Prevalence of diastolic dysfunction in normotensive asymptomatic patients with well-controlled type 2 diabetes mellitus
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《中华医药杂志》英文版
Department of Cardiology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
Correspondence to A. Rauoof Malik,427 Fourth Street SW, Apartment # G4, Rochester,MN 55902,USA
Tel: (1) 507-288-8028,E-mail:marauf2903@yahoo.co.in,malik.rauoof@mayo.edu
[Abstract] Objective Left ventricular (LV) diastolic dysfunction is known to occur in early stages of diabetic cardiomyopathy but its exact prevalence is not clearly known. The present study was conducted to assess the prevalence of diastolic dysfunction in diabetic patients in the absence of hypertension or CAD.Methods Fifty consecutive asymptomatic normotensive patients (mean age 47.54±6.78 years) with well controlled diabetes type 2, free of any major clinical diabetic complications, and having no evidence of CAD on non-invasive testing, were studied for LV diastolic functions, using pulsed Doppler at the tip of mitral valve. The peak velocities of LV filling during the early rapid (E wave) and atrial contraction (A wave) phases, the ratio of the 2 filling velocities (E/A ratio), E wave deceleration time, and the isovolumic relaxation time, were recorded at end-expiration for 5 consecutive beats at baseline and again during the phase Ⅱ of Valsalva maneuver. Results Diastolic dysfunction was noted in 30 (60%) patients, out of whom, 18 (36% ) had impaired relaxation while 12 (24%) had pseudonormal pattern. No patient had restrictive filling pattern. Pseudonormal pattern accounted for 40% of the patients with diastolic dysfunction. Clinical characteristics and measurements on 2D echocardiography were within normal limits and were comparable between the 3 groups of patients.Conclusions LV diastolic dysfunction may be present in about 60% of asymptomatic patients with well-controlled diabetes mellitus type 2 without hypertension or CAD. Pseudonormal pattern may account for more than one-third of the diabetic patients with diastolic dysfunction and failure to recognize it may lead to significant underestimation of the true prevalence of LV diastolic dysfunction in these patients.
[Key words] diastolic;type 2 diabetes
INTRODUCTION
Congestive heart failure (CHF) is an important cause of morbidity and mortality among patients with type 2 diabetes mellitus. Diabetic subjects have an increased prevalence of CHF[1,2] and have a worse prognosis with the development of CHF compared to non-diabetics[3]. The risk of developing CHF is increased in diabetics even in the absence of coronary artery disease (CAD), hypertension, or valvular abnormalities and has been attributed to a separate disease entity called ‘diabetic cardiomyopathy' [4~7]. Further, there is evidence to suggest that a significant proportion of diabetic patients may suffer from subclinical left ventricular (LV) dysfunction, including diastolic dysfunction[8~10], and this fact may contribute to the increased diagnosis of ‘idiopathic cardiomyopathy' in diabetic population[11]. Diastolic dysfunction in diabetic patients is believed to represent an earlier stage in the natural history of diabetic cardiomyopathy[12~14], and its timely recognition may help to avoid or significantly delay the onset of CHF[5].
Previously published reports about the prevalence of LV diastolic dysfunction in diabetes are conflicting,mainly because of the confounding effect of systemic hypertension and CAD that frequently co-exist with diabetes and have significant effects on cardiac diastolic physiology[15]. Further, abnormalities in LV diastolic function may be occult, producing a so-called ‘pseudonormal' LV filling pattern, and might be missed unless specifically sought[14]. The present study was conducted to estimate the prevalence of diastolic functions in patients with well-controlled diabetes without any known major diabetic complication and without co-existing hypertension or known CAD. Any occult diastolic dysfunction was unmasked using a maneuver to acutely reduce the preload, thereby bringing out the pseudonormal LV filling pattern.
METHODS
The study was conducted on 50 consecutive patients (age 35~60 years, 72% men) with well controlled diabetes type 2, diagnosed as per the standard criteria[16]. Only the patients on medical nutrition therapy and/or oral hypoglycemic agents and free of any clinical diabetic complications (neuropathy, nephropathy, grade 2 or higher nephropathy) were selected. Adequacy of glycemic control was assessed as consistent venous blood glucose of 90 to 130 mg/dl pre-prandial and <180 mg/dl 1~2 h post-prandial on repeated measurements over previous 3 months. The patients had no history of hypertension or antihypertensive treatment and had normal office blood pressure (BP) on all of at least 2 occasions. Patients with known CAD, valvular or other structural heart disease, cardiac arrhythmia, renal, hepatic or other systemic disorder, and those taking cardiac medications were excluded. Informed consent was obtained from all the patients. The study was approved by the local hospital ethics committee. All the subjects had normal 12-lead resting electrocardiogram and normal treadmill test using Bruce protocol.
Echocardiography was performed using a commercially available equipment (Toshiba Powervision UZR I 328 A, Tokyo,Japan). The subjects were examined in left lateral decubitus position using standard views. Standard 2-D and M-mode recordings of LV were obtained as per the recommendations of the American Society of Echocardiography[17]. LV volumes and ejection fraction were measured by modified Simpson's formula. LV mass was calculated using Penn convention and indexed to body surface area. LV diastolic functions were assessed using pulsed Doppler at the tip of mitral valve. The peak velocities LV filling during the early rapid (E wave, m/s) and atrial contraction (A wave, m/s) phases, the ratio of the 2 filling velocities (E/A ratio), E wave deceleration time (Dt, ms from the peak of E wave to the point at which the deceleration velocity reaches the baseline), and the isovolumic relaxation time (IVRT, ms from aortic valve closure to the beginning of E wave) were recorded at end-expiration for 5 consecutive beats. Patients were then directed to perform a standard Valsalva maneuver by holding a regular breath and bearing down against closed glottis for at least 10 s. All the diastolic indices were again recorded during the phase II of the Valsalva maneuver. None of the patients had any myocardial wall motion or valvular abnormalities.For data analysis, the subjects were divided into groups based on the diastolic physiology, as part of the study design: I, normal diastolic physiology (E/A >1, Dt 160~240 ms, IVRT 70~90 ms); II, impaired relaxation (E/A <1, Dt >240 ms, IVRT >90 ms); III, pseudonormal pattern (normal baseline filling pattern with E/A <1 and a decrease in E/A ratio of >25% during Valsalva); IV, restrictive filling pattern (E/A >1.5, Dt <160 ms, IVRT <70 ms) [18]. The data are expressed as mean±SD or as number (%). Student's t-test and chi-square test were used for between-group comparisons (against group I taken as the reference). Paired t-test was used for within-group before-after comparisons. In view of the multiple testing, a 2-sided P value of <0.01 was taken as the criterion of statistical significance.
RESULTS
Satisfactory 2D and Doppler measurements were obtained in all the patients. Twenty (40%) of the patients had normal LV filling pattern at baseline and during Valsalva maneuver (Group I). Impaired relaxation (Group II) and pseudonormal filling pattern (Group III) were observed in 18 (36%) and 12 (24%) patients, respectively. Overall, 60% of our patients had diastolic dysfunction and pseudonormal filling pattern accounted for 40% of these cases. None of our patients had restrictive (group IV) filling pattern. The baseline characteristics of the 3 groups of patients were comparable (Table 1). Measurements on 2D echocardiography were within normal limits and were comparable between the 3 groups of patients except for smaller left atrial diameter and greater LV posterior wall thickness in patients with pseudonormal filling (Table 2).
Table 1 Subject Characteristics
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein;*a, Group Ⅱ vs Group Ⅰ; b, Group Ⅲ vs Group Ⅰ
Table 2 Transthoracic Echocardiographic Measurements in Different Subject Groups
LV, left ventricular; IVS, interventricular septum;*a, Group Ⅱ vs Group Ⅰ; b, Group Ⅲ vs Group Ⅰ
On mitral Doppler examination, patients with impaired relaxation had lower E velocity, higher A velocity, lower E/A ratio, and more prolonged Dt as compared to normal or pseudonormal filling patterns. IVRT was not significantly different between the 3 filling patterns. On Valsalva maneuver, A and E velocities and E/A ratio did not change significantly in patients with normal filling or impaired relaxation. On the other hand, E velocity decreased significantly in group Ⅲ patients without any significant change in A velocity,resulting in a significant decrease in E/A ratio in these patients (Table 3).
Dt increased in patients with all the 3 filling patterns but especially in group Ⅲ patients. IVRT showed a significant increase in patients with normal LV filling and a borderline significant increase in those with pseudonormal LV filling pattern. In patients with impaired relaxation, IVRT did not increase significantly (Table 3).
Table 3 Mitral Pulsed Doppler Parameters before and after Valsalva Maneuver
Dt, deceleration time; IVRT, isovolumic relaxation time;*a, Group Ⅱ vs Group Ⅰ; b, Group Ⅲ vs Group Ⅰ;Paired t-test (pre- versus post Valsalva)
DISCUSSION
The most important finding of the present study was the presence of LV diastolic dysfunction in 60% of asymptomatic diabetic patients, with more than one-third of these having pseudonormal LV filling pattern. Our results indicate that patients with well controlled diabetes type 2 without hypertension or CAD have a high prevalence of LV diastolic dysfunction and that routine transthoracic echo-Doppler examination without a maneuver to unmask the occult abnormalities in LV filling may underestimate the frequency of diastolic dysfunction in these patients.
LV diastolic dysfunction is known to occur in diabetic subjects and is considered to represent an early stage of diabetic cardiomyopathy[12~14]. However, published reports about the prevalence of diastolic dysfunction in diabetes have been variable, largely due to the differences in methodology and criteria used to diagnose it. Several earlier studies that reported lower frequency of diastolic dysfunction in diabetes[19~22] did not take into account the pseudonormal pattern which reflects an intermediate stage in the progression of the abnormalities in LV relaxation and filling. As LV diastolic function deteriorates, moderately increased left atrial pressure superimposed on LV relaxation abnormality may produce a filling pattern that appears to be grossly normal[23]. Preload reduction with Valsalva maneuver decreases left atrial pressure, thereby unmasking abnormal LV relaxation. Thus identification of pseudonormal filling pattern may be very important since it represents a more advanced degree of diastolic dysfunction than impaired relaxation. The use of Valsalva maneuver is a reliable and simple way to diagnose occult LV diastolic dysfunction[24] and has been found to agree closely with pulmonary venous Doppler assessment in this regard[25].
Our observation of a relatively high prevalence of LV diastolic dysfunction in diabetics is consistent with several recent studies. In a community-based study, 48% of randomly selected diabetic subjects were found to have diastolic dysfunction[26]. Poirier,et al.[25], using similar methodology as the present study, noted diastolic dysfunction in 60% of normotensive well controlled diabetics, with nearly equal proportion having pseudonormal pattern or impaired relaxation (32% and 28% respectively). Zabalgoitia,et al.[27]found impaired relaxation in 30% of normotensive patients with well controlled diabetes, although the frequency of pseudonormal filling pattern in their study was lower (17%). In a study of 133 obese persons, LV diastolic dysfunction, diagnosed on the basis of mitral and pulmonary venous Doppler assessment, was found in 54% of normotensive normocholesterolemic patients with well controlled type 2 diabetes[28]. In another, recent study in 288 subjects (mean age 56 years), non-insulin dependent diabetes was the strongest independent correlate of LV diastolic dysfunction. About 66% of the diabetic patients had baseline mitral A/E ratio <1 and another 23% patients had increased (>55 cm/s) velocity propagation of transmitral flow on color M-mode echocardiography, suggesting the presence of pseudonormal filling pattern. However, about 38% of normal controls also met the criteria of diastolic dysfunction in this study[29].
The exact mechanism for the development of diastolic dysfunction in diabetes is not clear and may be due to metabolic disturbances[30], myocardial fibrosis[31], and coronary microvascular dysfunction[32]. Further, diabetic subjects frequently have hypertension, which is known to be associated with LV diastolic dysfunction[33,34] and may have a synergistic effect with diabetes in producing myocardial abnormalities[31]. CAD also frequently co-exists with diabetes and is in itself associated with abnormalities in LV diastolic properties[35,36]. The demonstration in the present study, as also in some previous studies[25,27,37],of a high prevalence of diastolic dysfunction in asymptomatic well-controlled diabetic patients without hypertension or CAD suggests that LV diastolic dysfunction may be separate distinct phenotypic expression of early diabetic heart disease[7,14].
As against the high prevalence of diastolic dysfunction noted in the present study, LV systolic function was within normal limits and identical between the 3 groups of diastolic physiology. Further, LV dimensions and LV mass index were also identical and within normal limits. The finding of LV diastolic dysfunction in the presence of normal LV mass and systolic function lends further support to the existence of a primary diabetic cardiomyopathy of predominantly diastolic nature. Further, because diastolic dysfunction may occur early in diabetes[22,37] and may indicate high cardiovascular risk[38], its timely recognition may provide a window of opportunity for early therapeutic intervention to prevent progression to CHF[5].
An unusual finding in the present study was a slightly lower left atrial size in diabetic patients with pseudonormal pattern as compared to those with normal filling pattern. Other observers have reported higher LA size in presence of abnormal[25] or pseudonormal[27] LV filling pattern in diabetic subjects. We do not have any obvious explanation for this deviant observation. Small sample sizes could be one possible explanation, though a real difference between study populations cannot be ruled out.
The present study has some limitations. First, CAD was presumed to be absent on the basis of clinical presentation and treadmill test both of which, alone as well as together, may sometimes fail to detect CAD. Although we tried to minimize this possibility by only including patients without regional wall motion abnormalities on echocardiography, we cannot say with certainty that our patients did not have subclinical coronary atherosclerosis. Secondly, we did not measure pulmonary venous flow velocities, although use of Valsalva maneuver in every patient made this less important. We studied a small sample of highly selected patients and, as such, the generalizability of our results may be limited. Further studies in larger groups of subjects are needed to more clearly define the prevalence and pattern of diastolic function abnormalities in wide groups of diabetic patients.
CONCLUSIONS
Asymptomatic LV diastolic dysfunction may be present in about 60% of patients with well-controlled diabetes mellitus type 2 without hypertension or CAD, with about 40% of these having pseudonormal LV filling pattern. Failure to actively look for occult abnormality in diastolic physiology may lead to significant underestimation of the true prevalence of LV diastolic dysfunction in these patients.
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(Editor Jaque)(Khurshid A Khan, Sheikh J)
Correspondence to A. Rauoof Malik,427 Fourth Street SW, Apartment # G4, Rochester,MN 55902,USA
Tel: (1) 507-288-8028,E-mail:marauf2903@yahoo.co.in,malik.rauoof@mayo.edu
[Abstract] Objective Left ventricular (LV) diastolic dysfunction is known to occur in early stages of diabetic cardiomyopathy but its exact prevalence is not clearly known. The present study was conducted to assess the prevalence of diastolic dysfunction in diabetic patients in the absence of hypertension or CAD.Methods Fifty consecutive asymptomatic normotensive patients (mean age 47.54±6.78 years) with well controlled diabetes type 2, free of any major clinical diabetic complications, and having no evidence of CAD on non-invasive testing, were studied for LV diastolic functions, using pulsed Doppler at the tip of mitral valve. The peak velocities of LV filling during the early rapid (E wave) and atrial contraction (A wave) phases, the ratio of the 2 filling velocities (E/A ratio), E wave deceleration time, and the isovolumic relaxation time, were recorded at end-expiration for 5 consecutive beats at baseline and again during the phase Ⅱ of Valsalva maneuver. Results Diastolic dysfunction was noted in 30 (60%) patients, out of whom, 18 (36% ) had impaired relaxation while 12 (24%) had pseudonormal pattern. No patient had restrictive filling pattern. Pseudonormal pattern accounted for 40% of the patients with diastolic dysfunction. Clinical characteristics and measurements on 2D echocardiography were within normal limits and were comparable between the 3 groups of patients.Conclusions LV diastolic dysfunction may be present in about 60% of asymptomatic patients with well-controlled diabetes mellitus type 2 without hypertension or CAD. Pseudonormal pattern may account for more than one-third of the diabetic patients with diastolic dysfunction and failure to recognize it may lead to significant underestimation of the true prevalence of LV diastolic dysfunction in these patients.
[Key words] diastolic;type 2 diabetes
INTRODUCTION
Congestive heart failure (CHF) is an important cause of morbidity and mortality among patients with type 2 diabetes mellitus. Diabetic subjects have an increased prevalence of CHF[1,2] and have a worse prognosis with the development of CHF compared to non-diabetics[3]. The risk of developing CHF is increased in diabetics even in the absence of coronary artery disease (CAD), hypertension, or valvular abnormalities and has been attributed to a separate disease entity called ‘diabetic cardiomyopathy' [4~7]. Further, there is evidence to suggest that a significant proportion of diabetic patients may suffer from subclinical left ventricular (LV) dysfunction, including diastolic dysfunction[8~10], and this fact may contribute to the increased diagnosis of ‘idiopathic cardiomyopathy' in diabetic population[11]. Diastolic dysfunction in diabetic patients is believed to represent an earlier stage in the natural history of diabetic cardiomyopathy[12~14], and its timely recognition may help to avoid or significantly delay the onset of CHF[5].
Previously published reports about the prevalence of LV diastolic dysfunction in diabetes are conflicting,mainly because of the confounding effect of systemic hypertension and CAD that frequently co-exist with diabetes and have significant effects on cardiac diastolic physiology[15]. Further, abnormalities in LV diastolic function may be occult, producing a so-called ‘pseudonormal' LV filling pattern, and might be missed unless specifically sought[14]. The present study was conducted to estimate the prevalence of diastolic functions in patients with well-controlled diabetes without any known major diabetic complication and without co-existing hypertension or known CAD. Any occult diastolic dysfunction was unmasked using a maneuver to acutely reduce the preload, thereby bringing out the pseudonormal LV filling pattern.
METHODS
The study was conducted on 50 consecutive patients (age 35~60 years, 72% men) with well controlled diabetes type 2, diagnosed as per the standard criteria[16]. Only the patients on medical nutrition therapy and/or oral hypoglycemic agents and free of any clinical diabetic complications (neuropathy, nephropathy, grade 2 or higher nephropathy) were selected. Adequacy of glycemic control was assessed as consistent venous blood glucose of 90 to 130 mg/dl pre-prandial and <180 mg/dl 1~2 h post-prandial on repeated measurements over previous 3 months. The patients had no history of hypertension or antihypertensive treatment and had normal office blood pressure (BP) on all of at least 2 occasions. Patients with known CAD, valvular or other structural heart disease, cardiac arrhythmia, renal, hepatic or other systemic disorder, and those taking cardiac medications were excluded. Informed consent was obtained from all the patients. The study was approved by the local hospital ethics committee. All the subjects had normal 12-lead resting electrocardiogram and normal treadmill test using Bruce protocol.
Echocardiography was performed using a commercially available equipment (Toshiba Powervision UZR I 328 A, Tokyo,Japan). The subjects were examined in left lateral decubitus position using standard views. Standard 2-D and M-mode recordings of LV were obtained as per the recommendations of the American Society of Echocardiography[17]. LV volumes and ejection fraction were measured by modified Simpson's formula. LV mass was calculated using Penn convention and indexed to body surface area. LV diastolic functions were assessed using pulsed Doppler at the tip of mitral valve. The peak velocities LV filling during the early rapid (E wave, m/s) and atrial contraction (A wave, m/s) phases, the ratio of the 2 filling velocities (E/A ratio), E wave deceleration time (Dt, ms from the peak of E wave to the point at which the deceleration velocity reaches the baseline), and the isovolumic relaxation time (IVRT, ms from aortic valve closure to the beginning of E wave) were recorded at end-expiration for 5 consecutive beats. Patients were then directed to perform a standard Valsalva maneuver by holding a regular breath and bearing down against closed glottis for at least 10 s. All the diastolic indices were again recorded during the phase II of the Valsalva maneuver. None of the patients had any myocardial wall motion or valvular abnormalities.For data analysis, the subjects were divided into groups based on the diastolic physiology, as part of the study design: I, normal diastolic physiology (E/A >1, Dt 160~240 ms, IVRT 70~90 ms); II, impaired relaxation (E/A <1, Dt >240 ms, IVRT >90 ms); III, pseudonormal pattern (normal baseline filling pattern with E/A <1 and a decrease in E/A ratio of >25% during Valsalva); IV, restrictive filling pattern (E/A >1.5, Dt <160 ms, IVRT <70 ms) [18]. The data are expressed as mean±SD or as number (%). Student's t-test and chi-square test were used for between-group comparisons (against group I taken as the reference). Paired t-test was used for within-group before-after comparisons. In view of the multiple testing, a 2-sided P value of <0.01 was taken as the criterion of statistical significance.
RESULTS
Satisfactory 2D and Doppler measurements were obtained in all the patients. Twenty (40%) of the patients had normal LV filling pattern at baseline and during Valsalva maneuver (Group I). Impaired relaxation (Group II) and pseudonormal filling pattern (Group III) were observed in 18 (36%) and 12 (24%) patients, respectively. Overall, 60% of our patients had diastolic dysfunction and pseudonormal filling pattern accounted for 40% of these cases. None of our patients had restrictive (group IV) filling pattern. The baseline characteristics of the 3 groups of patients were comparable (Table 1). Measurements on 2D echocardiography were within normal limits and were comparable between the 3 groups of patients except for smaller left atrial diameter and greater LV posterior wall thickness in patients with pseudonormal filling (Table 2).
Table 1 Subject Characteristics
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein;*a, Group Ⅱ vs Group Ⅰ; b, Group Ⅲ vs Group Ⅰ
Table 2 Transthoracic Echocardiographic Measurements in Different Subject Groups
LV, left ventricular; IVS, interventricular septum;*a, Group Ⅱ vs Group Ⅰ; b, Group Ⅲ vs Group Ⅰ
On mitral Doppler examination, patients with impaired relaxation had lower E velocity, higher A velocity, lower E/A ratio, and more prolonged Dt as compared to normal or pseudonormal filling patterns. IVRT was not significantly different between the 3 filling patterns. On Valsalva maneuver, A and E velocities and E/A ratio did not change significantly in patients with normal filling or impaired relaxation. On the other hand, E velocity decreased significantly in group Ⅲ patients without any significant change in A velocity,resulting in a significant decrease in E/A ratio in these patients (Table 3).
Dt increased in patients with all the 3 filling patterns but especially in group Ⅲ patients. IVRT showed a significant increase in patients with normal LV filling and a borderline significant increase in those with pseudonormal LV filling pattern. In patients with impaired relaxation, IVRT did not increase significantly (Table 3).
Table 3 Mitral Pulsed Doppler Parameters before and after Valsalva Maneuver
Dt, deceleration time; IVRT, isovolumic relaxation time;*a, Group Ⅱ vs Group Ⅰ; b, Group Ⅲ vs Group Ⅰ;Paired t-test (pre- versus post Valsalva)
DISCUSSION
The most important finding of the present study was the presence of LV diastolic dysfunction in 60% of asymptomatic diabetic patients, with more than one-third of these having pseudonormal LV filling pattern. Our results indicate that patients with well controlled diabetes type 2 without hypertension or CAD have a high prevalence of LV diastolic dysfunction and that routine transthoracic echo-Doppler examination without a maneuver to unmask the occult abnormalities in LV filling may underestimate the frequency of diastolic dysfunction in these patients.
LV diastolic dysfunction is known to occur in diabetic subjects and is considered to represent an early stage of diabetic cardiomyopathy[12~14]. However, published reports about the prevalence of diastolic dysfunction in diabetes have been variable, largely due to the differences in methodology and criteria used to diagnose it. Several earlier studies that reported lower frequency of diastolic dysfunction in diabetes[19~22] did not take into account the pseudonormal pattern which reflects an intermediate stage in the progression of the abnormalities in LV relaxation and filling. As LV diastolic function deteriorates, moderately increased left atrial pressure superimposed on LV relaxation abnormality may produce a filling pattern that appears to be grossly normal[23]. Preload reduction with Valsalva maneuver decreases left atrial pressure, thereby unmasking abnormal LV relaxation. Thus identification of pseudonormal filling pattern may be very important since it represents a more advanced degree of diastolic dysfunction than impaired relaxation. The use of Valsalva maneuver is a reliable and simple way to diagnose occult LV diastolic dysfunction[24] and has been found to agree closely with pulmonary venous Doppler assessment in this regard[25].
Our observation of a relatively high prevalence of LV diastolic dysfunction in diabetics is consistent with several recent studies. In a community-based study, 48% of randomly selected diabetic subjects were found to have diastolic dysfunction[26]. Poirier,et al.[25], using similar methodology as the present study, noted diastolic dysfunction in 60% of normotensive well controlled diabetics, with nearly equal proportion having pseudonormal pattern or impaired relaxation (32% and 28% respectively). Zabalgoitia,et al.[27]found impaired relaxation in 30% of normotensive patients with well controlled diabetes, although the frequency of pseudonormal filling pattern in their study was lower (17%). In a study of 133 obese persons, LV diastolic dysfunction, diagnosed on the basis of mitral and pulmonary venous Doppler assessment, was found in 54% of normotensive normocholesterolemic patients with well controlled type 2 diabetes[28]. In another, recent study in 288 subjects (mean age 56 years), non-insulin dependent diabetes was the strongest independent correlate of LV diastolic dysfunction. About 66% of the diabetic patients had baseline mitral A/E ratio <1 and another 23% patients had increased (>55 cm/s) velocity propagation of transmitral flow on color M-mode echocardiography, suggesting the presence of pseudonormal filling pattern. However, about 38% of normal controls also met the criteria of diastolic dysfunction in this study[29].
The exact mechanism for the development of diastolic dysfunction in diabetes is not clear and may be due to metabolic disturbances[30], myocardial fibrosis[31], and coronary microvascular dysfunction[32]. Further, diabetic subjects frequently have hypertension, which is known to be associated with LV diastolic dysfunction[33,34] and may have a synergistic effect with diabetes in producing myocardial abnormalities[31]. CAD also frequently co-exists with diabetes and is in itself associated with abnormalities in LV diastolic properties[35,36]. The demonstration in the present study, as also in some previous studies[25,27,37],of a high prevalence of diastolic dysfunction in asymptomatic well-controlled diabetic patients without hypertension or CAD suggests that LV diastolic dysfunction may be separate distinct phenotypic expression of early diabetic heart disease[7,14].
As against the high prevalence of diastolic dysfunction noted in the present study, LV systolic function was within normal limits and identical between the 3 groups of diastolic physiology. Further, LV dimensions and LV mass index were also identical and within normal limits. The finding of LV diastolic dysfunction in the presence of normal LV mass and systolic function lends further support to the existence of a primary diabetic cardiomyopathy of predominantly diastolic nature. Further, because diastolic dysfunction may occur early in diabetes[22,37] and may indicate high cardiovascular risk[38], its timely recognition may provide a window of opportunity for early therapeutic intervention to prevent progression to CHF[5].
An unusual finding in the present study was a slightly lower left atrial size in diabetic patients with pseudonormal pattern as compared to those with normal filling pattern. Other observers have reported higher LA size in presence of abnormal[25] or pseudonormal[27] LV filling pattern in diabetic subjects. We do not have any obvious explanation for this deviant observation. Small sample sizes could be one possible explanation, though a real difference between study populations cannot be ruled out.
The present study has some limitations. First, CAD was presumed to be absent on the basis of clinical presentation and treadmill test both of which, alone as well as together, may sometimes fail to detect CAD. Although we tried to minimize this possibility by only including patients without regional wall motion abnormalities on echocardiography, we cannot say with certainty that our patients did not have subclinical coronary atherosclerosis. Secondly, we did not measure pulmonary venous flow velocities, although use of Valsalva maneuver in every patient made this less important. We studied a small sample of highly selected patients and, as such, the generalizability of our results may be limited. Further studies in larger groups of subjects are needed to more clearly define the prevalence and pattern of diastolic function abnormalities in wide groups of diabetic patients.
CONCLUSIONS
Asymptomatic LV diastolic dysfunction may be present in about 60% of patients with well-controlled diabetes mellitus type 2 without hypertension or CAD, with about 40% of these having pseudonormal LV filling pattern. Failure to actively look for occult abnormality in diastolic physiology may lead to significant underestimation of the true prevalence of LV diastolic dysfunction in these patients.
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(Editor Jaque)(Khurshid A Khan, Sheikh J)