnormal cardiac autonomic function may be a link between the insulin
resistance syndrome and LVH.
vi. Hyperinsulinemia has been shown to be a potent inducer of endothelin (ET)-1
release, more so in subjects with the insulin resistance syndrome than in normal
subjects or subjects with insulinoma159, and insulin resistance is associated with
an altered balance between the vasoconstricting effects of ET-1 and the
vasodilating effects of NO160. Cardiomyocytes produce prepro-ET-1 during
development of hypertrophy133,134, and prepro-ET-1 production has been related
to cardiomyocyte protein synthesis161 and RWT133.
vii. Insulin resistance is related to an increased pressor response to angiotensin II162.
Fructose-fed rats (a model of insulin resistance) also exhibit an increased pressor
response to angiotensin II163 and LVH, which is preventable with an angiotensin
II type-1 receptor (AT1) blocker, indicating that angiotensin II may be responsible
for the LVH in this model of insulin resistance164. Angiotensin II has been
proposed to play a major role in the development of LVH, and angiotensinogen
is produced in cardiomyocytes during hypertrophy development133,134. In a
transgenic mouse model, increased cardiomyocyte angiotensinogen production
was related to LVH and increased RWT, an effect that was reversible by ACE
inhibition or AT1 blockade165. However, the hypertrophic effect of angiotensin II
seems to be mediated by cardiac ET-1161, and cardiac hypertrophy develops also
in aortic-banded AT1A knock-out mice166,167 and in pressure overload animal
models after treatment with an ACE inhibitor or AT1 blocker168,169, suggesting
that hypertrophy is a complex process that cannot be explained solely by the
effects of angiotensin II170.
viii. Insulin resistance to glucose uptake is often related to a decreased vasodilatory
response to insulin171,172. Insulin resistance has been associated with a deranged
microcirculation173 as well as a defect in the ability of insulin to increase aortic
compliance174. In a recent study175, a decreased insulin-stimulated femoral artery
blood flow was related to increased left ventricular wall thickness. After ACE
inhibitor treatment, but not after β-receptor blocker treatment, an increased
40
insulin-stimulated blood flow was related to a reduced left ventricular wall
thickness. Increased vascular stiffness and peripheral resistance induce an
increased afterload, which is of pathogenetic importance for left ventricular
concentric remodeling22 and LVH.
ix. The development from physiologic to pathologic LVH with increased
myocardial fibrosis may also be accelerated by insulin. An altered
echocardiographic myocardial texture indicative of increased fibrosis has been
found in hypertensive subjects with LVH, but not in athletes with the same
degree of LVH176. This texture alteration has also been found to correlate to
hyperinsulinemia during an OGTT177, supported by the finding of increased
myocardial fibrosis in an animal model of the insulin resistance syndrome and
diabetes mellitus type-2178. Hyperinsulinemia may increase serum aldosterone
levels in obese, insulin resistant individuals179, and elevated aldosterone levels
play an important role in the development of myocardial fibrosis180.
Further support for the hypothesis that insulin resistance or hyperinsulinemia may
play a causal role in the development of LVH comes from an elegant study in which
induced chronic moderate hyperinsulinemia in rats, with control of hormones with
effects opposing insulin, was followed by pronounced cardiac hypertrophy, without
elevated blood pressure124. LVH is also present in endocrine disorders with insulin
resistance and hyperinsulinemia such as acromegaly181 and hypothyroidism182.
The abundance of proposed mechanisms behind LVH and the difficulty to fit the
results from various experimental studies into the same hypothesis indicate that
there are probably several LVH phenotypes, with different molecular background170.
In view of our findings, it seems reasonable to hypothesize that the growthstimulating effects of insulin in humans mainly affect RWT, whereas hemodynamic
load mainly affects LVMI. If the primary hypertrophic stimulus is an increase in a
growth-stimulating hormone such as insulin, it is possible that the cardiomyocytes
respond with an increased cross-sectional area leading to an increased RWT, rather
than elongation or any other adaptation leading to an enlarged left ventricular
cavity. These geometric parameters are however not independent of each other, and
LaPlace’s law (figure 18) indicates that a possible consequence of an increased wall
thickness is a dilatation of the left ventricle, in order to keep wall tension constant.
It is also possible that metabolic and hemodynamic factors act in a synergistic
manner and potentiate the effects of one another on left ventricular mass and
geometry. An augmenting effect of insulin on the pressor responses of
norepinephrine183 and angiotensin II162,163 has been found. Further support for a
synergistic effect is seen in table 1, in which more significant relations between left
ventricular mass and signs of insulin resistance have been found in hypertensive
populations than in normotensive populations or the general population.
41
Insulin resistance and left ventricular hypertrophy as parallel phenomena
LVH and the insulin resistance syndrome may be parallel consequences of one or
more common etiologic factors, such as an increased activity in the sympathetic
nervous system, vascular alterations or aging. Left ventricular wall thickness and the
prevalence of left ventricular concentric remodeling increase with age32. This is
mainly due to cardiac myocyte hypertrophy, for which an increased stroke work
resulting from increased arterial stiffness has been proposed to be an etiological
factor184. Because insulin sensitivity also decreases with age, the described
association between components of the insulin resistance syndrome and the growth
of left ventricular walls could in part be a consequence of aging, a process proceeding
faster in some subjects prone to both insulin resistance and cardiac remodeling.
Fig. 18: LaPlace’s law
P* r
W all tension =
W all thickness
P = intraventricular blood pressure
r = left ventricular cavity radius
Left ventricular hypertrophy as a causal factor for hypertension and insulin resistance
LVH has been shown to precede and has been proposed to contribute to the
development of hypertension185,186. LVH has also been proposed to be a possible
cause for increased sympathetic nervous activity. Subjects with LVH have been
shown to have a reduced cardiac sensitivity to the effectors of the sympathetic
nervous system, which may lead to a compensatory systemic sympathetic
hyperactivity151. An increased sympathetic activity has also been suggested as a
potential cause for the insulin resistance syndrome187.
LaPlace’s law (figure 18) indicates the relation between blood pressure, left
ventricular wall tension, wall thickness and chamber diameter. Hitherto, this law has
mostly been used to legitimize the theory that an increased blood pressure leads to
increased left ventricular wall thickness in order to keep wall tension constant.
However, this law also indicates that an alternative response to an increased blood
pressure could be a diminished chamber diameter, with no change in wall thickness
(concentric remodeling). LaPlace’s law does not indicate a certain chain of events, or
the reason for the initiating event, but rather the consequences of the initiating event.
This also means that if an increased wall thickness (possibly due to growth
stimulation by insulin) were the initiating event, this would result in an increased
blood pressure or a dilatation of the left ventricle, or a combination of these.
42
The clinical importance of left ventricular hypertrophy
Electrophysiologic co-morbidity of left ventricular hypertrophy
The most consistent finding in study IV was that almost all major ECG abnormalities
were related to an increased LVMI. Furthermore, both left ventricular systolic and
diastolic dysfunction were related to an increased Sokolow-Lyon Voltage, a
commonly used ECG sign of LVH.
Subjects having suffered from a myocardial infarction (definite abnormal Q-wave at
the ECG) showed an elevated LVMI, and the prevalence of Q-waves was highest in
the eccentric LVH group. Whether or not the increased LVMI is the cause or the
consequence of the myocardial infarction in this group of patients can not be told
from a cross-sectional study like this. It seems likely that both of these associations
between an abnormal Q-wave at the ECG and an increased LVMI exist in the present
sample, as structural changes of the left ventricle frequently occur following a
myocardial infarction, changes most likely to result in an enlarged left ventricle188
and eccentric LVH. The situation is probably the same for left bundle-branch block,
which most often is a consequence of a myocardial infarction189.
ST-segment or T-wave changes are non-specific ECG items found in coronary artery
disease and several other cardiac disorders, including LVH. The prevalence of ST- or
T-wave abnormalities was highest in the concentric LVH group, which might
indicate a higher prevalence of angina pectoris and ischemia or the left ventricular
strain pattern of LVH in this group.
Subjects with frequent premature beats or atrioventricular block type 1 (without Q-,
S-T- or T-wave abnormalities) had an increased LVMI and a thick IVS. This
resembles the geometry found in patients with hypertrophic cardiomyopathy in
whom conduction disturbances and ventricular arrhythmias are commonly found190.
None of the subjects in the present study fulfilled the criteria for hypertrophic
cardiomyopathy191, but the pathophysiological events linking septal enlargement to
ventricular arrhythmias and atrioventricular block may be similar in these groups of
subjects. Arrhythmias have previously been shown to be related to LVH192,193, and
LVH is a strong risk factor for sudden death14.
The most commonly used index of left ventricular diastolic function, the E/A ratio,
was not altered in the present sample even in subjects with Q-waves, in whom left
ventricular diastolic dysfunction has previously been shown in middle-aged
subjects194,195. The possible reason for this is that left ventricular diastolic function
and thus the E/A ratio declines with age also in healthy subjects196 and that the effect
of aging in itself overrides the effects of the different pathological conditions in the
present sample aged 70. This seems also to be the case for IVRT, the
echocardiographic index of the earliest left ventricular diastolic phase.
43
In a sub-sample without Minnesota code ECG abnormalities, existing LVH was
mainly eccentric, and was better found with the Sokolow-Lyon Voltage than the
Cornell assessments. This is in contrast to the findings in the whole cohort, where the
sensitivities and specificities for echocardiographic LVH were similar for SokolowLyon Voltage and the Cornell assessments. Sokolow-Lyon Voltage, one of the most
commonly used ECG signs of LVH, was not only related to an increased LVMI, but
also to impairments in both systolic and diastolic function.
Prognostic significance of echocardiographic and electrocardiographic left
ventricular hypertrophy
In study V, echocardiographic LVMI and the ECG-LVH criterion Cornell Product
>244 µVs predicted mortality independently of each other and of other
cardiovascular risk factors, which indicates that echocardiographic and ECG-LVH
were not identical conditions. It was also shown that many but not all of the subjects
whose deaths were predicted by ECG-LVH were also identified by echocardiography
and vice versa.
The main new finding was that the previously known prognostic value of ECG-LVH
to some extent was independent of echocardiographic LVMI and vice versa. We
therefore assessed the clinically relevant question of how much additional prognostic
information would be gained by referring a subject to an echocardiographic
examination if the subject’s ECG-LVH and hypertension status was known. Our
conclusion was that the additional prognostic value of an echocardiographic LVH
assessment if ECG Cornell Product ≤244 µVs was low in normotensive subjects,
whereas in hypertensive subjects or the population as a whole, echocardiography
and ECG provided complementary prognostic information. ECG is today generally
regarded as merely a less sensitive method than echocardiography for detecting
anatomic LVH, but in view of the findings of the present study, the LVH information
obtained with ECG should rather be regarded as of equal prognostic importance as
echocardiographic LVH information. The implication for the clinician assessing the
risk associated with LVH is that the decision of which patient to refer to
echocardiography should be based on knowledge of ECG-LVH and hypertension
status. A normotensive patient without ECG-LVH may well have echocardiographic
LVH, but it is probably of a benign, ”physiologic” nature of low prognostic
importance and hardly motivates an echocardiographic examination.
Total mortality seemed to increase linearly with increasing LVMI, but the risk for
cardiovascular mortality was markedly increased only in the fourth quartile of
LVMI, seemingly in accordance with one large previous study6, but in contrast to
two studies5,15, in which the relation between LVMI and cardiovascular morbidity
was apparently linear. Defining LVH as LVMI ≥150 g/m2, (a cut-off level originally
derived from a healthy, middle-aged sample of men living in Framingham, USA24)
seemed to limit the information carried in the continuous variable LVMI regarding
prediction of all-cause mortality, but was relevant for the prediction of
cardiovascular mortality and morbidity in the present population. Altogether, the
cut-off level 150 g/m2 seems appropriate for LVMI measured with the leading edge
44
to leading edge convention and the Troy formula, corresponding to 131 g/m2
measured with the Penn convention and the modified cube formula24.
Eccentric LVH was the most hazardous of the left ventricular geometric patterns
investigated in the present study, followed by concentric remodeling. This is in
contrast to findings in previous studies (table 2), in which concentric LVH has been
associated with the worst prognosis. The reason for this discrepancy may be that the
previous studies were carried out in middle-aged hypertensive subjects and the
present study in a general elderly population, with a fairly high prevalence of
ischemic heart disease. Eccentric LVH in the elderly is often an end-stage geometry
in patients with congestive heart failure due to ischemic heart disease, but it is also
found in a substantial proportion of apparently healthy subjects without ischemic
heart disease2. In the present study, the predictive power of eccentric LVH was not
attenuated when adjusting for previous hospitalization for ischemic heart disease,
suggesting that eccentric LVH is not a benign condition in this age-group even in
absence of ischemic heart disease.
High LVMI was a stronger independent risk factor for cardiovascular disease than
most other well known risk factors in this age group investigated (including the
novel risk factor proinsulin, which was an independent predictor of cardiovascular
mortality in a 27-year follow-up study from age 50 in this cohort (Björn Zethelius,
MD, unpublished data, 2000), and no other investigated risk factors than LVMI and
Cornell Product were independent predictors of total mortality. In study II, we found
that components of the insulin resistance syndrome were closest related to the
concentric remodeling geometry. Controlling for factors of the insulin resistance
syndrome in study V, the concentric remodeling geometry still implied an increased
risk, indicating that concentric remodeling is not only an integrated measurement of
risk factors of the insulin resistance syndrome, but in itself adds to the total risk.
Strengths and limitations of the study
The determination of the main effect variables in the present study have been made
with M-mode echocardiography. Measurement of left ventricular mass with this
technique is considered as the golden standard, and has been extensively validated
against autopsy materials and as a predictor of subsequent morbidity and mortality.
It is however investigator-dependent, and sufficient image quality may be difficult to
obtain in certain individuals, such as elderly or patients with pulmonary disease.
Proper angulation of the M-mode ultrasound may also be difficult. In the present
study, only one echocardiographer (Bertil Andrén) made all the analyses, which
eliminates one source of measurement error. At the start of the echocardiographic
study in 1991, there was no consensus on which formula to use for calculation of left
ventricular mass. The procedures used were in accordance with the contemporary
recommendation from the ASE. Comparisons have been made between the
techniques used in the present study and the techniques more commonly used
today91. The methods have been shown to be equally reliable, and the values of left
ventricular mass obtained with one technique can easily be converted to
corresponding values of the other technique24,91.
45
One of the main investigations of the study was assessment of insulin sensitivity with
the hyperinsulinemic euglycemic clamp technique, in which serum insulin levels are
elevated approximately 10-fold from fasting levels for 2 hours. This may seem high,
but corresponds to post-prandial insulin levels in insulin resistant individuals. In this
setting, the glucose infused is a direct measurement of the total insulin-mediated
glucose uptake in the whole body, independent of the insulin-producing capacity of
the pancreatic β-cells. The clamp technique is considered the golden standard for
measuring insulin sensitivity, because the influences of counter-regulatory hormones
can be minimized.
An obvious limitation of the study is the lack of women and other ethnic and age
groups. This affects the generalizability to other groups, and motivates further
studies for confirmation of the findings of the present study. However, the limitation
of the population to one sex, age group and ethnic group eliminates the need for
adjustment for the influence of these important determinants of LVMI and factors of
the insulin resistance syndrome. The present cohort has been closely followed for
twenty years and may therefore be healthier than average Swedish 70-year-old men.
Thus, associations in the present study may be weaker than in the general
population.
One limitation of the prospective study I is the lack of dietary records at baseline,
and resulting lack of knowledge about any potential dietary certainties in the studied
population, which might influence the generalizability of the findings of the present
study. Other limitations of the study include absence of echocardiographic data at
baseline and possible bias due to loss to follow-up.
One of the strengths of study V is that all subjects were of the same age at baseline,
which overcomes the problem of age differences between quantiles of LVMI found in
other studies5,6,15. Limitations of the study include possible misclassification of
endpoints, although the accuracy of the Swedish hospital discharge and cause-ofdeath registers have been shown to be high197.
46
Conclusions
Dyslipidemia and a high serum proportion of saturated fatty acids and low
proportion of linoleic acid, as well as obesity and hypertension, at age 50 predicted
the prevalence of LVH at age 70 in this twenty-year follow-up of a fairly large
prospectively determined sample of men from the general population. The impact of
obesity, dyslipidemia and an unfavorable serum fatty acid profile on LVH was
independent of history of ischemic heart disease, valvular disease and use of
antihypertensive medication, indicating that lipids may be important in the etiology
of LVH.
Cross-sectionally at age 70, components of the insulin resistance syndrome, such as
clamp insulin sensitivity index, OGTT glucose levels, triglycerides, waist-to-hip ratio
and 24-h blood pressure, were significantly related to left ventricular RWT and
concentric remodeling but less to LVH.
In a healthy normotensive sample of men, RWT was inversely related to insulin
sensitivity in skeletal muscle and borderline significantly directly related to insulin
sensitivity in the myocardium in elderly men, whereas LVMI was not related to
myocardial or skeletal muscle insulin sensitivity.
Echocardiographic signs of LVH were seen both in subjects with ECG signs of
myocardial infarction as well as in subjects with several other ECG diagnoses.
Furthermore, both systolic and diastolic dysfunction were related to increased QRS
amplitudes on the ECG. These findings suggest an important role for LVH in overall
cardiac electrophysiological pathology, and the finding of ECG abnormalities in
elderly men should raise the suspicion of structural and/or functional left ventricular
abnormality.
Total and cardiovascular mortality risk increased with increasing echocardiographic
LVMI, independently of other cardiovascular risk factors, and cardiovascular risk
was fairly well assessed with dichotomized echocardiographic LVH and geometric
subgroups. ECG-LVH also predicted total and cardiovascular mortality, especially
the Cornell Product criterion, which predicted total mortality independently of LVMI
and other risk factors. Thus, echocardiographic and ECG-LVH are not identical
conditions, and to fully assess the considerable risk associated with either condition,
both an ECG and an echocardiogram should be performed, especially in
hypertensive subjects.
47
Future perspectives
The results of the present study show that there may be potential roles for dietary fat
quality and components of the insulin resistance syndrome, such as insulin
resistance, obesity, hypertension and dyslipidemia, in the etiology of LVH and
increased RWT. Proof of causality cannot be obtained solely by epidemiological
studies, but intervention studies need to be made. Several intervention studies
investigating the etiology of LVH have been made, most addressing the role of
hypertension35,36, but some investigating other possible etiologic factors, such as
obesity41,42, a sedentary lifestyle and an unhealthy diet43. In fact, treating the latter
factors has been shown to be as effective as antihypertensive medication in
decreasing left ventricular mass41-43. The correlation between degree of blood
pressure lowering and degree of LVH reduction in previous studies is not strong34,
which may indicate that other properties of the antihypertensive drugs than their
antihypertensive effect may influence left ventricular mass and RWT. It was for
instance recently proposed that ”available data support the hypothesis that
antihypertensive drugs that inhibit the activity of the renin-angiotensin system or, to
a lesser extent, the sympathetic nervous system, reduce LVH more consistently than
drugs that stimulate these systems”198.
Recently, attention has been paid to the metabolic effects of antihypertensive
drugs199-209, and it has been shown that these drugs have the capacity to reduce or
increase insulin sensitivity by as much as 30%. In view of these data and the results
from the present study, it is tempting to propose that the metabolic effects of an
antihypertensive treatment may contribute to the capacity of the treatment to reduce
LVH and RWT, and may explain some of the variance in the effects of different
classes of antihypertensive drugs on LVH. To illustrate these relations, we have
constructed graphs (figures 19 and 20) showing changes in left ventricular mass and
RWT in relation to changes in blood pressure and insulin sensitivity, using data from
several published randomized clinical trials of antihypertensive drugs and weight
reduction35,42,199-212 and unpublished data from trials in our clinic with losartan,
irbesartan, verapamil and mibefradil (Hans Lithell, MD, unpublished data, 2000). In
figure 20, the mean effect of β1-receptor blockers on insulin sensitivity was derived
from investigations in approximately 150 subjects, because β1-receptor blockers have
been used as reference drugs in many of the insulin sensitivity trials. The mean
effects of the other drug classes on insulin sensitivity were derived from studies of
two to five different drugs from each class. As can be seen in figures 19 and 20, the
degree of reduction of left ventricular mass or RWT was not correlated to the degree
of blood pressure reduction. However, there was a clear inverse correlation between
the change in RWT and the change in insulin sensitivity (Spearman's rank-order
correlation coefficient –0.89, p=0.02). This is in agreement with the findings of our
study II, in which RWT was inversely related to insulin sensitivity. The remaining
variance in figures 19 and 20 may be due to other properties of the treatments, such
as their ability to inhibit the renin-angiotensin system or the sympathetic nervous
system.
48
Fig. 19: Average changes in mean arterial pressure in relation to average changes in relative
wall thickness (A) and left ventricular mass (B), in several randomized trials
B
0
D
-5
β1b
AIIa
Ca
ACEi
-10
-17
⌧∆Left ventricular mass(%)
⌧∆Relative wall thickness (%)
A
W
-5
Ca
β1b
-10
AIIa
-15
ACEi
-20
-17
-15
-13
-11
⌧∆Mean arterial pressure (%)
D
α1b
W
-15
-13
-11
⌧∆Mean arterial pressure (%)
D = diuretics
β1b = β1-receptor blockers
AIIa = angiotensin-II1-receptor blockers
Ca = calcium antagonists
ACEi = angiotensin-converting enzyme inhibitors
W = weight loss
α1b = α1-receptor blockers
Fig. 20: Average changes in whole-body glucose disposal in relation to average changes in
relative wall thickness (A) and left ventricular mass (B), in several randomized trials
0
-5
B
D
⌧∆Left ventricular mass(%)
⌧∆Relative wall thickness (%)
A
β1b
AIIa
Ca
-10
-20
ACEi
W
-5
Ca
-10
W BGD = whole-body glucose disposal
D = diuretics
β1b = β1-receptor blockers
AIIa = angiotensin-II1-receptor blockers
Ca = calcium antagonists
ACEi = angiotensin-converting enzyme inhibitors
W = weight loss
α1b = α1-receptor blockers
49
α1b
AIIa
-15
ACEi
-20
-20
0
20
⌧∆W BGD (%)
β1b
D
W
0
20
⌧∆W BGD (%)
In order to establish the role of the insulin resistance syndrome in LVH, intervention
studies specifically addressing this issue should be performed. Some attempts have
been made to investigate these factors41-43,213, but the results of these studies are
difficult to ascribe to the effects on insulin sensitivity per se. In one study213, the
effects of two antihypertensive drugs on glucose and insulin metabolism were
related to their LVH-reducing effects. The recent emergence of drugs specifically
designed to enhance insulin sensitivity makes studies of the role of insulin resistance
in LVH possible. One way of studying this issue might include determination of
insulin sensitivity with the hyperinsulinemic euglycemic clamp technique,
determination of RWT and left ventricular mass with echocardiography or nuclear
magnetic resonance tomography, and a comparison between treatments with a drug
that improves insulin sensitivity but does not affect blood pressure and a drug that
lowers blood pressure but does not affect insulin sensitivity.
50
Acknowledgements
I wish to express my sincere gratitude and appreciation to all those who have helped me
complete this thesis, with special thanks to:
Lars Lind, my principal supervisor, for introducing me to medical research, for his neverending enthusiasm and ideas, and for always having time for stimulating discussions.
Hans Lithell, head of the Section for Geriatrics, my supervisor, for his continuous
encouraging support and for providing a creative and enjoyable research atmosphere.
Bertil Andrén, for providing the echocardiographic examinations on which this thesis is
based, and for creative input in the articles.
Lars Berglund and Rawya Mohsen, for always having time and patience for any question a
PhD-student may have.
Bengt Vessby and Margareta Öhrvall, for providing me with the opportunity of
developing my clinical skills in the meeting of patients with the insulin resistance syndrome.
Johan Ärnlöv, for being a good friend and for valuable support in the fields of career
development, jazz music and physical activity (especially office-golf, FIFA 99 and walking or
jogging along the Thames, Mississippi, Hudson and Fyris rivers).
My friends and colleagues at the Section for Geriatrics — Liisa Byberg, Björn Zethelius,
Arvo Hänni, Kristina Björklund, Anu Hedman, Kristina Dunder, Lennart Hansson, Merike
Boberg, Per-Erik Andersson, Lena Kilander, Richard Reneland, Margareta Falkeborn,
Ann-Cristin Åberg and Claes Risinger — and the Section for Clinical Nutrition Research
— Ulf Risérus, Annika Smedman, Eva Södergren, Agneta Andersson, Anette Järvi,
Johanna Helmersson, Cecilia Nälsén, Marie Lemcke-Norojärvi, Samar Basu, Brita
Karlström, Anders Sjödin and Achraf Daryani — especially those who have participated in
the valuable ”doktorandklubben” seminars, for intellectual stimulation, helping hands and
good laughs.
My co-authors Niklas Nyström, Sven Valind, Antti Aro, Nicholas Hales, Agneta
Holmäng, Per Björntorp and Anders Waldenström, for valuable help with the articles and
rapid correspondence.
Jan Hall, Siv Tengblad, Eva Sejby and Barbro Simu for their excellent laboratory work.
The staff at the Metabolic Ward, for their devotion and competence in conducting this
demanding longitudinal study, and for being a great team
All the brave Uppsala-men who have participated in the study for almost 30 years.
Anna, for expert guidance in the art of thesis cover design and the English language, but
most of all for patience, support, devotion and love beyond understanding.
This study was supported by grants from the Swedish Medical Research Council (grant no.
5446), the Thuréus Foundation, the Swedish National Association against Heart and Lung
Disease, the Foundation for Geriatric Research (Stiftelsen för Geriatrisk Forskning), Geriatric
Fund (Geriatriska Fonden), the Ernfors Foundation, Trygg Hansa, ”Förenade Liv” Mutual
Group Life Insurance Company, and Uppsala University.
The cover illustration is a positron emission tomogram from the PET-Center, Uppsala
University.
Uppsala in December 2000
51
Summary in Swedish
Sammanfattning på svenska
Vänsterkammarhypertrofi (en förstoring av hjärtats vänstra kammare) och det
metabola syndromet (en anhopning av kardiovaskulära riskfaktorer såsom fetma,
insulinresistens och förhöjda nivåer av blodtryck, blodfetter och insulin) är mycket
vanliga tillstånd som är förknippade med en markant ökad kardiovaskulär risk.
Under 1970-73 inbjöds alla 50-åriga män boende i Uppsala till en hälsoundersökning
för att kartlägga riskfaktorer för kardiovaskulär sjukdom. Vid en uppföljning 20 år
senare upprepades mätningarna, och vänsterkammarens massa och geometri mättes
med ultraljud hos 475 män. I denna prospektiva longitudinella studie fann vi att ett
ogynnsamt fettsyramönster i blodet samt delar av det metabola syndromet (fetma,
blodfettsrubbning och högt blodtryck) vid 50 års ålder ökade sannolikheten för att ha
vänsterkammarhypertrofi vid 70 års ålder. I en tvärsnittsstudie vid 70 års ålder var
delar av det metabola syndromet (bukfetma, insulinresistens, nedsatt sockertolerans,
blodfettsrubbning och högt blodtryck) kopplade till en ökad relativ väggtjocklek i
vänster kammare, men inte till vänsterkammarhypertrofi. I ett litet friskt urval av
dessa män var en ökad relativ väggtjocklek i vänster kammare kopplad till
insulinresistens i skelettmuskel och antytt ökad insulinkänslighet i hjärtmuskel,
medan vänsterkammarmassan inte var kopplad till insulinkänslighet i skelett- eller
hjärtmuskel. Vid 70 års ålder var vänsterkammarhypertrofi ett genomgående
ultraljudsfynd vid ett flertal vanliga EKG-diagnoser. I en prospektiv
mortalitetsstudie med början vid 70 års ålder och med fem års uppföljning fann vi att
ultraljudsmässig och EKG-mässig vänsterkammarhypertrofi medförde ökad
dödlighet, oberoende av varandra och av andra kardiovaskulära riskfaktorer. Detta
innebär att ultraljudsmässig och EKG-mässig vänsterkammarhypertrofi ger olika,
men lika viktig, prognostisk information.
Sammanfattningsvis var det metabola syndromets komponenter kopplade till
vänsterkammarhypertrofi 20 år senare, men tvärsnittsmässigt starkare kopplade till
en ökad relativ väggtjocklek i vänster kammare. Ultraljudsmässig och EKG-mässig
vänsterkammarhypertrofi medförde ökad dödlighet, oberoende av varandra och det
metabola syndromets komponenter.
52
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