|Year : 2019 | Volume
| Issue : 3 | Page : 136-140
Fragmented QRS complex is independently associated with coronary microvascular function in asymptomatic patients with diabetes mellitus
Ragab A Mahfouz, Mohamed A Arab, Ibetsam I El-Dosoky
Department of Cardiology, Zagazig University Hospital, Zagazig, Egypt
|Date of Web Publication||3-Dec-2019|
Prof. Ragab A Mahfouz
Department of Cardiology, Zagazig University, Zagazig
Source of Support: None, Conflict of Interest: None
Aim: We aimed to investigate the relation between fragmented QRS (fQRS), coronary flow reserve (CFR), and cardiac dysfunction in asymptomatic patients with type 2 diabetes mellitus (DM). Subjects and Methods: Prospectively, 129 participants with DM (83 males; mean age: 49 ± 12 years). Surface electrocardiograms of all participates were analyzed for the presence of fQRS. Furthermore, individuals were evaluated for CFR, using transthoracic echocardiography with adenosine (0.14 μg/kg). They underwent both conventional and tissue Doppler imaging to evaluate cardiac functions. Lipid profile and fasting blood glucose were obtained. Results: CFR <2.0 was found in 74 (57%), while fQRS was detected in 80 (62%). Individuals with reduced CFR had a higher prevalence of fQRS compared with those with preserve CFR (96% vs. 16%, P < 0.001). Patients with fQRS had a lower CFR compared with those without fQRS (1.6 ± 0.3 vs. 2.7 ± 0.5, P < 0.001). The number of fQRS was inversely correlated with CFR (P < 0.001), S' wave (P < 0.01), and positively correlated with E/e' (P < 0.01), left atrial volume index (P < 0.02), triglycerides/high-density lipoprotein-cholesterol ratio (P < 0.01), and fasting blood sugar (P < 0.05). In addition, reduced CFR was closely correlated with increased E/e' ratio (P < 0.01) and lower S-wave (P < 0.03). On multivariate analysis, fQRS and CFR were independently associated (P < 0.001). ROC revealed that the number of QRS ≥3 was the optimal number (area under the curve = 0.92) to predict microvascular dysfunction. Conclusions: fQRS in asymptomatic patents with DM is associated with subclinical microvascular and left ventricular diastolic dysfunction. These findings revealed that the fQRS in the surface electrocardiography could be considered a simple marker for microvascular dysfunction in patients with DM.
Keywords: Coronary flow, diabetes mellitus, fragmented QRS
|How to cite this article:|
Mahfouz RA, Arab MA, El-Dosoky II. Fragmented QRS complex is independently associated with coronary microvascular function in asymptomatic patients with diabetes mellitus. J Indian coll cardiol 2019;9:136-40
|How to cite this URL:|
Mahfouz RA, Arab MA, El-Dosoky II. Fragmented QRS complex is independently associated with coronary microvascular function in asymptomatic patients with diabetes mellitus. J Indian coll cardiol [serial online] 2019 [cited 2020 Apr 7];9:136-40. Available from: http://www.joicc.org/text.asp?2019/9/3/136/272173
| Introduction|| |
Micro- and macro-vascular complications are frequent among patients with diabetes mellitus (DM). Cardiovascular disease is the most common cause of death in diabetic patients and not diabetes per se., Studies showed that endothelial dysfunction occurs before the development of overt atherosclerosis in diabetic patients.,,, Although the precise causes of left ventricular (LV) myocardial remodeling in patients with diabetes remain unclear, several factors such as a metabolic abnormality, autonomic dysfunction, myocardial fibrosis, and reduced myocardial perfusion due to small vessel disease, have been reported as possible pathophysiologic mechanisms.,
Fragmented QRS complex (fQRS) on surface electrocardiography (ECG) develops as a result of inhomogeneous and delayed ventricular conduction. It is associated with myocardial ischemia, fibrosis, myocardial scarring as well as adverse cardiovascular outcomes in different cardiovascular diseases.,,
Imaging studies with nuclear and magnetic resonance have demonstrated that the presence of fQRS on ECGs is associated with myocardial perfusion impairment and the development of scar tissue. Moreover, it is clearly known that the presence of fQRS is a predictor of increased cardiovascular mortality in patients with acute coronary syndromes.
We hypothesized that fQRS complex as a marker of myocardial remodeling and fibrotic burden is an early predictor of impaired microvascular and subclinical myocardial functional dysfunction. Therefore, we investigated the association between FQRS and coronary flow reserve (CFR) in asymptomatic patients with type 2 DM.
| Subjects and Methods|| |
The current study included 129 consecutive asymptomatic participants with type 2 diabetes (83 males; mean age: 49 ± 12 years), who were collected from a diabetic clinic. Patients with hypertension, atrial fibrillation, congenital heart disease, valvular heart disease, serum creatinine >2.0 mg/dl, type 1 diabetes and those with a positive exercise stress test were excluded. Patients with ejection fraction (EF) <50% and those with wall motion abnormalities were also excluded from the study.
Assessment of fragmented QRS
Resting 12-lead ECG with 12 derivations recordings (filter range: 0.15–100 Hz; AC filter: 60 Hz; 25 mm/s; 10 mm/mV) were obtained and analyzed. We defined FQRS as the presence of different RSR' patterns with or without Q waves in two contiguous derivations (QRS time <120 ms): Presence of an additional R wave (R'), notching of R or S wave, or >1 R' fragmentation without typical bundle branch block. The ECG of each patient was evaluated by two independent cardiologists, who were blinded to the subject's data, with an excellent interobserver variability (k = 0.95, P < 0.001).
All individuals underwent conventional echo-Doppler examination through a standard 2-dimensional transducer device (Vingmed System Vivid 5; GE Vingmed Ultrasound, Horten, Norway); images were obtained in the left lateral decubitus position. Left atrial volume index (LAVI) and LV measurements and EF% were calculated. Pulsed-wave Doppler evaluation, from the apical four-chamber view, with the sample volume positioned at the tips of the mitral valve. Furthermore, we obtained the early (E)/late (A) ventricular filling velocity (E/A) ratio.
The tissue Doppler imaging (TDI) was activated, and images were obtained from the apical four and apical two-chamber views. The TDI sample volume was placed sequentially at septal and lateral sides of the mitral annulus (measurements were done at 50 m/s at the end of the expiration) to obtain: peak systolic myocardial velocity (S'), early diastolic velocity (e' velocity), and late diastolic myocardial velocity (a' velocity). The mean early (e') diastolic and late diastolic myocardial velocities were calculated (cm/s). Then, the average E/e' ratio (as the surrogate marker of LV filling pressure) was evaluated.
Assessment of the coronary flow reserve
With color flow mapping in a modified apical two-chamber view, the blood flow velocity in the distal portion of the left anterior descending (LAD) coronary artery at the anterior interventricular sulcus, mid- to distal-LAD coronary artery was identified using a high-frequency transducer (5–7 MHz). With a sample volume (2.5 or 3.0 mm wide) positioned on the color signal in the LAD, Doppler spectral tracings of flow velocity in the LAD were recorded. We first recorded baseline spectral Doppler signals in the LAD, then intravenous adenosine was administered (0.14 mg/kg/min) to record spectral Doppler signals during hyperemia. The coronary flow velocities were measured at baseline and peak hyperemic conditions from the Doppler signal recordings. Measurements were averaged over three cardiac cycles. CFR was calculated as the ratio of hyperemic to basal flow velocity value, and a value <2.0 were considered pathological.
Data were expressed as a mean ± standard deviation or the number (percent) of patients. Comparison between groups was performed using the unpaired t-test for continuous variables and Chi-square test for categorical variables. Spearman correlation was used for correlation analysis. Univariate regression analysis was performed to determine the association between the presence of fQRS and the following variables: fasting blood sugar, glycosylated hemoglobin, triglycerides (TG)/high-density lipoprotein-cholesterol (HDL-C) ratio, microalbuminuria, E/e', and CFR. The significant variables with univariate analysis were entered into multivariate regression analysis. A probability value of P < 0.05 was considered statistically significant. Statistically analysis was performed using version 8.0 (SAS Institute, Cary, NC, USA).
| Results|| |
Among the 129 asymptomatic patients with DM, 57% (74/129) had subclinical coronary microvascular dysfunction (CFR <2.0). Furthermore, the overall prevalence of fQRS was 62% (80/129). Demographic, clinical, and echocardiographic characteristics of the patients with and without reduced CFR are given in [Table 1]. Patients with reduced CFR had a higher prevalence of fQRS (96% vs. 16%, P < 0.001), a larger left atrium volume index (P< 0.001), a higher E/e' ratio (P< 0.001) and S wave (P< 0.001) than those without reduced CFR. The study groups were similar with respect to all other demographic, clinical, echocardiographic, and laboratory findings [Table 1]. The study cohort were also categorized based on the presence or absence of fQRS into two groups: one was fQRS (+) and the other was fQRS (−). [Table 2] shows that fQRS (+) group had an increased LAVI (P< 0.05), elevated E/e' (P< 0.01), lower S' (P< 0.01) and a significantly reduced CFR values than those without fQRS [1.6 ± 0.3 vs. 2.7 ± 0.5, P < 0.001; [Figure 1]. [Table 3] depicts the correlation analysis between fQRS and the significant univaraite difference. There was a significant inverse relationship between the number of leads with fQRS and CFR [r = -0.61, P < 0.001; [Figure 2] and average S' wave (r = −0.25, P < 0.01). Meanwhile, the number of leads with fQRS had positive correlations with E/e' (r = 0.28, P < 0.001), fasting blood glucose (r = 0.23, P < 0.05), and TG/HDL-C ratio (r = 0.35, P < 0.01).
|Table 2: Echocardiographic characteristics of asymptomatic patients with diabetes mellitus|
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|Figure 1: Coronary flow reserve in diabetic patients with fragmented QRS versus patients without fragmented QRS (1.6 ± 0.3 vs. 2.7 ± 0.5, P < 0.001)|
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|Table 3: Correlation analysis of fragmented QRS and studied variable in asymptomatic individuals with diabetes mellitus|
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|Figure 2: Correlation between the number of fragmented QRS and coronary flow reserve in patients with diabetes mellitus (r = −0.61, P < 0.001)|
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Univariate logistic regression analysis showed that the presence of fQRS (odds ratio [OR] =7.95, P < 0.001), elevated E/e' (OR = 1.65, P < 05), increased LAVI (OR = 1.83, P < 0.01), decreased S wave (OR = 1.72, P < 0.01), higher TG/HDL-C ratio (OR = 2.13, P < 0.03), higher systolic blood pressure level (OR = 1.62, P < 0.05), and increased fasting blood glucose level (OR = 2.01, P < 0.03) were associated reduced CFR in asymptomatic patients with DM. Multivariate logistic regression analysis identified the presence of fQRS on surface ECG of asymptomatic patients with type 2 DM (OR = 5.48, 95% (1.64–9.23, [P< 0.001]), as independent indicators of microvascular dysfunction (reduced CFR), [Table 4].
|Table 4: Univariate and multivariate predictors of microvascular dysfunction (coronary flow reserve <2.0) Asymptomatic patints with diabetes mellitus|
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ROC analysis demonstrated that the presence of ≥3 leads was the optimal number of leads with the highest area under the curve (AUC) to predict a CFR <2 in asymptomatic patients with DM. The sensitivity was 83% and specificity was 95% and AUC was 0.92 [Figure 3].
|Figure 3: Receiver operating characteristic curve analysis showing that the number of leads with fragmented QRS ≥3 was the optimal number for predicting microvascular dysfunction in patients with diabetes mellitus|
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| Discussion|| |
The study revealed that the prevalence of fQRS in asymptomatic participants with DM was 62%. Furthermore, we found that 57% of our cohort had microvascular dysfunction (CFR < 2). Importantly, the prevalence of fQRS was significantly higher among participants with reduced CFR compared with those normal CFR. Notably, the presence of fQRS was determined to be significantly associated with decreased CFR. Another important aspect, the presence of fQRS was correlated with E/e' ratio (a surrogate marker of LV filling and diastolic function) and LV longitudinal function. A finding indicates that fQRS might be a marker of early systolic and diastolic dysfunction in asymptomatic patients with DM. Multivariate analysis showed that fQRS is an independent predictor for reduced CFR and interestingly, ROC shows that fQRS leads ≥3 was the optimal number for predicting reduced CFR in asymptomatic patients with DM. These findings suggest that the presence of fQRS could be an easily marker of subclinical microvascular dysfunction in asymptomatic patients with DM. Therefore, we supposed that the early detection of myocardial fibrosis may be possible by screening for the presence of fQRS in the superficial ECG before the onset of clinical findings in asymptomatic patients with DM.
Many reports showed that the presence of fQRS is an independent predictor of adverse events in different cardiovascular diseases.,,, Nevertheless, its significance in asymptomatic individuals with DM is not well investigated.
Previous studies found that the presence of fQRS was an independent predictor of impaired myocardial perfusion and LV function evaluated by myocardial single-photon emission computed tomography imaging in individuals, who had coronary artery disease.,,
Both univariate and multivariate analyses demonstrated the independent relationship between CFR and the presence of fQRS on ECG in asymptomatic individuals with DM. These data obviously reveal the utility of fQRS to predict higher fibrotic burden in myocardium in asymptomatic individuals with DM.
The impaired microvascular function (reduced CFR) in patients with type 2 DM is a multifaceted phenomenon. Reduced capillary volume, fibrotic changes in small vessels, increased thickness of capillary basement membranes are important proposed structural abnormalities in small vessels. Spite of the preserved endothelium-dependent dilatation of the coronary microvasculature at the early phase of diabetes, endothelium-independent dilatation is significantly impaired due to increased oxidative stress and glycosylation end products with activation protein kinase-C could explain the impaired microvascular dysfunction in patients with DM.
Of note, we observed that the number of leads with fQRS was independently related with reduced CFR, indicating that fQRS can be used to both qualitatively and quantitatively to detect coronary microvascular dysfunction in patients with DM.
Although the underlying pathogenesis of myocardial fibrosis in DM is not clearly understood, regional myocardial ischemia due to impaired CFR and impaired myocardial metabolism may result in myocardial fibrosis.
Another aspect of the current study is the impaired LV longitudinal function (lower S wave, spite of normal EF%) and a higher E/e' ratio (diastolic dysfunction) in individuals with fQRS compared with those without fQRS. Coronary microvascular dysfunction, fibrotic burden, and consequently decreased LV compliance could explain the association between the presence of fQRS and LV dysfunction in patients with DM.
Paulus and Tschöpe supposed that a systemic proinflammatory state due to diabetes causes coronary microvascular endothelial inflammation, and this results in sequences of pathophysiological changes leads at the end to cardiomyocytes stiffness and interstitial fibrosis contribute to the development of high diastolic LV stiffness and diastolic dysfunction. Moreover, hyperglycemia per se results in cardiac remodeling due to metabolic disturbances and apoptosis of myocardial cells. These changes lead to more collagen deposition and remodeling. The cumulative effect is stiffening of myocardial cells that impair normal contractile functions.
The main limitation of the current study is the absence of confirmation of fibrosis and fibrotic burden through magnetic resonance imaging is another limitation. Furthermore, we depended on a noninvasive evaluation of the CFR using transthoracic Echo-Doppler technique. In addition, the study was conducted in a single center and the patients were highly selected.
| Conclusions|| |
The presence of fQRS on the surface ECG in asymptomatic patients with DM is associated with pronounced subclinical microvascular and LV dysfunction. These findings revealed the fQRS in the surface ECG could be considered as a simple marker for early detection of microvascular dysfunction in patients with DM.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W. Associations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease. Arch Intern Med 2007;167:1145-51.
Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, et al.
Diabetes mellitus, fasting glucose, and risk of cause-specific death. N
Engl J Med 2011;364:829-41.
Nitenberg A, Valensi P, Sachs R, Dali M, Aptecar E, Attali JR. Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function. Diabetes 1993;42:1017-25.
Nitenberg A, Paycha F, Ledoux S, Sachs R, Attali JR, Valensi P. Coronary artery responses to physiological stimuli are improved by deferoxamine but not by L-arginine in non-insulin-dependent diabetic patients with angiographically normal coronary arteries and no other risk factors. Circulation 1998;97:736-43.
Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al.
Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002;106:653-8.
Marwick TH. Diabetic heart disease. Heart 2006;92:296-300.
Galderisi M. Diastolic dysfunction and diabetic cardiomyopathy: Evaluation by Doppler echocardiography. J Am Coll Cardiol 2006;48:1548-51.
Das MK, Saha C, El Masry H, Peng J, Dandamudi G, Mahenthiran J, et al.
Fragmented QRS on a 12-lead ECG: A predictor of mortality and cardiac events in patients with coronary artery disease. Heart Rhythm 2007;4:1385-92.
Jain R, Singh R, Yamini S, Das MK. Fragmented ECG as a risk marker in cardiovascular diseases. Curr Cardiol Rev 2014;10:277-86.
Tanriverdi Z, Dursun H, Colluoglu T, Kaya D. Single derivation fragmented QRS can predict poor prognosis in successfully revascularized acute STEMI patients. Arq Bras Cardiol 2017;109:213-21.
Park SJ, On YK, Kim JS, Park SW, Yang JH, Jun TG, et al.
Relation of fragmented QRS complex to right ventricular fibrosis detected by late gadolinium enhancement cardiac magnetic resonance in adults with repaired tetralogy of fallot. Am J Cardiol 2012;109:110-5.
Liang D, Zhang J, Lin L, Zong W. The difference on features of fragmented QRS complex and influences on mortality in patients with acute coronary syndrome. Acta Cardiol Sin 2017;33:588-95.
Das MK, Zipes DP. Fragmented QRS: A predictor of mortality and sudden cardiac death. Heart Rhythm 2009;6:S8-14.
Sicari R, Rigo F, Cortigiani L, Gherardi S, Galderisi M, Picano E. Additive prognostic value of coronary flow reserve in patients with chest pain syndrome and normal or near-normal coronary arteries. Am J Cardiol 2009;103:626-31.
Cetin MS, Ozcan Cetin EH, Canpolat U, Cay S, Topaloglu S, Temizhan A, et al.
Usefulness of fragmented QRS complex to predict arrhythmic events and cardiovascular mortality in patients with noncompaction cardiomyopathy. Am J Cardiol 2016;117:1516-23.
Das MK, Maskoun W, Shen C, Michael MA, Suradi H, Desai M, et al.
Fragmented QRS on twelve-lead electrocardiogram predicts arrhythmic events in patients with ischemic and nonischemic cardiomyopathy. Heart Rhythm 2010;7:74-80.
Michael MA, El Masry H, Khan BR, Das MK. Electrocardiographic signs of remote myocardial infarction. Prog Cardiovasc Dis 2007;50:198-208.
Mahenthiran J, Khan BR, Sawada SG, Das MK. Fragmented QRS complexes not typical of a bundle branch block: A marker of greater myocardial perfusion tomography abnormalities in coronary artery disease. J Nucl Cardiol 2007;14:347-53.
Lee BK, Lim HS, Fearon WF, Yong AS, Yamada R, Tanaka S, et al.
Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease. Circulation 2015;131:1054-60.
Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications. Endocr Rev 2004;25:543-67.
Mourmoura E, Vial G, Laillet B, Rigaudière JP, Hininger-Favier I, Dubouchaud H, et al.
Preserved endothelium-dependent dilatation of the coronary microvasculature at the early phase of diabetes mellitus despite the increased oxidative stress and depressed cardiac mechanical function ex vivo
. Cardiovasc Diabetol 2013;12:49.
Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013;62:263-71.
Konno T, Chen D, Wang L, Wakimoto H, Teekakirikul P, Nayor M, et al.
Heterogeneous myocyte enhancer factor-2 (Mef2) activation in myocytes predicts focal scarring in hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A 2010;107:18097-102.
Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy: Pathophysiology and clinical features. Heart Fail Rev 2013;18:149-66.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]