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The relationship between right ventricular deformation and heart rate variability in asymptomatic diabetic patients
The relationship between right ventricular deformation and heart rate variability in asymptomatic diabetic patients Marijana Tadic, Vladan Vukomanovic, Cesare Cuspidi, Jelena SuzicLazic, Biljana Pencic-Popovic, Jana Radojkovic, Rade Babic, Vera Celic PII: DOI: Reference:
S1056-8727(17)30113-7 doi: 10.1016/j.jdiacomp.2017.04.007 JDC 7004
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
19 January 2017 26 March 2017 8 April 2017
Please cite this article as: Tadic, M., Vukomanovic, V., Cuspidi, C., Suzic-Lazic, J., Pencic-Popovic, B., Radojkovic, J., Babic, R. & Celic, V., The relationship between right ventricular deformation and heart rate variability in asymptomatic diabetic patients, Journal of Diabetes and Its Complications (2017), doi: 10.1016/j.jdiacomp.2017.04.007
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The relationship between right ventricular deformation and heart rate variability
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& - These authors contributed equally.
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Marijana Tadic, MD, PhD †& Vladan Vukomanovic, MD †& Prof. Cesare Cuspidi, MD * Jelena Suzic-Lazic, MD † Biljana Pencic-Popovic, MD, PhD † Jana Radojkovic, MD † Prof. Rade Babic, MD, PhD Assoc. Prof. Vera Celic, MD, PhD †
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in asymptomatic diabetic patients
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† University Clinical Hospital Center “Dr. Dragisa Misovic - Dedinje” Department of Cardiology Heroja Milana Tepica 1 11000 Belgrade, Serbia * University of Milan-Bicocca and Istituto Auxologico Italiano, Clinical Research Unit Viale della Resistenza 23, 20036 Meda, Italy
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Institute of Cardiovascular Diseases Dedinje Department of Cardiology Heroja Milana Tepica 1 11000 Belgrade, Serbia Potential conflict of interest: NONE
Corresponding author: Marijana Tadic, MD, PhD University Clinical Hospital Center “Dr. Dragisa Misovic - Dedinje” Department of Cardiology Heroja Milana Tepica 1 11000 Belgrade, Serbia e-mail: [email protected]
Running title: Heart rate variability, right ventricle and diabetes
ACCEPTED MANUSCRIPT Abstract Objective: To investigate heart rate variability (HRV) and right ventricular (RV)
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remodeling in asymptomatic diabetic patients, as well as the relationship between HRV indices and RV structure, function and deformation.
Method: This cross-sectional study included 59 asymptomatic patients with type 2
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diabetes and 45 healthy controls without cardiovascular risk factors. All study subjects underwent 24-h Holter monitoring, laboratory analyses and complete two-
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dimensional echocardiography examination (2DE).
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Results: RV diastolic function and longitudinal deformation were significantly impaired in diabetic individuals comparing with controls. RV global longitudinal
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strain and layer-specific longitudinal strains were significantly decreased in diabetic group. The same trend of changes in RV deformation was observed for global RV and lateral wall. All parameters of time and frequency domain of HRV were reduced in diabetic subjects. RV endocardial longitudinal strain together with LV mass index,
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mitral E/e’ ratio and HbA1c correlated with HRV parameters. However, multivariate
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linear regression analysis showed that only RV endocardial longitudinal strain and LV mass index are associated with HRV parameters independently of age, BMI, HbA1c, RV free wall thickness and pulmonary artery pressure. Conclusions: RV subendocardial strain is independently associated with HRV parameters in the whole study population. This reveals potentially important role of determination of layer-specific RV longitudinal function as important marker of preclinical cardiac damage, but also indirectly show the impairment of cardiac autonomic function in diabetic patients. Key words: diabetes, right ventricle, heart rate variability, strain.
ACCEPTED MANUSCRIPT HbA1c – glycolised hemoglobin HRV – heart rate variability
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LV – left ventricle
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RV – right ventricle
ACCEPTED MANUSCRIPT Introduction Impairment in glucose homeostasis, primarily insulin resistance, is
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significantly associated with the dysfunction of autonomic nervous system assessed by heart rate variability (HRV) /1,2/. In individuals with diabetes this association is even more evident /3/. Investigations showed that sympathetic and parasympathetic
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components of autonomic nervous system are significantly reduced in diabetic patients /4,5/. However, there are also studies that revealed reduction in the
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parasympathetic and increment in sympathetic component /2/.
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Previous analyses showed association between left ventricular structural and functional remodeling and cardiac autonomic neuropathy in diabetic patients /6,7/. On
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the other hand, the studies that investigate the association between HRV and right ventricular (RV) remodeling are still lacking. Our study group previously showed that RV structure, function and mechanics have been significantly impacted by prediabetes and diabetes /8/, but the cardiac autonomic function has not been explored
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in diabetic patients.
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The introduction of speckle tracking analysis provided the accurate insight in cardiac mechanics, which has several important advantages over conventional tissue Doppler imaging: evaluation of mechanics in the whole myocardial thickness, angle independence, significantly less load dependence. Multilayer strain provides the information of each of three myocardial layers (endocardial, mid-myocardial and epicardial) with potentially higher predictive value than conventional global strain. The rational of layer-specific evaluation in the present study is to detect myocardial changes in asymptomatic and normotensive diabetic patients as early as possible.
ACCEPTED MANUSCRIPT HRV is an indirect measure of autonomic nervous function and it was proved to be good independent predictors of cardio- and cerebrovascular morbidity and
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mortality in diabetic patients /9,10/. RV remodeling also has an important role in the prediction of cardiovascular outcomes in various groups of patients, including even general population /11-13/. However, so far there are no data regarding the influence
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of RV dysfunction on morbidity and mortality in diabetic population.
The aim of this study was to evaluate HRV and RV structure, function and
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mechanics in uncomplicated and asymptomatic diabetic patients. Furthermore, the
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relationship between cardiac autonomic system changes assessed by HRV and RV remodeling in this population of patients was also investigated.
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Methodology
This cross-sectional study involved 59 normotensive uncomplicated patients with type 2 diabetes and 45 normotensive subjects free of cardiovascular diseases. The diagnosis of diabetes was based on the current recommendations /14/. Diabetes
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was defined if the blood glucose level was ≥ 7mmol/l and HbA1c ≥ 6.5% or usage of
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antidiabetic treatment /14/. Exclusion criteria were arterial hypertension, antihypertensive treatment, heart
failure, coronary artery disease, previous cerebrovascular events, atrial fibrillation, congenital heart disease, more than mild valve heart disease, obesity (BMI ≥ 35 kg/m2), neoplastic disease, cirrhosis of the liver or kidney failure. Clinic BP values were obtained in two separate visits three weeks apart. BP was measured by aneroid sphygmomanometer in the morning hours by taking the average value of two consecutive measurements in the sitting position 10 minutes apart. BP was calculated as average values between all measurements.
ACCEPTED MANUSCRIPT Anthropometric measures (height, weight) and laboratory analyses (level of fasting glucose, blood creatinine and urea, total cholesterol and triglycerides) were
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obtained from all the subjects included in the study. Body mass index and body surface were calculated for each patient. The study was approved by the local Ethics Committee, and informed consent was obtained from all the participants.
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24-hour Holter monitoring
24-hour Holter monitoring was performed the three-channel digital Schiller
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Microvit MT-101 system (Schiller AG, Baar, Switzerland) and analyzed by the
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Schiller software (Schiller AG, Baar, Switzerland). The minimum duration of recording was 18 hours (after exclusion of non-sinusal cardiac cycles). Time-domain
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HRV parameters were calculated on the 24-hour, daytime and nighttime recordings after excluding non-sinusal cardiac cycles, according to guidelines /15/. SDNN was defined as the standard deviation of all normal RR intervals. SDANN, which reflects long-term HRV and therefore mainly sympathetic activity or sympathovagal balance,
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was defined as the standard deviation of the averaged normal RR intervals for all 5-
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min segments. rMSSD was calculated as the root mean square of the difference between the coupling intervals of adjacent RR intervals. pNN50 which reflects shortterm beat-to-beat HRV and consequently primarily vagal activity was calculated as the proportion of adjacent RR intervals that varied by more than 50 ms. After power spectral density estimation, standard frequency-domain HRV measures were calculated for 24-hour, daytime and nighttime /15/. Low frequency domain (LF) was defined between 0.04 and 0.15 Hz; high frequency domain (HF) was defined between 0.15 and 0.4 Hz; total spectral power (TP) for all intervals up to 0.4 Hz; and ratio of low to high frequency power (LF/HF).
ACCEPTED MANUSCRIPT Echocardiography Echocardiographic examinations were performed by using a commercially
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available Vivid 7 (GE Vingmed, Horten, Norway). Reported values of all 2DE parameters were obtained as the average value of 3 consecutive cardiac cycles. LV diameters, posterior wall and septum thickness, were
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measured according to the current recommendations /16/. Relative wall thickness was calculated according to formula. LV ejection fraction (EF) was calculated by using
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the biplane method. LV mass was calculated by using the Devereux formula /16/, and
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indexed for the height powered to 2.7. However, LV mass was also assessed by ASE formula and indexed for body surface area /17/. Left atrial maximal volume was
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obtained in the 4-chamber view during ventricular end-systole and indexed for BSA. Pulsed-wave Doppler assessment of transmitral LV was obtained in the apical 4-chamber view according to the guidelines /18/. Tissue Doppler imaging was used to obtain LV myocardial velocities in the apical 4-chamber view, with a sample volume
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placed at the septal and lateral segments of the mitral annulus during early diastole
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(e´). The average of the peak early diastolic relaxation velocity (e´) of the septal and lateral mitral annulus was calculated, and the E/e´ ratio was computed. The RV basal diameter was measured in the apical four-chamber view /19/.
RV thickness was measured in the subcostal view /19/. RV global systolic function was assessed as the tricuspid annular plane systolic excursion (TAPSE). Right atrial maximal volume was obtained in the 4-chamber view during ventricular end-systole and indexed for BSA. Tricuspid inflow (E) and tissue Doppler velocities (e’t, st) were evaluated in the apical 4-chamber view /19/, and E/e’t ratio was calculated. Systolic pulmonary artery pressure (PASP) was assessed in the patients with minimal/mild tricuspid regurgitation in any available echocardiographic view that
ACCEPTED MANUSCRIPT could provide adequate Doppler signal for PASP calculation (39 controls and 50 patients with diabetes).
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Two-dimensional right ventricular strain 2DE strain imaging was performed by using 3 consecutive cardiac cycles of 2DE images in the apical 4-chamber view. EchoPAC 2.01 (GE-Healthcare, Horten,
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Norway), as a commercially available software, was used for the 2DE strain analysis.
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The global longitudinal strain for the RV lateral wall and global RV were determined separately.
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Multilayer longitudinal strain was determined by modified 2DE strain software. The modified 2DE strain speckle tracking includes the delineation of the
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endocardial border, similarly to traditional 2DE strain, but instead of a single chain of nodes, the myocardial wall is automatically defined with multiple chains of nodes, allowing investigation of 3 myocardial layers: endocardial, mid-myocardial and
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epicardial.
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Statistical analysis Continuous variables were presented as mean ± standard error (SE), and the
Student t-test was used to detect differences between the two groups for the variables that showed normal distribution. Differences in proportions were compared by using the χ². Pearson´s correlation coefficients were used for determining the correlation between different demographic and echocardiographic parameters and HRV parameters. Almost all HRV parameters, except SDNN and SDANN, were transformed by natural logarithm, before using of t-test or linear regressions because of their high positive skewed distribution. The variables which showed p-value ≤0.10 were included into the stepwise multiple regression analyses. PASP was not included
ACCEPTED MANUSCRIPT in the multivariate analysis because there was no difference in PASP between the observed groups. The p-value <0.05 was considered statistically significant.
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Results The gender distribution and blood pressure values were similar between the observed groups, whereas BMI and BSA were significantly higher in diabetics (Table
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1). Blood levels of glucose and HbA1c were higher in diabetic patients, which was expected considering the inclusion criteria. Triglycerides and urea levels were higher
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in diabetic patients (Table 1).
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Patients with diabetes used antidiabetic treatment in 73% (64% patients were treated with medications and 17% were treated with insulin). Among diabetic patients
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34% were treated with statins. 24-hour Holter monitoring
Heart rates during 24 hours and day were similar between the observed groups
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(Table 2). Nighttime heart rate was higher in diabetic patients than in controls (Table 2). SDNN, SDANN, rMSSD and p50NN were significantly lower in diabetic patients.
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24-h, daytime and nighttime LF, HF and TP were significantly lower in diabetic group than in controls (Table 2, Figure 1). Echocardiographic parameters LV diameters and ejection fraction are similar between groups (Table 3). All parameters of LV hypertrophy: interventricular septum thickness, posterior wall thickness, relative wall thickness and LV mass indexes were significantly higher in diabetic patients (Table 3). LA volume index was also higher in diabetic group. Parameters of LV diastolic function and LV diastolic filling (transmitral E/A and E/e’) were deteriorated in diabetic patients comparing with controls.
ACCEPTED MANUSCRIPT 2DE strain analysis All differences in mechanical parameters between the observed groups were
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adjusted for age, BMI and triglycerides level. The 2DE analysis of the RV global and RV free wall deformation showed that 2DE global longitudinal RV function was lower in diabetic patients than in controls (Table 4).
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RV global longitudinal layer specific strains (endo-, mid- and epicardial) were
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lower in diabetic patients than in controls (Table 4, Figure 2). The same results were obtained for layer specific strains of RV free wall (Table 4).
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Correlation and multivariate regression analysis In univariate correlation analysis 24-h LF correlated with age, HbA1c, LV
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mass index, mitral E/e’ ratio and RV endocardial longitudinal strain. However, in multivariate regression analysis, only HbA1c (β=-0.278, p<0.001), LV mass index (β=-0.159, p=0.047) and RV endocardial longitudinal strain (β=0.193, p=0.008) were
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independent predictors of 24-h LF (Table 5). 24-h HF correlated with HbA1c, LV mass index and RV endocardial
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longitudinal strain. However, only HbA1c (β=-0.179, p=0.035) and RV endocardial longitudinal strain (β=-0.167, p=0.041) were independently associated with 24-h HF (Table 5).
Discussion Several findings of the present investigation deserve further discussion. The results show that global longitudinal strain, as well as layer-specific RV strain is significantly impacted by diabetes, which is new finding. Additionally, the current results showed that cardiac autonomic system assessed by HRV is significantly reduced in diabetic patients, which is concurrent with previous studies, but the investigation revealed that HRV indices correlated with RV longitudinal deformation
ACCEPTED MANUSCRIPT irrespective of LV and RV structure and diastolic function, which has not investigated so far.
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The number of studies that investigated RV structure and function in diabetic population is scarce /20-22/, and research that involves determination of RV mechanics is even more limited /8,23/. The current results confirm previous findings
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regarding impaired RV diastolic function and longitudinal strain in diabetic population /20-23/. However, this investigation went one step further and evaluated
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layer-specific strain in these patients. The rising question is why multilayer strain is
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important and could it provide the additional information about early cardiac remodeling and does it have prognostic value in diabetic patients.
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Recent study showed that LV longitudinal strain was independently associated with cardiovascular events in patients with diabetes type 2, but without history of cardiovascular complications /24/. On the other side, Lee et al. revealed that layerspecific longitudinal LV strain, particularly epicardial, was the only independent
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prognostic factor in regularly-treated hypertensive patients /25/. Data regarding
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prognostic value of RV mechanics in diabetic population are still lacking. However, there are evidence that diabetes impacts RV function and mechanics /8,23,26,27/, as well as RV layer-specific longitudinal strain /28/. Furthermore, RV global longitudinal strain has also been recognized as independent predictor of cardiovascular morbidity and mortality in wide range of pathological conditions /11,12/. Therefore, it is quite reasonable to hypothesize that RV global and layerspecific strain are important predictors of cardiovascular morbidity and mortality in diabetic population. The present analysis confirmed that RV diastolic function, RV global longitudinal strain, as well as longitudinal strain of all RV myocardial layers
ACCEPTED MANUSCRIPT (endocardial, mid-myocardial and epicardial), are significantly impaired in asymptomatic diabetic patients. In this study was also demonstrated that all changes
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in RV free wall and septal mechanics occur in parallel, which is believed to represent a very important finding because it shows that diabetes impacts RV independently of LV and interventricular septum. Interestingly, this difference maintain even if there
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was no significant alteration in RV wall thickness between controls and diabetic
functional and mechanical impairments.
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patients. These results imply that RV structural changes occur significantly after
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The current study revealed that cardiac autonomic function is depressed in diabetic patients. The results showed that both, sympathetic and parasympathetic
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autonomic function activities, are significantly reduced in diabetic population, which agree with some previous findings /4,5/, but not with all of them /2/. What is more interesting, HRV indices are associated with RV endocardial longitudinal strain independently of LV and RV structure and diastolic function.
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Impaired RV function and mechanics, as well as deteriorated cardiac
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autonomic nervous system, could be explained by increased oxidative stress, endothelial dysfunction, increase inflammation, micro- and macro-vascular changes /29/. All these changes induce myocardial interstitial fibrosis that further could initiate deterioration of RV function and mechanics. The changes in pulmonary circulation and retrograde transmission of increased LV filling pressure on the RV should not be forgotten. A related animal study tested a model of streptozocin-induced diabetic rat heart with dual scintigraphy using thulium for evaluation of myocardial perfusion and MIBG (Metaiodobenzylguanidine) for the assessment of sympathetic nerve activity /30/. The authors reported regional differences in MIBG scan even though no regional difference in thulium scan was noticed /30/. This implicates the existence of regional
ACCEPTED MANUSCRIPT inhomogeneity in sympathetic imbalance in diabetic rat heart /30/. Howarth et al. reported that action potential durations (APD) of right atrium and right ventricle in
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streptozocin-induced diabetic rat were more prolonged than in control rats, while there were no changes of APD detected in left atrium and left ventricle /31/. This finding suggest that regional variability in APD in right-sided heart may cause
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contraction in this specific diabetic rat heart.
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electrical conduction disturbances leading to imbalanced activity of myocardial
The present study has several clinical implications: first, evaluation of global
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and layer-specific longitudinal RV strain, as well as assessment of HRV, could be effective methods in demonstrating subtle changes in diabetic patients as indicators of
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preclinical cardiac damage; second, RV strain and HRV could be used in follow-up these patients; third, our study showed that predominantly endocardial longitudinal RV strain was associated with HRV parameters. This indicates that muscle
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arrangement of endocardial layer in the RV is dominated by autonomic nervous system that could be susceptible to the deterioration caused by poor glycemic control.
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Myocytes are predominantly oriented in the longitudinal direction in the subendocardial layer /32,33/. Circumferentially oriented myocytes are found in the thinner sub-epicardium. Consequently, the RV contraction pattern is predominantly longitudinal /34,35/, which could explain the association between HRV indices and RV longitudinal strain. LV remodeling could be partly responsible for the relationship between RV and HRV in diabetic patients. However, multivariate models that included parameters of LV structure and diastolic function showed that RV endocardial longitudinal strain was associated with HRV indices irrespective of LV mass index and mitral E/e’ ratio.
ACCEPTED MANUSCRIPT Limitations The present study has several limitations. All patients with comorbidities were
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excluded, which decreases potential generalization of the obtained results. However, this represents also strength of the current study because the majority of studies were performed in patients with other comorbidities. HRV is indirect measurement of
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autonomic nervous system and could be a weaker predictor of the sympathovagal imbalance than direct measurements such as muscle sympathetic nerve activity. The
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cross-sectional nature of this study does not allow evaluation of causal relationship
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between diabetes, HRV and RV remodeling. Conclusion
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The present investigation showed that autonomic nervous function and RV function and mechanics are significantly deteriorated in asymptomatic diabetic individuals. The current findings revealed a significant relationship between HRV
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indices and RV layer-specific longitudinal strain, which could partially explain increase cardiovascular morbidity and mortality in this population. Future
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longitudinal investigations are needed to investigate a long-term prognostic importance of the interaction between HRV and RV remodeling on cardiovascular morbidity and mortality in diabetic patients.
Key points:
Right ventricular mechanics is deteriorated in patients with diabetes.
Longitudinal right ventricular strain is impaired in all three myocardial layers.
Autonomic nervous system is related with right ventricular remodeling in diabetic population.
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Figure 1
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Figure 2
ACCEPTED MANUSCRIPT Table 1. Demographic characteristics and clinical parameters of study population.
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Diabetes (n=59) 54 ± 1 28 (47) 29.3 ± 0.4 2.06 ± 0.03 131 ± 1 81 ± 7 5 ± 0.4 43 (73) 38 (64) 10 (17) 20 (34) 7.9 ± 0.2 7.5 ± 0.2 73 ± 2 6.2 ± 0.2 2.3 ± 0.1 5.6 ± 0.1
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Age (years) Female (%) BMI (kg/m2) BSA (m2) Clinic systolic BP (mmHg) Clinic diastolic BP (mmHg) Diabetes duration (years) Antidiabetic treatment (%) Medicament (%) Insulin (%) Statins (%) Plasma glucose (mmol/l) HbA1c (%) Creatinine (mmol/l) Urea (mmol/l) Triglycerides (mmol/l) Total cholesterol (mmol/l)
Controls (n=45) 49 ± 1.3 21 (47) 24.3 ± 0.4 1.83 ± 0.03 128 ± 1 79 ± 1 5.2 ± 0.1 5.0 ± 0.1 69 ± 2 5.3 ± 0.2 1.8 ± 0.1 5.8 ± 0.2
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BMI- body mass index, BP- blood pressure, BSA- body surface area.
p 0.004 1.000 <0.001 <0.001 0.076 0.152 <0.001 <0.001 0.165 0.008 <0.001 0.335
ACCEPTED MANUSCRIPT Table 2. Heart rate variability parameters in the study population (adjusted for age and BMI). Diabetes (n=59) 78 ± 1 81 ± 1.2 72 ± 0.9 125 ± 5 114 ± 5 3.1 ± 0.04 1.3 ± 0.1 6.1 ± 0.1 6.3 ± 0.1 5.8 ± 0.1 5.0 ± 0.1 4.5 ± 0.1 5.2 ± 0.1 7.1 ± 0.1 7.0 ± 0.1 7.3 ± 0.1
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24-h heart rate (beats/min) Daytime heart rate (beats/min) Nighttime heart rate (beats/min) SDNN (ms) SDANN (ms) Ln rMSSD (ms) Ln p50NN (%) Ln 24-h LF (ms2) Ln Daytime LF (ms2) Ln Nighttime LF (ms2) Ln 24-h HF (ms2) Ln Daytime HF (ms2) Ln Nighttime HF (ms2) Ln 24-h TP (ms2) Ln Daytime TP (ms2) Ln Nighttime TP (ms2)
Controls (n=45) 76 ± 1 83 ± 1.3 63 ± 0.9 150 ± 6 135 ± 8 3.4 ± 0.04 2.0 ± 0.1 6.6 ± 0.1 7.0 ± 0.1 6.5 ± 0.1 5.5 ± 0.1 5.1 ± 0.1 5.7 ± 0.1 8.1 ± 0.1 8.0 ± 0.1 8.2 ± 0.1
p 0.188 0.271 <0.001 0.003 0.022 <0.001 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 0.001 <0.001 <0.001 <0.001
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HF- high-frequency domain (0.15-0.40 Hz), LF- low-frequency domain (0.04-0.15 Hz), NS- no statistical diference, p50NN- percentage of adjacent R-R intervals that varied by more than 50 ms, rMSSD- root mean square of the difference between the coupling intervals of adjacent R-R intervals, SDANNstandard deviation of the averaged normal RR intervals for all 5-min segments, SDNN- standard deviation of all normal RR intervals, TP- total power (0.01-0.40 Hz).
ACCEPTED MANUSCRIPT Table 3. Echocardiographic parameters of study population (adjusted for age and BMI).
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Diabetes (n=59) 50.3 ± 0.5 10.3 ± 0.2 9.8 ± 0.1 0.39 ± 0.005 89.4 ± 1.4 49.2 ± 1.1 63 ± 1 29.8 ± 0.5 0.72 ± 0.04 11.1 ± 0.4
0.121 <0.001 <0.001 <0.001 0.008 <0.001 0.281 0.004 <0.001 <0.001
32.7 ± 0.5 4.2 ± 0.1 22.0 ± 0.5 26.2 ± 0.5 5.4 ± 0.2 12.0 ± 0.4 27.0 ± 0.9
0.718 0.135 0.998 0.003 0.001 0.996 0.002
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32.4 ± 0.6 4.0 ± 0.1 22.0 ± 0.4 23.7 ± 0.5 4.5 ± 0.2 12.0 ± 0.4 24.0 ± 0.6
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Right ventricular parameters RV basal diameter (mm) RV thickness (mm) TAPSE (mm) RA volume index (ml/m2) Tricuspid E/e´ ratio s’ (cm/s) PASP (mmHg)
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LV end-diastolic diameter (mm) Interventricular septum thickness (mm) Posterior wall thickness (mm) Relative wall thickness LVMI (g/m2) LVM/Ht2.7 (g/m2.7) EF (%) LA volume index (ml/m2) E/A ratio Mitral E/e´ ratio
Controls (n=45) 49.0 ± 0.6 9.2 ± 0.2 8.8 ± 0.1 0.36 ± 0.004 83.6 ± 1.3 40.9 ± 1.0 64 ± 1 27.5 ± 0.5 1.14 ± 0.04 8.1 ± 0.3
p
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A- late diastolic mitral flow (pulse Doppler), DT – deceleration time, E- early diastolic mitral/tricuspid flow (pulse Doppler), e´- peak early diastolic relaxation velocity (e´) of the septal and lateral mitral annulus (tissue Doppler) or lateral tricuspid annulus, EF-ejection fraction, Ht-height, IVS-interventricular septum, LA-left atrium, LV- left ventricle, LVM-left ventricle mass, PASP- pulmonary artery systolic pressure, RA – right atrium, RV – right ventricle, s’- peak systolic velocity of the lateral tricuspid annulus assessed by tissue Doppler, TAPSE – tricuspid annular plane systolic excursion.
ACCEPTED MANUSCRIPT Table 4. 2DE speckle tracking assessment of the right ventricular function in the study population (adjusted for age and BMI).
Two-dimensional mechanical parameters Longitudinal RV strain (%) Global RV Lateral wall
-25.8 ± 0.5 -29.1 ± 0.6
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Longitudinal global RV strain (%) Endocardial -28.8 ± 0.6 Mid-myocardial -25.7 ± 0.5 Epicardial -22.9 ± 0.4 Longitudinal lateral wall RV strain (%) Endocardial -31.6 ± 0.6 Mid-myocardial -29.2 ± 0.5 Epicardial -26.6 ± 0.5
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RV – right ventricle
-23.7 ± 0.4 -26.8 ± 0.4
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Two-dimensional multilayer strain
Diabetes (n=59)
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Controls (n=45)
p
0.001 0.002
-26.4 ± 0.5 -23.8 ± 0.4 -21.0 ± 0.3
0.003 0.001 <0.001
-29.3 ± 0.5 -26.6 ± 0.4 -24.4 ± 0.4
0.007 <0.001 <0.001
ACCEPTED MANUSCRIPT Table 5. Association between clinical, two-dimensional right ventricular parameters and heart rate variability indices. Ln 24-h LF (ms2)
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0.42
0.33
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Age (years) BMI (kg/m2) HbA1c (%) LV mass index (g/m2.7) Mitral E/e´ ratio RV wall thickness (mm) Tricuspid E/e’ ratio PASP (mmHg) RV endocardial longitudinal strain (%) r2
r -0.168† -0.133 -0.341‡ -0.281‡ -0.305‡ -0.113 -0.094 -0.064 0.289‡
Multivariate Multivariate Correlation regression* regression* β r β -0.088 -0.112 -0.093 -0.278‡ -0.203‡ -0.105 -0.159† -0.237‡ -0.179† -0.097 -0.133 -0.071 -0.074 -0.109 -0.080 -0.092 0.073 0.193‡ 0.244‡ 0.167†
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Correlation
Ln 24-h HF (ms2)
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BMI- body mass index, HF- high-frequency domain (0.15-0.40 Hz), E- early diastolic mitral flow (pulse Doppler), e´- average of the peak early diastolic relaxation velocity (e´) of the septal and lateral mitral annulus (tissue Doppler), LF- low-frequency domain (0.04-0.15 Hz), LV- left ventricle, RV – right ventricle, PASP- pulmonary artery systolic pressure, †- p<0.05, ‡- p<0.01, *PASP was not included in the multivariate analysis because there was no difference between the observed groups.
27
S1056-8727(17)30113-7 doi: 10.1016/j.jdiacomp.2017.04.007 JDC 7004
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
19 January 2017 26 March 2017 8 April 2017
Please cite this article as: Tadic, M., Vukomanovic, V., Cuspidi, C., Suzic-Lazic, J., Pencic-Popovic, B., Radojkovic, J., Babic, R. & Celic, V., The relationship between right ventricular deformation and heart rate variability in asymptomatic diabetic patients, Journal of Diabetes and Its Complications (2017), doi: 10.1016/j.jdiacomp.2017.04.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
The relationship between right ventricular deformation and heart rate variability
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& - These authors contributed equally.
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Marijana Tadic, MD, PhD †& Vladan Vukomanovic, MD †& Prof. Cesare Cuspidi, MD * Jelena Suzic-Lazic, MD † Biljana Pencic-Popovic, MD, PhD † Jana Radojkovic, MD † Prof. Rade Babic, MD, PhD Assoc. Prof. Vera Celic, MD, PhD †
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in asymptomatic diabetic patients
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† University Clinical Hospital Center “Dr. Dragisa Misovic - Dedinje” Department of Cardiology Heroja Milana Tepica 1 11000 Belgrade, Serbia * University of Milan-Bicocca and Istituto Auxologico Italiano, Clinical Research Unit Viale della Resistenza 23, 20036 Meda, Italy
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Institute of Cardiovascular Diseases Dedinje Department of Cardiology Heroja Milana Tepica 1 11000 Belgrade, Serbia Potential conflict of interest: NONE
Corresponding author: Marijana Tadic, MD, PhD University Clinical Hospital Center “Dr. Dragisa Misovic - Dedinje” Department of Cardiology Heroja Milana Tepica 1 11000 Belgrade, Serbia e-mail: [email protected]
Running title: Heart rate variability, right ventricle and diabetes
ACCEPTED MANUSCRIPT Abstract Objective: To investigate heart rate variability (HRV) and right ventricular (RV)
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remodeling in asymptomatic diabetic patients, as well as the relationship between HRV indices and RV structure, function and deformation.
Method: This cross-sectional study included 59 asymptomatic patients with type 2
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diabetes and 45 healthy controls without cardiovascular risk factors. All study subjects underwent 24-h Holter monitoring, laboratory analyses and complete two-
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dimensional echocardiography examination (2DE).
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Results: RV diastolic function and longitudinal deformation were significantly impaired in diabetic individuals comparing with controls. RV global longitudinal
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strain and layer-specific longitudinal strains were significantly decreased in diabetic group. The same trend of changes in RV deformation was observed for global RV and lateral wall. All parameters of time and frequency domain of HRV were reduced in diabetic subjects. RV endocardial longitudinal strain together with LV mass index,
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mitral E/e’ ratio and HbA1c correlated with HRV parameters. However, multivariate
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linear regression analysis showed that only RV endocardial longitudinal strain and LV mass index are associated with HRV parameters independently of age, BMI, HbA1c, RV free wall thickness and pulmonary artery pressure. Conclusions: RV subendocardial strain is independently associated with HRV parameters in the whole study population. This reveals potentially important role of determination of layer-specific RV longitudinal function as important marker of preclinical cardiac damage, but also indirectly show the impairment of cardiac autonomic function in diabetic patients. Key words: diabetes, right ventricle, heart rate variability, strain.
ACCEPTED MANUSCRIPT HbA1c – glycolised hemoglobin HRV – heart rate variability
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LV – left ventricle
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RV – right ventricle
ACCEPTED MANUSCRIPT Introduction Impairment in glucose homeostasis, primarily insulin resistance, is
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significantly associated with the dysfunction of autonomic nervous system assessed by heart rate variability (HRV) /1,2/. In individuals with diabetes this association is even more evident /3/. Investigations showed that sympathetic and parasympathetic
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components of autonomic nervous system are significantly reduced in diabetic patients /4,5/. However, there are also studies that revealed reduction in the
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parasympathetic and increment in sympathetic component /2/.
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Previous analyses showed association between left ventricular structural and functional remodeling and cardiac autonomic neuropathy in diabetic patients /6,7/. On
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the other hand, the studies that investigate the association between HRV and right ventricular (RV) remodeling are still lacking. Our study group previously showed that RV structure, function and mechanics have been significantly impacted by prediabetes and diabetes /8/, but the cardiac autonomic function has not been explored
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in diabetic patients.
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The introduction of speckle tracking analysis provided the accurate insight in cardiac mechanics, which has several important advantages over conventional tissue Doppler imaging: evaluation of mechanics in the whole myocardial thickness, angle independence, significantly less load dependence. Multilayer strain provides the information of each of three myocardial layers (endocardial, mid-myocardial and epicardial) with potentially higher predictive value than conventional global strain. The rational of layer-specific evaluation in the present study is to detect myocardial changes in asymptomatic and normotensive diabetic patients as early as possible.
ACCEPTED MANUSCRIPT HRV is an indirect measure of autonomic nervous function and it was proved to be good independent predictors of cardio- and cerebrovascular morbidity and
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mortality in diabetic patients /9,10/. RV remodeling also has an important role in the prediction of cardiovascular outcomes in various groups of patients, including even general population /11-13/. However, so far there are no data regarding the influence
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of RV dysfunction on morbidity and mortality in diabetic population.
The aim of this study was to evaluate HRV and RV structure, function and
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mechanics in uncomplicated and asymptomatic diabetic patients. Furthermore, the
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relationship between cardiac autonomic system changes assessed by HRV and RV remodeling in this population of patients was also investigated.
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Methodology
This cross-sectional study involved 59 normotensive uncomplicated patients with type 2 diabetes and 45 normotensive subjects free of cardiovascular diseases. The diagnosis of diabetes was based on the current recommendations /14/. Diabetes
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was defined if the blood glucose level was ≥ 7mmol/l and HbA1c ≥ 6.5% or usage of
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antidiabetic treatment /14/. Exclusion criteria were arterial hypertension, antihypertensive treatment, heart
failure, coronary artery disease, previous cerebrovascular events, atrial fibrillation, congenital heart disease, more than mild valve heart disease, obesity (BMI ≥ 35 kg/m2), neoplastic disease, cirrhosis of the liver or kidney failure. Clinic BP values were obtained in two separate visits three weeks apart. BP was measured by aneroid sphygmomanometer in the morning hours by taking the average value of two consecutive measurements in the sitting position 10 minutes apart. BP was calculated as average values between all measurements.
ACCEPTED MANUSCRIPT Anthropometric measures (height, weight) and laboratory analyses (level of fasting glucose, blood creatinine and urea, total cholesterol and triglycerides) were
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obtained from all the subjects included in the study. Body mass index and body surface were calculated for each patient. The study was approved by the local Ethics Committee, and informed consent was obtained from all the participants.
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24-hour Holter monitoring
24-hour Holter monitoring was performed the three-channel digital Schiller
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Microvit MT-101 system (Schiller AG, Baar, Switzerland) and analyzed by the
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Schiller software (Schiller AG, Baar, Switzerland). The minimum duration of recording was 18 hours (after exclusion of non-sinusal cardiac cycles). Time-domain
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HRV parameters were calculated on the 24-hour, daytime and nighttime recordings after excluding non-sinusal cardiac cycles, according to guidelines /15/. SDNN was defined as the standard deviation of all normal RR intervals. SDANN, which reflects long-term HRV and therefore mainly sympathetic activity or sympathovagal balance,
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was defined as the standard deviation of the averaged normal RR intervals for all 5-
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min segments. rMSSD was calculated as the root mean square of the difference between the coupling intervals of adjacent RR intervals. pNN50 which reflects shortterm beat-to-beat HRV and consequently primarily vagal activity was calculated as the proportion of adjacent RR intervals that varied by more than 50 ms. After power spectral density estimation, standard frequency-domain HRV measures were calculated for 24-hour, daytime and nighttime /15/. Low frequency domain (LF) was defined between 0.04 and 0.15 Hz; high frequency domain (HF) was defined between 0.15 and 0.4 Hz; total spectral power (TP) for all intervals up to 0.4 Hz; and ratio of low to high frequency power (LF/HF).
ACCEPTED MANUSCRIPT Echocardiography Echocardiographic examinations were performed by using a commercially
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available Vivid 7 (GE Vingmed, Horten, Norway). Reported values of all 2DE parameters were obtained as the average value of 3 consecutive cardiac cycles. LV diameters, posterior wall and septum thickness, were
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measured according to the current recommendations /16/. Relative wall thickness was calculated according to formula. LV ejection fraction (EF) was calculated by using
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the biplane method. LV mass was calculated by using the Devereux formula /16/, and
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indexed for the height powered to 2.7. However, LV mass was also assessed by ASE formula and indexed for body surface area /17/. Left atrial maximal volume was
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obtained in the 4-chamber view during ventricular end-systole and indexed for BSA. Pulsed-wave Doppler assessment of transmitral LV was obtained in the apical 4-chamber view according to the guidelines /18/. Tissue Doppler imaging was used to obtain LV myocardial velocities in the apical 4-chamber view, with a sample volume
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placed at the septal and lateral segments of the mitral annulus during early diastole
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(e´). The average of the peak early diastolic relaxation velocity (e´) of the septal and lateral mitral annulus was calculated, and the E/e´ ratio was computed. The RV basal diameter was measured in the apical four-chamber view /19/.
RV thickness was measured in the subcostal view /19/. RV global systolic function was assessed as the tricuspid annular plane systolic excursion (TAPSE). Right atrial maximal volume was obtained in the 4-chamber view during ventricular end-systole and indexed for BSA. Tricuspid inflow (E) and tissue Doppler velocities (e’t, st) were evaluated in the apical 4-chamber view /19/, and E/e’t ratio was calculated. Systolic pulmonary artery pressure (PASP) was assessed in the patients with minimal/mild tricuspid regurgitation in any available echocardiographic view that
ACCEPTED MANUSCRIPT could provide adequate Doppler signal for PASP calculation (39 controls and 50 patients with diabetes).
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Two-dimensional right ventricular strain 2DE strain imaging was performed by using 3 consecutive cardiac cycles of 2DE images in the apical 4-chamber view. EchoPAC 2.01 (GE-Healthcare, Horten,
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Norway), as a commercially available software, was used for the 2DE strain analysis.
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The global longitudinal strain for the RV lateral wall and global RV were determined separately.
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Multilayer longitudinal strain was determined by modified 2DE strain software. The modified 2DE strain speckle tracking includes the delineation of the
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endocardial border, similarly to traditional 2DE strain, but instead of a single chain of nodes, the myocardial wall is automatically defined with multiple chains of nodes, allowing investigation of 3 myocardial layers: endocardial, mid-myocardial and
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epicardial.
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Statistical analysis Continuous variables were presented as mean ± standard error (SE), and the
Student t-test was used to detect differences between the two groups for the variables that showed normal distribution. Differences in proportions were compared by using the χ². Pearson´s correlation coefficients were used for determining the correlation between different demographic and echocardiographic parameters and HRV parameters. Almost all HRV parameters, except SDNN and SDANN, were transformed by natural logarithm, before using of t-test or linear regressions because of their high positive skewed distribution. The variables which showed p-value ≤0.10 were included into the stepwise multiple regression analyses. PASP was not included
ACCEPTED MANUSCRIPT in the multivariate analysis because there was no difference in PASP between the observed groups. The p-value <0.05 was considered statistically significant.
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Results The gender distribution and blood pressure values were similar between the observed groups, whereas BMI and BSA were significantly higher in diabetics (Table
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1). Blood levels of glucose and HbA1c were higher in diabetic patients, which was expected considering the inclusion criteria. Triglycerides and urea levels were higher
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in diabetic patients (Table 1).
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Patients with diabetes used antidiabetic treatment in 73% (64% patients were treated with medications and 17% were treated with insulin). Among diabetic patients
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34% were treated with statins. 24-hour Holter monitoring
Heart rates during 24 hours and day were similar between the observed groups
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(Table 2). Nighttime heart rate was higher in diabetic patients than in controls (Table 2). SDNN, SDANN, rMSSD and p50NN were significantly lower in diabetic patients.
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24-h, daytime and nighttime LF, HF and TP were significantly lower in diabetic group than in controls (Table 2, Figure 1). Echocardiographic parameters LV diameters and ejection fraction are similar between groups (Table 3). All parameters of LV hypertrophy: interventricular septum thickness, posterior wall thickness, relative wall thickness and LV mass indexes were significantly higher in diabetic patients (Table 3). LA volume index was also higher in diabetic group. Parameters of LV diastolic function and LV diastolic filling (transmitral E/A and E/e’) were deteriorated in diabetic patients comparing with controls.
ACCEPTED MANUSCRIPT 2DE strain analysis All differences in mechanical parameters between the observed groups were
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adjusted for age, BMI and triglycerides level. The 2DE analysis of the RV global and RV free wall deformation showed that 2DE global longitudinal RV function was lower in diabetic patients than in controls (Table 4).
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RV global longitudinal layer specific strains (endo-, mid- and epicardial) were
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lower in diabetic patients than in controls (Table 4, Figure 2). The same results were obtained for layer specific strains of RV free wall (Table 4).
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Correlation and multivariate regression analysis In univariate correlation analysis 24-h LF correlated with age, HbA1c, LV
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mass index, mitral E/e’ ratio and RV endocardial longitudinal strain. However, in multivariate regression analysis, only HbA1c (β=-0.278, p<0.001), LV mass index (β=-0.159, p=0.047) and RV endocardial longitudinal strain (β=0.193, p=0.008) were
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independent predictors of 24-h LF (Table 5). 24-h HF correlated with HbA1c, LV mass index and RV endocardial
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longitudinal strain. However, only HbA1c (β=-0.179, p=0.035) and RV endocardial longitudinal strain (β=-0.167, p=0.041) were independently associated with 24-h HF (Table 5).
Discussion Several findings of the present investigation deserve further discussion. The results show that global longitudinal strain, as well as layer-specific RV strain is significantly impacted by diabetes, which is new finding. Additionally, the current results showed that cardiac autonomic system assessed by HRV is significantly reduced in diabetic patients, which is concurrent with previous studies, but the investigation revealed that HRV indices correlated with RV longitudinal deformation
ACCEPTED MANUSCRIPT irrespective of LV and RV structure and diastolic function, which has not investigated so far.
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The number of studies that investigated RV structure and function in diabetic population is scarce /20-22/, and research that involves determination of RV mechanics is even more limited /8,23/. The current results confirm previous findings
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regarding impaired RV diastolic function and longitudinal strain in diabetic population /20-23/. However, this investigation went one step further and evaluated
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layer-specific strain in these patients. The rising question is why multilayer strain is
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important and could it provide the additional information about early cardiac remodeling and does it have prognostic value in diabetic patients.
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Recent study showed that LV longitudinal strain was independently associated with cardiovascular events in patients with diabetes type 2, but without history of cardiovascular complications /24/. On the other side, Lee et al. revealed that layerspecific longitudinal LV strain, particularly epicardial, was the only independent
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prognostic factor in regularly-treated hypertensive patients /25/. Data regarding
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prognostic value of RV mechanics in diabetic population are still lacking. However, there are evidence that diabetes impacts RV function and mechanics /8,23,26,27/, as well as RV layer-specific longitudinal strain /28/. Furthermore, RV global longitudinal strain has also been recognized as independent predictor of cardiovascular morbidity and mortality in wide range of pathological conditions /11,12/. Therefore, it is quite reasonable to hypothesize that RV global and layerspecific strain are important predictors of cardiovascular morbidity and mortality in diabetic population. The present analysis confirmed that RV diastolic function, RV global longitudinal strain, as well as longitudinal strain of all RV myocardial layers
ACCEPTED MANUSCRIPT (endocardial, mid-myocardial and epicardial), are significantly impaired in asymptomatic diabetic patients. In this study was also demonstrated that all changes
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in RV free wall and septal mechanics occur in parallel, which is believed to represent a very important finding because it shows that diabetes impacts RV independently of LV and interventricular septum. Interestingly, this difference maintain even if there
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was no significant alteration in RV wall thickness between controls and diabetic
functional and mechanical impairments.
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patients. These results imply that RV structural changes occur significantly after
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The current study revealed that cardiac autonomic function is depressed in diabetic patients. The results showed that both, sympathetic and parasympathetic
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autonomic function activities, are significantly reduced in diabetic population, which agree with some previous findings /4,5/, but not with all of them /2/. What is more interesting, HRV indices are associated with RV endocardial longitudinal strain independently of LV and RV structure and diastolic function.
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Impaired RV function and mechanics, as well as deteriorated cardiac
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autonomic nervous system, could be explained by increased oxidative stress, endothelial dysfunction, increase inflammation, micro- and macro-vascular changes /29/. All these changes induce myocardial interstitial fibrosis that further could initiate deterioration of RV function and mechanics. The changes in pulmonary circulation and retrograde transmission of increased LV filling pressure on the RV should not be forgotten. A related animal study tested a model of streptozocin-induced diabetic rat heart with dual scintigraphy using thulium for evaluation of myocardial perfusion and MIBG (Metaiodobenzylguanidine) for the assessment of sympathetic nerve activity /30/. The authors reported regional differences in MIBG scan even though no regional difference in thulium scan was noticed /30/. This implicates the existence of regional
ACCEPTED MANUSCRIPT inhomogeneity in sympathetic imbalance in diabetic rat heart /30/. Howarth et al. reported that action potential durations (APD) of right atrium and right ventricle in
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streptozocin-induced diabetic rat were more prolonged than in control rats, while there were no changes of APD detected in left atrium and left ventricle /31/. This finding suggest that regional variability in APD in right-sided heart may cause
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contraction in this specific diabetic rat heart.
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electrical conduction disturbances leading to imbalanced activity of myocardial
The present study has several clinical implications: first, evaluation of global
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and layer-specific longitudinal RV strain, as well as assessment of HRV, could be effective methods in demonstrating subtle changes in diabetic patients as indicators of
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preclinical cardiac damage; second, RV strain and HRV could be used in follow-up these patients; third, our study showed that predominantly endocardial longitudinal RV strain was associated with HRV parameters. This indicates that muscle
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arrangement of endocardial layer in the RV is dominated by autonomic nervous system that could be susceptible to the deterioration caused by poor glycemic control.
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Myocytes are predominantly oriented in the longitudinal direction in the subendocardial layer /32,33/. Circumferentially oriented myocytes are found in the thinner sub-epicardium. Consequently, the RV contraction pattern is predominantly longitudinal /34,35/, which could explain the association between HRV indices and RV longitudinal strain. LV remodeling could be partly responsible for the relationship between RV and HRV in diabetic patients. However, multivariate models that included parameters of LV structure and diastolic function showed that RV endocardial longitudinal strain was associated with HRV indices irrespective of LV mass index and mitral E/e’ ratio.
ACCEPTED MANUSCRIPT Limitations The present study has several limitations. All patients with comorbidities were
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excluded, which decreases potential generalization of the obtained results. However, this represents also strength of the current study because the majority of studies were performed in patients with other comorbidities. HRV is indirect measurement of
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autonomic nervous system and could be a weaker predictor of the sympathovagal imbalance than direct measurements such as muscle sympathetic nerve activity. The
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cross-sectional nature of this study does not allow evaluation of causal relationship
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between diabetes, HRV and RV remodeling. Conclusion
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The present investigation showed that autonomic nervous function and RV function and mechanics are significantly deteriorated in asymptomatic diabetic individuals. The current findings revealed a significant relationship between HRV
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indices and RV layer-specific longitudinal strain, which could partially explain increase cardiovascular morbidity and mortality in this population. Future
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longitudinal investigations are needed to investigate a long-term prognostic importance of the interaction between HRV and RV remodeling on cardiovascular morbidity and mortality in diabetic patients.
Key points:
Right ventricular mechanics is deteriorated in patients with diabetes.
Longitudinal right ventricular strain is impaired in all three myocardial layers.
Autonomic nervous system is related with right ventricular remodeling in diabetic population.
ACCEPTED MANUSCRIPT References 1. Meyer ML, Gotman NM, Soliman EZ, Whitsel EA, Arens R, Cai J, Daviglus
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ML, Denes P, González HM, Moreiras J, Talavera GA, Heiss G. Association of glucose homeostasis measures with heart rate variability among Hispanic/Latino adults without diabetes: the Hispanic Community Health
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2016;21(3):223-35. 4. Rothberg LJ, Lees T, Clifton-Bligh R, Lal S. Association between heart rate variability measures and blood glucose levels: implications for noninvasive glucose monitoring for diabetes. Diabetes Technol Ther. 2016;18(6):366-76. 5. Fakhrzadeh H, Yamini-Sharif A, Sharifi F, Tajalizadekhoob Y, Mirarefin M, Mohammadzadeh M, Sadeghian S, Badamchizadeh Z, Larijani B. Cardiac autonomic neuropathy measured by heart rate variability and markers of subclinical atherosclerosis in early type 2 diabetes. ISRN Endocrinol. 2012;2012:168264.
ACCEPTED MANUSCRIPT 6. Sacre JW, Franjic B, Jellis CL, Jenkins C, Coombes JS, Marwick TH. Association of cardiac autonomic neuropathy with subclinical myocardial
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Figure 1
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Figure 2
ACCEPTED MANUSCRIPT Table 1. Demographic characteristics and clinical parameters of study population.
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Diabetes (n=59) 54 ± 1 28 (47) 29.3 ± 0.4 2.06 ± 0.03 131 ± 1 81 ± 7 5 ± 0.4 43 (73) 38 (64) 10 (17) 20 (34) 7.9 ± 0.2 7.5 ± 0.2 73 ± 2 6.2 ± 0.2 2.3 ± 0.1 5.6 ± 0.1
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Age (years) Female (%) BMI (kg/m2) BSA (m2) Clinic systolic BP (mmHg) Clinic diastolic BP (mmHg) Diabetes duration (years) Antidiabetic treatment (%) Medicament (%) Insulin (%) Statins (%) Plasma glucose (mmol/l) HbA1c (%) Creatinine (mmol/l) Urea (mmol/l) Triglycerides (mmol/l) Total cholesterol (mmol/l)
Controls (n=45) 49 ± 1.3 21 (47) 24.3 ± 0.4 1.83 ± 0.03 128 ± 1 79 ± 1 5.2 ± 0.1 5.0 ± 0.1 69 ± 2 5.3 ± 0.2 1.8 ± 0.1 5.8 ± 0.2
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BMI- body mass index, BP- blood pressure, BSA- body surface area.
p 0.004 1.000 <0.001 <0.001 0.076 0.152 <0.001 <0.001 0.165 0.008 <0.001 0.335
ACCEPTED MANUSCRIPT Table 2. Heart rate variability parameters in the study population (adjusted for age and BMI). Diabetes (n=59) 78 ± 1 81 ± 1.2 72 ± 0.9 125 ± 5 114 ± 5 3.1 ± 0.04 1.3 ± 0.1 6.1 ± 0.1 6.3 ± 0.1 5.8 ± 0.1 5.0 ± 0.1 4.5 ± 0.1 5.2 ± 0.1 7.1 ± 0.1 7.0 ± 0.1 7.3 ± 0.1
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24-h heart rate (beats/min) Daytime heart rate (beats/min) Nighttime heart rate (beats/min) SDNN (ms) SDANN (ms) Ln rMSSD (ms) Ln p50NN (%) Ln 24-h LF (ms2) Ln Daytime LF (ms2) Ln Nighttime LF (ms2) Ln 24-h HF (ms2) Ln Daytime HF (ms2) Ln Nighttime HF (ms2) Ln 24-h TP (ms2) Ln Daytime TP (ms2) Ln Nighttime TP (ms2)
Controls (n=45) 76 ± 1 83 ± 1.3 63 ± 0.9 150 ± 6 135 ± 8 3.4 ± 0.04 2.0 ± 0.1 6.6 ± 0.1 7.0 ± 0.1 6.5 ± 0.1 5.5 ± 0.1 5.1 ± 0.1 5.7 ± 0.1 8.1 ± 0.1 8.0 ± 0.1 8.2 ± 0.1
p 0.188 0.271 <0.001 0.003 0.022 <0.001 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 0.001 <0.001 <0.001 <0.001
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HF- high-frequency domain (0.15-0.40 Hz), LF- low-frequency domain (0.04-0.15 Hz), NS- no statistical diference, p50NN- percentage of adjacent R-R intervals that varied by more than 50 ms, rMSSD- root mean square of the difference between the coupling intervals of adjacent R-R intervals, SDANNstandard deviation of the averaged normal RR intervals for all 5-min segments, SDNN- standard deviation of all normal RR intervals, TP- total power (0.01-0.40 Hz).
ACCEPTED MANUSCRIPT Table 3. Echocardiographic parameters of study population (adjusted for age and BMI).
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Diabetes (n=59) 50.3 ± 0.5 10.3 ± 0.2 9.8 ± 0.1 0.39 ± 0.005 89.4 ± 1.4 49.2 ± 1.1 63 ± 1 29.8 ± 0.5 0.72 ± 0.04 11.1 ± 0.4
0.121 <0.001 <0.001 <0.001 0.008 <0.001 0.281 0.004 <0.001 <0.001
32.7 ± 0.5 4.2 ± 0.1 22.0 ± 0.5 26.2 ± 0.5 5.4 ± 0.2 12.0 ± 0.4 27.0 ± 0.9
0.718 0.135 0.998 0.003 0.001 0.996 0.002
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32.4 ± 0.6 4.0 ± 0.1 22.0 ± 0.4 23.7 ± 0.5 4.5 ± 0.2 12.0 ± 0.4 24.0 ± 0.6
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Right ventricular parameters RV basal diameter (mm) RV thickness (mm) TAPSE (mm) RA volume index (ml/m2) Tricuspid E/e´ ratio s’ (cm/s) PASP (mmHg)
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LV end-diastolic diameter (mm) Interventricular septum thickness (mm) Posterior wall thickness (mm) Relative wall thickness LVMI (g/m2) LVM/Ht2.7 (g/m2.7) EF (%) LA volume index (ml/m2) E/A ratio Mitral E/e´ ratio
Controls (n=45) 49.0 ± 0.6 9.2 ± 0.2 8.8 ± 0.1 0.36 ± 0.004 83.6 ± 1.3 40.9 ± 1.0 64 ± 1 27.5 ± 0.5 1.14 ± 0.04 8.1 ± 0.3
p
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A- late diastolic mitral flow (pulse Doppler), DT – deceleration time, E- early diastolic mitral/tricuspid flow (pulse Doppler), e´- peak early diastolic relaxation velocity (e´) of the septal and lateral mitral annulus (tissue Doppler) or lateral tricuspid annulus, EF-ejection fraction, Ht-height, IVS-interventricular septum, LA-left atrium, LV- left ventricle, LVM-left ventricle mass, PASP- pulmonary artery systolic pressure, RA – right atrium, RV – right ventricle, s’- peak systolic velocity of the lateral tricuspid annulus assessed by tissue Doppler, TAPSE – tricuspid annular plane systolic excursion.
ACCEPTED MANUSCRIPT Table 4. 2DE speckle tracking assessment of the right ventricular function in the study population (adjusted for age and BMI).
Two-dimensional mechanical parameters Longitudinal RV strain (%) Global RV Lateral wall
-25.8 ± 0.5 -29.1 ± 0.6
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Longitudinal global RV strain (%) Endocardial -28.8 ± 0.6 Mid-myocardial -25.7 ± 0.5 Epicardial -22.9 ± 0.4 Longitudinal lateral wall RV strain (%) Endocardial -31.6 ± 0.6 Mid-myocardial -29.2 ± 0.5 Epicardial -26.6 ± 0.5
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RV – right ventricle
-23.7 ± 0.4 -26.8 ± 0.4
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Two-dimensional multilayer strain
Diabetes (n=59)
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Controls (n=45)
p
0.001 0.002
-26.4 ± 0.5 -23.8 ± 0.4 -21.0 ± 0.3
0.003 0.001 <0.001
-29.3 ± 0.5 -26.6 ± 0.4 -24.4 ± 0.4
0.007 <0.001 <0.001
ACCEPTED MANUSCRIPT Table 5. Association between clinical, two-dimensional right ventricular parameters and heart rate variability indices. Ln 24-h LF (ms2)
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Age (years) BMI (kg/m2) HbA1c (%) LV mass index (g/m2.7) Mitral E/e´ ratio RV wall thickness (mm) Tricuspid E/e’ ratio PASP (mmHg) RV endocardial longitudinal strain (%) r2
r -0.168† -0.133 -0.341‡ -0.281‡ -0.305‡ -0.113 -0.094 -0.064 0.289‡
Multivariate Multivariate Correlation regression* regression* β r β -0.088 -0.112 -0.093 -0.278‡ -0.203‡ -0.105 -0.159† -0.237‡ -0.179† -0.097 -0.133 -0.071 -0.074 -0.109 -0.080 -0.092 0.073 0.193‡ 0.244‡ 0.167†
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Correlation
Ln 24-h HF (ms2)
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BMI- body mass index, HF- high-frequency domain (0.15-0.40 Hz), E- early diastolic mitral flow (pulse Doppler), e´- average of the peak early diastolic relaxation velocity (e´) of the septal and lateral mitral annulus (tissue Doppler), LF- low-frequency domain (0.04-0.15 Hz), LV- left ventricle, RV – right ventricle, PASP- pulmonary artery systolic pressure, †- p<0.05, ‡- p<0.01, *PASP was not included in the multivariate analysis because there was no difference between the observed groups.
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