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(Circulation. 1996;93:1396-1402.)
© 1996 American Heart Association, Inc.
Articles |
Left Ventricular Diastolic Function in Hypertension and Role of Plasma Glucose and Insulin
Comparison With Diabetic Heart
From the Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School (Newark).
Correspondence to T.J. Regan, MD, UMDNJ-New Jersey Medical School, 185 S Orange Ave, MSB I-536, Newark, NJ 07103-2714.
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Abstract |
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Background Experimental production of glucose intolerance has been associated with increased diastolic stiffness of the left ventricle, accompanied by interstitial fibrosis. Because carbohydrate metabolism is altered in hypertension, we undertook the present study to assess the relation of diastolic dysfunction in hypertension to plasma glucose and insulin concentrations. The latter are also affected by obesity. To facilitate this analysis, we studied moderately obese hypertensives. Elucidation of these relations was then sought in diabetic subjects.
Methods and Results Subjects undergoing catheterization for chest pain were included in the study when significant coronary disease was not present. In groups 1 (lean), 2 (obese), 3 (lean hypertensive), and 4 (obese hypertensives), intraventricular pressures and volumes were determined. Fasting plasma glucose, insulin, hemoglobinAIC, and glucose tolerance were assessed. Basal ejection fraction and end-systolic wall stress were normal in the four groups. Chamber stiffness was significantly elevated in the hypertensives and was higher in group 4 than in group 3 (P<.05). Diastolic dysfunction was correlated with fasting blood glucose (r=.69, P<.006) but not with plasma insulin or left ventricular mass. Chamber stiffness was also increased in diabetics, with a larger effect in the obese.
Conclusions Hypertension is associated with increased diastolic stiffness of the left ventricle, which is enhanced by moderate obesity, and abnormal carbohydrate metabolism. Experimentally and in humans, hypertension is associated with interstitial fibrosis of mycardium, the presumed basis for the diastolic dysfunction. Chamber stiffness in group 4 hypertensives was similar to that in the lean diabetics but less than that in the obese diabetics. Although the latter exhibited a correlation with plasma hemoglobinAIC, the large rise in stiffness suggests a potential role for growth factors in further alteration of myocardial composition.
Key Words: obesity • cardiomyopathy • systole
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Introduction |
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Essential hypertension may be associated with myocardial rather than coronary disease as the predominant clinical abnormality.1 A recent report indicated that the early functional alteration of the left ventricle is often diastolic rather than systolic.2 Furthermore, abnormalities in glucose and insulin metabolism have been described for the hypertensive state.3 Because glucose intolerance in a normotensive canine model has been associated with diastolic dysfunction and interstitial fibrosis of the ventricle,4 the role of the metabolic abnormality in the myocardial response to hypertension has been questioned.
Moderate obesity is often present in patients with hypertension and may alone affect diastolic function,5 as well as insulin and glucose metabolism.6 To facilitate a determination of the myocardial/metabolic relation, we evaluated the influence of associated obesity. Left ventricular diastolic and systolic functions, as well as mass, have been assessed in the absence of significant coronary occlusive disease in hypertensive patients.
Normal and hypertensive patients, either lean or obese, were compared for hemodynamic and metabolic alterations. In view of the initial observations in these groups, a study of lean and obese diabetics was undertaken to assess the relation of more substantial glycemia to left ventricular dysfunction.7
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Methods |
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Patient Selection
The present study entailed a study of left ventricular function in patients without significant coronary artery disease as determined with arteriography and was approved by the institutional review board. Asymptomatic subjects were not included. During the investigation, 175 patients with chest pain were referred for a diagnostic cardiac catheterization.
Exclusions were based on history, physical examination, and clinical laboratory data, including a combination of diabetes and hypertension, myocardial infarction or failure, chronic arrhythmias, valvular or pericardial disease, ethanol abuse, age of >70 years, or significant disease of other organ systems. In the study of nondiabetics, patients with a family history of diabetes were not included. Patients with an inadequate ventriculogram or a hemodynamic alteration during cardiac catheterization were also excluded. Individuals with a BMI of >34 kg/m2 and those receiving diuretics or ß-adrenergic inhibitors were not studied.
Angiographic evidence of narrowing of 
50% in any of the three major
epicardial vessels was a basis for noninclusion. Study patients were
further classified as lean or obese. To determine BMI, each patient was
weighed and had his or her height measured while wearing only a
hospital gown. Men with a BMI of >26.7 kg/m2 and women
with a BMI of >27.3 kg/m2 were defined as
obese.8 In each diagnostic category, the obese
were compared with the nonobese.
A prior diagnosis of hypertension was based on multiple readings by nursing personnel over several weeks with a systolic blood pressure of >140 mm Hg and a diastolic blood pressure of >90 mm Hg in an office setting. On the evening before catheterization, arterial pressure was measured in the left arm with a sphygmomanometer of appropriate cuff size, using the first and fifth phases of the Korotkoff sounds. After 10 minutes with the participant in the supine position, three consecutive measurements were taken and averaged.
For the hypertension series, group 1 and 2 were nonobese and obese control subjects without hypertension, respectively, whereas the nonobese of group 3 and the obese of group 4 were hypertensive. Therapy was omitted for the 18 hours preceding catheterization. There was no significant difference between the nonobese and obese groups in the use of therapies that may affect glucose and insulin metabolism.
Diabetics (type II) were diagnosed on the basis of history of chronic hyperglycemia with management by diet, hypoglycemic agents, or both. The subjects with diabetes mellitus were metabolically stable at the time of catheterization and were designated as diabetic/lean and diabetic/obese.
In addition to oral hypoglycemic agents for the diabetics, therapy for chest pain was exclusively calcium channel–blocking agents, nitrates, or both. Groups 1 and 2 in the nondiabetic series were treated similarly with these latter two agents. Among the hypertensives, both groups had been treated to a similar extent with angiotensin-converting enzyme inhibitors, calcium channel blockers, and nitrates.
Cardiac Catheterization
Patients underwent cardiac catheterization after
informed consent was obtained. All had normal sinus rhythm and were
studied with the use of left-side heart
catheterization with subjects in the postabsorptive
state while under mild sedation and local lidocaine anesthetic. Cardiac
catheterization and coronary angiography were
performed by standard techniques.
Left ventricular and arterial pressures were recorded with a fluid-filled catheter system optimally damped for frequency response with the use of Gould P23XL transducers. Ventricular pressures measured in the basal state with a micromanometer have been compared previously with those obtained with the fluid-filled catheter system.9 A close correspondence was observed except for the amplitude of -dP/dt. Pressures were recorded with a Honeywell physiological recording system PPG, with VR16 and V2203A pressure amplifiers. The VR16 amplifier was interfaced with a PPG Meddars 1000 computer for hemodynamic waveform analysis. The zero reference point was taken at midchest with the patient supine. Pressure waveforms were digitized at a sampling rate of 200 points/s for processing with the microcomputer and were averaged over several cardiac cycles.
Left Ventricular Volume
Left ventricular cineangiography was performed in
the 30° right anterior oblique projection,10 and
ventricular pressures were recorded immediately before
dye injection. Quantitative analysis of volumes by left
ventricular cineangiogram has correlated well
with the dye dilution technique.11 Ventriculograms were
excluded from analysis if there were atrial or
ventricular premature beats.
Each volume determination was corrected with a magnification factor.12 A grid was filmed at the midchest level, with the imaging equipment in the same position and magnification as during ventriculography. The end-diastolic and end-systolic contours of the normal sinus beat from the projected cinefilm were traced on paper. A correction factor was calculated by outlining the grid squares enclosed by the end-diastolic contour and counting the number of squares within the outline (true area) and measuring the area within the outline by planimetry (projected area). Thus, the linear correction factor equaled the square root of the true area divided by the projected area. In the single-plane formula, the cube of the linear correction factor [(CF)3] adjusts the volume for magnification: VCc=8/3n(CF)3A2/L, where VCc is calculated volume, L is long axis of the ventricular ellipsoid, and A is area of the ventricular silhouette as determined by planimetry. These volumes were further corrected by a single-plane regression equation: Va=0.81VCc+1.9, where Va is actual volume and VCc is calculated volume.
LVEDV and LVESV were indexed for body surface area. Ejection fraction was calculated from the ratio (EDV-ESV)/EDV. As a measure of left ventricular afterload, ESWS, measured by cineangiography, was derived from end-systolic ventricular dimensions, wall thickness, and peak systolic pressure.13
Left Ventricular Diastolic
Pressure-Volume Relation
The curvilinear nature of the diastolic
ventricular pressure-volume relation has been
previously emphasized.14 15 Accordingly, the relation
between diastolic pressure and volume in the present
study was assumed to be monoexponential, and the
sequential data were fitted by an exponential equation:
P=bekv, where P is pressure in mm Hg, V
is volume in mL/m2 of body surface area, e is
base of the natural log, and b and k are the
variables to be fitted to the curve. K
represents a modulus of KP in the intact ventricle. Two
coordinates (early diastolic and end diastolic)
of pressure and volume were used. The early diastolic
coordinates consisted of the lowest level of diastolic
pressure before the mitral valve opened and the
end-systolic volume. End-diastolic pressure
and volume were used as the second coordinate. The KP constant
K was calculated as the slope of the natural logarithm of
pressure to volume: lnP=kV+ln.
KP was derived from the relation dP/dV=kP,14 15 and stiffness was normalized for the end-diastolic volume.16 Chamber rather than myocardial elastic stiffness (E) was calculated where E=K*EDWS.15 EDWS was obtained from the end-diastolic ventricular pressure and the midwall thickness. Although these formulations may oversimplify the actual diastolic pressure-volume relation, they are considered to provide a reasonable representation of diastolic properties of myocardium.
Left Ventricular Mass
hED was determined in the midanterior position, and
left ventricular volume was estimated from the left
ventricular cineangiogram. This technique for
measurement of mass has been found to correlate well with the autopsy
weight.17 Left ventricular mass was indexed
for height in meters.
Glucose-Insulin Assay
On the day after cardiac catheterization and
after a 12-hour fast, two baseline blood samples were drawn from each
patient at 10-minute intervals for plasma glucose,18
hemoglobinAIC,19 and insulin levels.
Thereafter, glucose tolerance was assessed in group 1 (4 patients),
group 2 (3 patients), group 3 (12 patients), and group 4 (11 patients).
One container of Sustacal, a mixed meal containing 240 calories, was
fed to all four groups in the hypertensive study. The Sustacal meal,
containing a palatable mixture of glucose and amino acids, has
reportedly produced elevations of plasma glucose, insulin, and
C-peptide comparable to that seen after administration of oral
glucose.20 Venous blood was obtained and
centrifuged, and the plasma was stored at -20°C for glucose
and insulin determination. The radioimmunoassay for plasma insulin was
based on a double-antibody solid-phase technique (insulin RIA,
Pharmacia Diagnostics). The total area under the glucose
and insulin concentration curves was calculated with use of the
trapezoidal rule.21
Statistical Analysis
Data are expressed as mean±SEM. A standard one-way ANOVA
was used to compare the mean values between groups. The F test from
this procedure tested the null hypothesis of no difference between mean
values.
When a significant difference was found among the groups, Tukey's test was used to make two-way comparisons between groups. The Wilcoxon analysis was used for comparison between two groups. An indication of significance in the tables applies to all values greater than P<.05. Univariate regression analyses were used to estimate the strength of the association between hemodynamic and metabolic parameters; these measurements were made with the Statistical Analysis System (SAS Institute).
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Results |
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Hypertensives
Ages were comparable in the four subgroups of the hypertensive study (Table 1
). There were 18 whites, 16 blacks, and 13
Hispanics. Groups 2 and 4 had a mean BMI that was significantly higher
than that of groups 1 and 3. Heart rate was similar in the four groups,
and arterial pressure was normal in groups 1 and 2.
Systolic blood pressure was significantly higher in both
hypertensive groups.
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Systolic function in terms of ejection fraction and ESWS did
not differ in the four groups (Table 2). LVEDP was
significantly higher in lean and obese hypertensives than in either
normotensive group; the initial diastolic pressure did not
differ (see Table 2). End-diastolic volume index was
comparable in the four groups. The nonindexed volume was 165±13 mL in
group 1, 195±11 mL in group 2 (P<.02), 151±7.4 mL in
group 3, and 189±14 mL in group 4 (P<.03).
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KP, KPV, and K*EDWS were significantly higher in lean and obese hypertensives than in the control subjects of group 1. The association of obesity with hypertension revealed a significantly higher KPV and K*EDWS than in group 3. LVMI was significantly higher in lean and obese hypertensives than in the respective normotensives, but the difference between the hypertensive groups was not significant.
Relation of Metabolic Variables and
Diastolic Function
Fasting blood sugar and insulin levels were significantly higher
in groups 2 through 4 than in group 1 (Table 3). Group 4
was considered glucose intolerant rather than diabetic because fasting
glucose was 116±4.6 mg%, below the 140 mg% threshold for the
diagnosis of diabetes.22 Moreover,
hemoglobinAIC and glucose tolerance did not differ
significantly from groups 2 and 3. The planimetered area for plasma
glucose during the glucose tolerance test was increased in each group
compared with group 1 but did not reach significance. Only the obese of
group 2 showed a significant insulin response to the oral feeding,
64.8±18.2 mU h/L versus 37±5.3 in group 1.
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The parameters of diastolic function in the
four groups were compared with metabolic variables by
univariate analysis. Fasting glucose correlated
with KPV (P<.006) (Figure). LVMI was not
significantly related to fasting glucose, insulin, or KPV.
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Diabetics
Fifteen patients were included in the diabetes study. The lean and
obese diabetics had similar clinical characteristics except for the
adiposity parameters (Table 4). Heart rate
was comparable and arterial pressure was normal in both
groups. Fasting blood glucose and hemoglobinAIC were
154±22 mg% and 6.9±0.85%, respectively, in the lean diabetic
subjects. In the obese diabetics, the values were 175±36.7 mg% (NS)
and 10.9±1.4% (P<.05) versus the lean group.
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Ejection fraction and ESWS were not significantly different. LVEDP, KP,
and KPV were significantly greater in the obese group, whereas
K*EDWS was just outside this range (Table 5). When comparing lean hypertensives with lean
diabetics, only KP was significantly higher in the latter. Obese
diabetics, however, had significantly higher KP, KPV, and LVMI than did
obese hypertensives.
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Discussion |
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Hypertensive subjects in this study exhibited a significant increase in left ventricular diastolic stiffness with normal systolic function. The abnormality was greater in the moderately obese than in their lean counterparts. A correlation with modest elevations of plasma glucose was postulated to relate to the ventricular diastolic abnormality.
Chronic glucose intolerance as an isolated entity has been associated with increased left ventricular mass.23 Experimental glucose intolerance elicited increased diastolic stiffness without hypertrophy in a canine model that appeared to be related to interstitial collagen accumulation in the left ventricle.5 Interstitial fibrosis has also been observed in biopsied myocardium of hypertensives24 25 and at autopsy,26 with or without replacement fibrosis. No reports on plasma glucose or degree of obesity were provided.
Obesity
Isolated obesity, characterized as morbid, can be associated with
left ventricular hypertrophy and
interstitial fibrosis that may progress to heart
failure.27 More recently, mild-to-moderate obesity
as an isolated entity has been associated with alterations in
myocardium and glucose/insulin metabolism in
the presence of normal systolic function in
asymptomatic patients.6
Hyperinsulinemia has been closely related to left
ventricular mass in the obese but has also been associated
with enhanced regional sympathetic activity.28
Although asymptomatic subjects have exhibited impaired diastolic filling as determined with echocardiography,29 there has been no characterization of KPV in patients with moderate obesity that is <25% above the upper limit of BMI in normal subjects. In this study, LVMI was increased compared with group 1, but LVEDP, KPV, and EDWS, although higher than in the lean control subjects, were not significant, presumably because of an insufficient number of patients. Whether myocardial abnormalities contribute to the increased mortality risk associated with moderate obesity is not known.30
Hypertension
All of the parameters of diastolic
stiffness were increased in lean hypertensives compared with lean
control subjects, associated with an increase in basal fasting plasma
glucose and insulin. The modest extent of the diastolic
abnormality in the lean hypertensives suggests that the development of
heart failure may be less likely in the absence of obesity.
Diastolic abnormalities observed in the lean hypertensives were generally greater in group 4; LVEDP, KPV, and K*EDWS were significantly higher. In the obese hypertensives, further alterations that promote myocardial stiffness are suggested, which may be related to the higher fasting plasma glucose, as discussed below. Whether the myocardial process in hypertensives becomes more severe with age, prolonged duration of disease, further weight gain, or hyperglycemia remains to be determined.
Left ventricular hypertrophy, as a potential contributor, did not significantly correlate with KP in the hypertensive groups. Moreover, the diastolic abnormality has been previously observed without evident hypertrophy.2 A clear dissociation of these phenomena has been achieved in the spontaneously hypertensive rat with use of a therapeutic intervention that normalized myocardial fibrosis without affecting hypertrophy.31 Nevertheless, left ventricular stiffness was also normalized. A myocyte contribution to stiffness has been described in cell cultures and has been attributed to proteins of the cytoskeleton,32 but the role in hypertensive hypertrophy is not known.
Diabetes
Prior hemodynamic descriptions in diabetics have
not distinguished between the lean and obese states.7 When
moderate obesity was associated with diabetes in this study, there was
a greater abnormality of end-diastolic function, which
is assumed to be related to further alterations in myocardial
interstitium, but a contribution of hypertrophy in
diabetics with the larger ventricular mass is an important
consideration.
HemoglobinAIC levels were significantly higher in the obese diabetics, which is consistent with a greater degree of glycation in proteins that have a relatively slow turnover. Such a process affecting myocardial collagen may result in further interstitial accumulation and thus affect end-diastolic stiffness.31 Morphological evidence for collagen accumulation has been reported in human diabetes.7 24 26 33
Potential Mechanism
The pathophysiology of the diastolic abnormality in
the obese hypertensive may be related to alterations in glucose and
insulin metabolism. Although plasma insulin increments have
been associated with hypertrophy in moderately obese
subjects6 and hypertensives,3 the
hypertrophy of obese hypertensives was not associated with
additional insulin increments, which is consistent with a prior
report.34 Although the glucose-clamp technique may
better define the metabolic abnormality, it is noteworthy
that the degree of insulin resistance has been reported to be
equivalent in hypertension and diabetes.35 A prior
observation indicated that experimental glucose intolerance associated
with enhanced diastolic stiffness was not related to plasma
insulin.4 The influence of other hormones and
cytokines on this process is not yet defined.
The significantly higher plasma glucose in group 4 is consistent with the presence of glucose intolerance; its significance is discussed below. HemoglobinAIC was also elevated but not significantly; the latter may be a less-sensitive measure of altered glucose metabolism. Duplicate samples from patients showed a measurement difference of 5% compared with a difference of 0.03% for plasma glucose. Fasting glucose was better correlated with cardiac pathophysiology in obese hypertensives than was oral glucose tolerance, presumably due to variables such as prior diet and physical activity, which make the tolerance test a less reliable estimate of disordered glucose metabolism.36
The observation that the degree of fasting hyperglycemia in the hypertensive correlated with the myocardial stiffness abnormality may provide a clue to pathogenesis. In the glucose-intolerant canine model, fasting glucose was in the high normal range5 and apparently was sufficient to elicit an increase in diastolic stiffness and interstitial collagen in the absence of hypertension. That hyperglycemia may have a major role in pathogenesis is supported by observations in cultured mesangial37 and neural38 cells in which collagen synthesis was enhanced when the media contained elevated glucose concentrations. A more complex situation has been suggested from preliminary observations in the canine model with chronic glucose intolerance.39 Insoluble collagen was increased in myocardium. This appeared to be attributable to the formation of advanced glycosylation products, presumed to result in increased collagen cross-links.
It is noteworthy that the KP increase in lean diabetics was no greater than that in obese hypertensives, despite the higher plasma glucose in the former. Impaired cardiac transport of glucose in the diabetic may conceivably result in a smaller contribution to collagen synthesis and perhaps to the glycation process.
The stiffness increment in the obese diabetic was substantially higher than that in the obese hypertensive, which is in keeping with the greater carbohydrate abnormality, but appeared to be disproportionately high compared with that in the lean diabetic. Because increments of transforming growth factor-ß have been observed in diabetic human and animal tissues, associated with interstitial collagen accumulation,40 this factor may contribute to the degree of stiffness; the relation to the obese state has not, however, been defined.
Study Limitations
Although coronary angiography revealed nonsignificant
arterial disease, myocardial ischemia remains an
important consideration. There was no evident difference in the chest
pain present in the different subsets. Although intermittent spasm
could not be excluded, the maintained systolic function and the
absence of regional motion abnormalities of the left
ventricular wall by ventriculography support the view that
diminished coronary perfusion of a sustained nature was
unlikely in these subjects with moderate
hypertrophy.41
A larger number of subjects would be desirable for this investigation. Ideally, patients would undergo analysis from the disease onset, before the appearance of chest pain and the initiation of therapy, to allow us to better assess the influence of age, sex, and duration. Although there was no significant difference in the data generated in each ethnic group, a larger sample might be more revealing.
Because there was no significant difference in the treatment of lean and obese subjects, prior therapy was not considered to qualitatively affect the observed outcome in the comparison between subgroups. Moreover, angiotensin-converting enzyme inhibition and calcium channel blockage do not impair glucose and insulin metabolism.42
Characterization of the insulin/glucose relation would be more fully described if it were analyzed sequentially over many months. Such data in hypertensives and obese hypertensives are not yet available. Further definition of these parameters with the glucose-clamp technique and assay of growth factors may better define subsets in terms of pathogenesis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We express appreciation for the technical assistance of Remy Torres and the secretarial service of Sharon Withers.
Received July 17, 1995; revision received October 23, 1995; accepted October 29, 1995.
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