Abstract
Introduction:
The prevalence of type 2 diabetes mellitus (DM) has been increasing over the years, with cardiovascular disease being the leading cause of death. Diabetic cardiomyopathy is a clinical entity independent of coronary artery disease leading to heart failure in diabetic patients. Left ventricular diastolic dysfunction (LVDD) is an early manifestation of diabetic cardiomyopathy leading to significant morbidity and mortality.
Aim:
The aim of this study was to evaluate LVDD in normotensive patients with type 2 DM and correlate the severity of diastolic dysfunction with glycemic control using glycated hemoglobin (HbA1c).
Materials and Methods:
A hospital-based prospective observational study was conducted between January 2018 and June 2020 at a tertiary care hospital in Bengaluru, Karnataka, India. A total of 130 patients with type 2 DM without systemic hypertension were selected as the study population. Left ventricular function was assessed by performing a Doppler echocardiogram, and HbA1c was measured. Analysis of the data was done with the help of IBM SPSS statistics software 23.0 version.
Results:
One hundred and thirty patients (95 males and 35 females) were enrolled in our study, of which 55.4% (72 patients) had LVDD. Patients with LVDD were noticed to have a higher mean age (P < 0.001). Comparison of HbA1c levels between the subset of patients with and without LVVD using unpaired t-test was statistically insignificant and did not correlate with LVDD. On the assessment of electrocardiographic parameters, the corrected QT duration (QTc) showed a positive correlation with LVDD which was statistically significant. On the assessment of echocardiographic findings, deceleration time and the ratio of early mitral inflow velocity and mitral annular early diastolic velocity (E/e) done using unpaired t-test showed positive correlations with LVDD which were statistically significant.
Conclusion:
LVDD has a high prevalence in type 2 DM and is a cause of morbidity and mortality. Therefore, the detection of diabetic cardiomyopathy at an early stage with Doppler echocardiography has major therapeutic implications to prevent cardiovascular complications. Furthermore, it can aid the development of risk stratification strategies that can improve the quality of life and prevent morbidity.
Keywords: Diabetic cardiomyopathy, left ventricular diastolic dysfunction, type 2 diabetes mellitus
Résumé
Introduction:
La prévalence du diabète sucré de type 2 (DS) augmente depuis quelques années, les maladies cardiovasculaires étant la principale cause de décès. La cardiomyopathie diabétique est une entité clinique indépendante de la coronaropathie, entraînant une insuffisance cardiaque chez les patients diabétiques. La dysfonction diastolique ventriculaire gauche (DDVG) est une manifestation précoce de la cardiomyopathie diabétique, entraînant une morbidité et une mortalité importantes.
Objectif:
Cette étude visait à évaluer la DDVG chez des patients normotendus atteints de DS de type 2 et à corréler la gravité de la dysfonction diastolique avec le contrôle glycémique par l’hémoglobine glyquée (HbA1c). Matériel et méthodes : Une étude observationnelle prospective en milieu hospitalier a été menée entre janvier 2018 et juin 2020 dans un hôpital de soins tertiaires de Bengaluru, dans l’État du Karnataka, en Inde. Au total, 130 patients atteints de DS de type 2 sans hypertension systémique ont été sélectionnés pour constituer la population étudiée. La fonction ventriculaire gauche a été évaluée par échocardiographie Doppler et l’HbA1c a été mesurée. L’analyse des données a été réalisée à l’aide du logiciel de statistiques IBM SPSS version 23.0.
Résultats:
Cent trente patients (95 hommes et 35 femmes) ont été inclus dans notre étude, dont 55,4 % (72 patients) présentaient une dysfonction ventriculaire gauche (DVG). L’âge moyen des patients présentant une DVG était plus élevé (p < 0,001). La comparaison des taux d’HbA1c entre les sous-groupes de patients avec et sans DVG, à l’aide d’un test t non apparié, s’est avérée statistiquement non significative et n’était pas corrélée à la DVG. Lors de l’évaluation des paramètres électrocardiographiques, la durée QT corrigée (QTc) a montré une corrélation positive avec la DVG, statistiquement significative. L’évaluation des résultats échocardiographiques a révélé que le temps de décélération et le rapport entre la vitesse d’entrée mitrale précoce et la vitesse diastolique précoce annulaire mitrale (E/e), réalisés à l’aide d’un test t non apparié, présentaient des corrélations positives et statistiquement significatives avec la DDVG.
Conclusion:
La DDVG présente une prévalence élevée dans le diabète de type 2 et est une cause de morbidité et de mortalité. Par conséquent, la détection précoce de la cardiomyopathie diabétique par échocardiographie Doppler a des implications thérapeutiques majeures pour la prévention des complications cardiovasculaires. De plus, elle peut contribuer à l’élaboration de stratégies de stratification du risque susceptibles d’améliorer la qualité de vie et de prévenir la morbidité.
Mots-clés: Cardiomyopathie diabétique, dysfonction diastolique ventriculaire gauche, diabète de type 2
INTRODUCTION
The prevalence of diabetes mellitus (DM) has depicted an upward trend of growth over the years with India projecting an estimated 79.4 million people with DM in 2030.[1] Cardiovascular disease, especially coronary artery disease (CAD), is the most common cause of mortality among individuals with type 2 DM.[2] Some of the cardiovascular complications in DM include diabetic cardiomyopathy, greater mean left ventricular wall thickness, and left ventricular dysfunction.[3]
Diabetic cardiomyopathy is a clinical entity with a distinct primary disease process, independent of CAD leading to heart failure (HF) in diabetic patients.[4] They are distinctive because they are not the result of pericardial, congenital, valvular, ischemic diseases or hypertension. The pathophysiology is suggested to be microangiopathy caused by endothelial dysfunction, hormonal dysfunction, and a shift in the metabolism of smooth muscle cells.[5] Left ventricular diastolic dysfunction (LVDD) with preserved ejection fraction is suggested to be the first stage of diabetic cardiomyopathy.[6,7] It is crucial to detect diabetic cardiomyopathy at an early stage to promote the development of risk stratification protocols.[7]
Grading of diastolic dysfunction is suggested to be as follows: Grade I with impaired relaxation and decreased suction of the left ventricle (LV), grade II with pseudonormalization, increased stiffness of the LV and possible elevated filling pressure, and grade III with restrictive filling with elevated filling pressure and a noncompliant LV.[8] This latter grade may be reversible with a reduction of preload or irreversible with no benefit from the reduction of preload.[8]
The role of LVDD has been underappreciated by the medical fraternity. This is possible because diastole is a complex phenomenon with determinants that cannot be individually studied and occurs in several phases that constitute the relaxation and the consequent filling of the ventricle. Physical examination, electrocardiogram (ECG), and chest radiographs may be unreliable in making a diagnosis of LVDD in most individuals, and the invasive measurement of cardiac pressures, rates of LV relaxation, and LV compliance are expensive, are clinically impracticable, and require special catheter and software analysis programs.
Glycated hemoglobin (HbA1c) is an important indicator of long-term glycemic control with the ability to reflect the cumulative glycemic history of the preceding 2–3 months. In addition to providing a reliable measure of chronic hyperglycemia, it correlates well with the risk of long-term diabetes complications.[9] Elevated HbA1c has also been regarded as an independent risk factor for CAD and stroke in subjects with or without type 2 DM.[9] The valuable information provided by a single HbA1c test has rendered it a reliable biomarker for the diagnosis and prognosis of diabetes. HbA1c has now been recommended as a standard of care for testing and monitoring diabetes, specifically type 2 DM.[10]
Our study aimed to evaluate the prevalence of LVDD in normotensive patients with type 2 DM using echocardiography and to correlate the severity of LVDD with the long-term glycemic control assessed by HbA1c.
MATERIALS AND METHODS
Details of the study undertaken
This was a prospective observational study conducted at a tertiary care hospital in Karnataka, between January 2018 and July 2019. Our study was undertaken among patients with type 2 DM attending the outpatient and inpatient departments of the Department of General Medicine. One hundred and thirty normotensive patients with type 2 DM who gave informed consent were included in the study. Ethical clearance was obtained from the Institutional Ethics Committee.
Inclusion criteria
Normotensive patients not on antihypertensive medication diagnosed with type 2 DM aged more than 18 years were included in the study.
Exclusion criteria
Patients with systemic hypertension, antihypertensive medication use, history of heart disease, prevailing or prior cardiac symptomatology such as angina, dyspnea, comorbidities such as chronic obstructive pulmonary disease, chronic kidney disease, anemia, thyroid disorders, CAD, and a history of chronic smoking or alcohol intake were excluded from the study.
Parameters used in the study
Glycated hemoglobin level
The Institutional Central Diagnostic Laboratory utilized a Variant II Turbo HbA1c kit for analysis of blood samples with a National Glycohemoglobin Standardization Program percentage of 3.4–20.6.
Electrocardiogram
The parameters studied included P wave duration, corrected QT interval (QTc), QRS duration, and ST-T changes at rest.
Doppler echocardiography
All the patients underwent a Doppler echocardiogram with a commercially available ultrasound system. The echocardiogram was performed with the patient in the left lateral decubitus position and in standard views. The recordings were taken in accordance with the guidelines of the American Society of Echocardiography.[11,12] The parameters assessed included: deceleration time (DT), ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e’), and pulmonary vein Doppler to assess the pulmonary vein flow velocity and mitral inflow propagation velocity.
Statistical analysis
The collected data were analyzed with IBM corp, Armonk, NY, USA. During data analysis, descriptive statistics frequency analysis and percentage analysis were used for categorical variables and the mean and standard deviation were used for continuous variables. Normality of the continuous data was tested by the Kolmogorov–Smirnov test and the Shapiro–Wilk test. Independent t-test was used as a test of significance to identify the mean difference between two quantitative variables. The Chi-square test was used to find the significance in categorical data. The probability value of <0.05 was considered statistically significant.
RESULTS
Our study consisted of 130 patients with 95 males (73.1%) and 35 females (26.9%). The overall prevalence of LVDD in diabetic patients was 55.4% (72 patients). Of 72 patients with LVDD, 95.8% (69 patients) had grade I LVDD and 4.2% (3 patients) had grade 2 LVDD. None of the patients had grade 3 or grade 4 LVDD. Table 1 summarizes the mean values of the parameters assessed including baseline characteristics, electrocardiographic and echocardiographic parameters, their correlation with LVDD, and their statistical significance.
Table 1.
Mean values of the parameters assessed with their correlation with left ventricular diastolic dysfunction
| Parameters | LVDD | P | |
|---|---|---|---|
|
| |||
| Present | Absent | ||
| Mean age | 54.25±10.64 | 48.22±9.38 | 0.001 |
| Glycated hemoglobin (%) | 8.64±1.61 | 8.42±1.86 | 0.474 |
LVDD=Left ventricular diastolic dysfunction
As LVDD is a qualitative variable, a scatter diagram plot did not seem to be a good reflector to comment on its correlation with HbA1c [Figure 1]. However, the comparison of HbA1c values between the subsets of patients showed no statistical significance with P = 0.319. HbA1c was found to have no significant correlation with LVDD with P = 0.416. There was no gender predilection noted in the study with P = 0.215.
Figure 1.
Scatter plot showing the correlation between the grade of left ventricular diastolic dysfunction and glycated hemoglobin. LVDD = Left ventricular diastolic dysfunction, HbA1c = Glycated hemoglobin
Echocardiographic parameters
Deceleration time
The range of DT recordings in our study group was 140.0–320.0 ms with a mean of 223.65 ± 48.33 ms. Patients with diastolic dysfunction had a significantly higher DT (256.79 ± 35.04 ms) than the patients with normal diastolic function (182.50 ± 25.36 ms) [Figure 2]. Comparison of DT was done using unpaired t-test. This was found to be highly statistically significant (P < 0.001).
Figure 2.
Deceleration time (ms) comparison with respect to left ventricular diastolic dysfunction. LVDD = Left ventricular diastolic dysfunction, DT = Deceleration time
Ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e’)
The range of ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e’) in our study group was 3.2–15.0 with a mean of 7.62 ± 2.36. Patients with diastolic dysfunction had a higher E/e’ (8.10 ± 2.88) than the patients with normal diastolic function (7.01 ± 1.23) [Figure 3]. This was found to be highly statistically significant (P = 0.008).
Figure 3.
Ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e’) comparison with respect to left ventricular diastolic dysfunction. LVDD = Left ventricular diastolic dysfunction
Pulmonary venous flow velocities
The range of pulmonary venous flow velocities (PVFVs) in our study group was 68.0–132.0 m/s with a mean of 77.27 ± 10.0 m/s. The mean value of PVFV in the patients with diastolic dysfunction was found to be 77.47 ± 10.58 m/s, and it was 77.02 ± 9.32 m/s in the patients with normal diastolic function. This was found to be statistically insignificant (P = 0.798).
Electrocardiographic parameters
P wave duration
P wave duration was found to have no statistical significance (P = 0.207) with a mean of 0.88 ± 0.10 s in patients with LVDD and a mean of 0.90 ± 0.10 in patients without LVDD.
Mean QRS duration
The mean QRS duration in the patients with LVDD was 100.56 ± 14.62 and in those without LVDD was 99.66 ± 14.26. The P value was 0.725 which was statistically insignificant.
Corrected QT interval duration
The range of mean QTc in our study group was 380.0–436.0 ms with a mean of 409.28 ± 13.71 ms. Patients with diastolic dysfunction had a higher mean QTc (412.72 ± 14.17 ms) than the patients with normal diastolic function (405.00 ± 11.90 ms) [Figure 4]. P =0.001 was highly significant.
Figure 4.
QTc (ms) comparison with respect to left ventricular diastolic dysfunction. LVDD = Left ventricular diastolic dysfunction
DISCUSSION
Our study evaluated the prevalence of LVDD in normotensive patients with type 2 DM and attempted to correlate its severity with HbA1c with other parameters such as age and electrocardiographic findings. 55.4% of the participants of our study were found to have LVDD. It is similar to research conducted in Nepal in which the cohort of patients with type 2 DM had a prevalence for LVDD of 47.8%.[13] Another noteworthy study conducted by Patil et al. found a prevalence of LVDD in diabetic patients to be 54.33% which is similar to our study.[14]
A similar study conducted in Uttar Pradesh, India, also noted a significant association between an older age of patients and the incidence of LVDD.[15] Age-related increase in backward wave pressures and resultant increment in late systolic load is found to be determinant factors in the observed association of LVDD to older age groups.[16]
Slightly higher mean HbA1c levels were observed in our participants with LVDD; however, a Chi-square test did not show a statistically significant correlation. A similar study conducted in Pakistan showed a significant correlation between HbA1c levels and diastolic indices (P < 0.05).[17]
A large-scale systematic review in Europe concluded that QTc intervals were significantly longer in individuals with LVDD compared to individuals without LVDD.[18] A QTc interval ≥395 ms could essentially diagnose LVDD with a sensitivity and specificity of 81 and 79%.[19] As electrocardiography is not currently a commonly evaluated diagnostic tool for LVDD, these results look promising for future research about its diagnostic potential.
The several limitations of our study need to be addressed. The specificity and sensitivity of diagnosing LVDD by conventional Doppler alone is low. CAD was excluded by patients’ history and ECG in our study; however, no confirmatory invasive tests such as coronary angiography were done. HbA1c reflects only a short-term glycemic control and is highly variable depending on various short-term influences such as diet and compliance with medication which were not assessed in our study. Poor prediction of long-term glycemic control may occur when a highly variable test like HbA1c is used. Another factor that was not considered was the duration of DM.
Asymptomatic LVDD is the earliest manifestation of diabetic cardiomyopathy and has been associated with a higher risk of subsequent HF and mortality.[19] The cumulative probability of the development of HF at 5 years for diabetic patients with diastolic dysfunction has been estimated to be 36.9% compared to 16.8% for patients without diastolic dysfunction (P < 0.001).[19]
On observing the prognostic implications of LVDD, a need for robust screening of diabetic patients with regular echocardiography seems apparent. The use of E/e’ is a feasible and reproducible technique for assessing filling pressure, which holds true even with changes in loading, and also correlates with ambulatory left atrial pressure and hence could prove useful in the assessment of LVDD.[20,21,22] Adequate preventive measures with appropriate glycemic control may also be helpful.
CONCLUSION
Our study showed that LVDD was present in 55.4% of our participants with type 2 DM. There was a significant correlation of older age and prolonged QTc interval values with LVDD but no significant correlation between LVDD and glycemic control (HbA1c). As asymptomatic LVDD is the earliest stage of diabetic cardiomyopathy and has been seen to have poorer outcomes, we suggest that all diabetic patients should be subjected to 2D color Doppler echocardiographic assessment of cardiac function at regular intervals during long-term management. Further large-scale studies must be done to help clinicians plan early intervention strategies.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
We would like to thank all the patients who agreed to be part of this study.
Funding Statement
Nil.
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