Myocardial deformation and twist mechanics in adults with metabolic syndrome: Impact of cumulative metabolic burden
Disclosure: The authors declared no conflict of interest.
Funding agencies: This study was financed by the “Fondation Coeur et Artères”.
With abdominal obesity reaching epidemic proportions (), there are increased risks of cardiovascular morbidity and mortality with unfavorable metabolic consequences. Metabolic syndrome (MetS) is a clustering of cardio-metabolic risk factors, including abdominal obesity, insulin resistance, dyslipidemia and hypertension, and is a key phenotype leading to atherogenic and diabetogenic profiles ([2, 3]).
MetS is consensually associated with left ventricular (LV) hypertrophy and atrial enlargement ([4-6]). Previous studies using conventional and pulsed tissue Doppler imaging (TDI) echocardiography have also demonstrated decreased diastolic function in participants with MetS, while systolic function is usually well preserved ([5, 7]). However, the lack of sensitivity of these methods in detecting subtle myocardial dysfunction may have led to underestimation of systolic impairments. Additionally, since myocardial functionality results from a complex interplay between deformation (longitudinal and circumferential) and twist/untwist mechanics ([8, 9]), these studies only partially described the effects of MetS on myocardial function. Speckle tracking echocardiography (STE) may help to overcome these limitations by permitting angle-independent evaluation of deformation in both the longitudinal and circumferential planes, as well as twist mechanics (). The STE technique provides more sensitive and comprehensive indices of subclinical myocardial dysfunction in a number of pathologies ([10, 11]). Attenuated global longitudinal strain and systolic and diastolic strain rate (SR) in MetS participants have been reported using color-TDI ([12, 13]). However, these results suffer from similar limitations as pulsed TDI (e.g., longitudinal angle-dependency and restriction to basal and median segments), and fail to fully explain the myocardial pathophysiology associated with MetS. To our knowledge, no study has thus far examined the impact of MetS on myocardial mechanics using the more sensitive and comprehensive STE indices. The link between myocardial pathophysiology and abdominal obesity-related insulin-resistance and inflammation is an emerging interest (). Insulin-resistance and inflammation are known pathways leading to the development of MetS (), but whether they are associated with myocardial dysfunction remains uncertain, especially using newer STE indices.
Therefore, the aims were 1) to comprehensively investigate the impact of MetS on myocardial longitudinal, circumferential, and twist mechanics using STE, in middle-aged adults, and 2) explore associations between STE-based myocardial function indices and obesity-related insulin resistance and inflammation.
Participants and research design
This study formed part of the RESOLVE trial (). Following clinical prescreening of 156 potential participants on a consecutive basis, 92 participants with clinically diagnosed MetS (56% males) were included. Participants with incompatible diseases such as cardiopathy and arteriopathy were excluded. Fifty aged and gender-matched controls were also tested. Within the MetS population, we identified 28 participants with type-2 diabetes (fasting glucose levels >7 mmol L−1, or medicated for type-2 diabetes), and 72 participants with hypertension (resting blood pressure >140/90 mmHg, or medicated for hypertension).
Cross-sectional echocardiographic analyses were conducted using conventional, pulsed TDI and STE (vector velocity imaging) methods. Participants provided informed consent prior to commencement of testing, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by our local Hospital ethics committee.
Biochemical, clinical and anthropometric assessment
Blood biology and anthropometric data were used to classify the MetS status of participants (). Serum concentrations of triglycerides, high-density lipoprotein (HDL), low-density lipoproteins (LDL), and fasting glucose were measured, as well as insulin, homeostatic-model of assessment-insulin-resistance (HOMA-IR), and the following inflammatory markers: Interleukin-6 (IL-6), high sensitivity C-reactive protein (CRP), probrain natriuretic peptide (BNP), and tumor-necrosis factor-α (TNF-α).
Stature and body mass were assessed, and body mass index was subsequently calculated. Central fat was measured using dual-energy X-ray absorptiometry (DEXA), and waist circumference was measured at the level of the umbilicus. Blood pressure was obtained with a digital sphygmomanometer (Carescape-V100, Dinamap, GE technology, USA). Diagnosis of MetS was made according to the international diabetes federation definition (), using waist circumference, HDL cholesterol, triglycerides, blood pressure, and fasting blood glucose as diagnostic variables.
Echocardiographic image acquisition
Images were acquired by the same experienced operator (GW) according to standard procedures recommended by the American Society of Echocardiography, and based on the average of three cardiac-cycles. The participant was positioned in the left lateral decubitus position, and examined using an Esaote ultrasound equipment-pack (MyLab30, Esaote, Firenze, Italy), with a 3.5-Mhz sector scanning electronic transducer. Images were acquired in cine loops triggered to the QRS complex. All data were recorded digitally for subsequent blinded off-line analysis with specific software (MyLab desk 9.0, Esaote, Florence, Italy).
Conventional, pulsed doppler, and tissue doppler imaging echocardiography
M-Mode measurements were obtained in the parasternal long-axis view, and left atrial (LA) and LV dimensions were measured at both end-diastole and end-systole. LV mass was calculated by the Devereux formula and indexed for height (Cornell adjustment). LV ejection fraction was calculated from semiautomatic quantification of LV volumes, using vector velocity imaging.
Pulsed-Doppler LV trans-mitral velocity, including early (E) and atrial (A) waves, were measured in the apical four-chamber view. Isovolumic relaxation time was measured by pulsed Doppler in the apical five-chamber view, along with aortic ejection velocity. Pulsed Doppler pulmonary venous flow was measured at the base of the LA in the four-chamber view. Pulsed-TDI measures of myocardial systolic (Sm), early diastolic (Em), and Atrial (Am) velocities were assessed at the mitral annulus of the left ventricle, in apical four (septal and lateral) and two (anterior and inferior) chamber views. The E/Em ratio, recorded from the mitral annulus lateral wall, was used as an index of LV filling pressure. LV diastolic-dysfunction grading was determined using transmitral flow, pulmonary venous flow, and TDI indices, according to well-documented criteria ().
STE: Vector velocity imaging echocardiography
The STE modality of vector velocity imaging was used to quantify myocardial wall motion through a series of manually placed B-mode pixel tracking algorithms, which follow the endocardium throughout a cardiac cycle. This measurement technique was previously validated against magnetic resonance-imaging and sonomicrometry (). STE has been extensively used to investigate LV strain and twist in health and disease (). The strain and twist analyses performed in the present study followed the procedure recently described (), and focused only on the endocardial border, as the epicardial border could not be clearly visualized in the majority of participants, precluding the ability to quantify LV radial strain. LV longitudinal strain and SR were obtained from 2-D harmonic grey scale images in the apical four-chamber view, whilst circumferential strain and SR measures were obtained from the parasternal short-axis view (at basal and apical levels of the LV). Data were recorded for subsequent off-line analyses (X-Strain software, Esaote, Florence, Italy). On each cine-loop, an optimal frame was selected and the endocardial border was manually traced using the aided-heart-segmentation option. LV strain, SR and rotations were automatically obtained from a six or four segment model, depending on the view.
Only cine-loops with adequate endocardial border definition, adequate frame rate (>60 Hz), and good image tracking were used. Ten control and 24 MetS participants were excluded from the 142 participants initially included in the study, due to indistinct endocardial border definition. This was possibly related to the higher corpulence of these participants.
The LV rotations at basal and apical short-axis views were determined as average angular displacement of six myocardial segments. Care was taken to ensure that the basal short-axis view contained the mitral valve, and that the apical short-axis view was acquired distally to the papillary muscle. LV twist was calculated as the maximal instantaneous difference between basal and apical rotations. All measurements were averages derived from three consecutive cardiac cycles, and were paired with real-time electrocardiogram. To adjust all vector velocity imaging data for inter-participant differences in heart rate, a specific toolbox (Scilab 4.1-developed in our laboratory) was used to normalize time sequence as a percentage of systolic duration ().
Inter and intraobserver reproducibility was estimated in 20 randomly selected participants, and the coefficient of variation was 3.1 and 5.9%, respectively for strain, and 14.2 and 16.6%, respectively for twist.
Time taken in milliseconds from the start of QRS to a specified point was measured for intra-LV dyssynchrony. The specified points were peak TDI-derived Sm velocity for systolic intra-LV dyssynchrony, and peak TDI-derived Em velocity for diastolic intra-LV dyssynchrony (averaged from septal, lateral, anterior, and inferior annulus sites). The difference between maximum and minimum diastolic and systolic durations for the four sites (TDI Sm: Max-Min 4-sites and TDI Em: Max-Min 4-sites) was measured. Differences greater than previously validated criteria ([21, 22]) constituted a diagnosis of dyssynchrony.
Following checks for normal distribution, anthropometric and general participant data were presented as mean ± standard deviation. Differences in descriptive cardiac variables among MetS participants with various numbers of cardio-metabolic risk factors and controls were determined using one way analysis of variance (ANOVA), with Tukey's post hoc test. Because of uneven group sizes, Hedge's g was used to calculate effect size between MetS and control participants for specified variables. An effect size of >0.2 was considered small, >0.5 considered medium, and >0.8 considered large. Chi-square analysis allowed comparisons of the incidence of TDI and STE-derived intra-LV dyssynchrony in participants with and without MetS, as well as the distribution of LV diastolic-dysfunction in MetS and control participants. Arithmetic transformation was performed for non-Gaussian variables. Pearson's r correlation coefficient analysis was used to identify associations between metabolic risk factors and morphological, global functional and myocardial functional cardiac measures. Multiple stepwise linear regression analyses assessed the strongest predictors of variability in longitudinal strain. Statistical analyses were made using SPSS 16.0 for windows (SPSS Inc). Statistical significance was set a priori at P < 0.05.
Study population and clinical characteristics
Demographic characteristics of MetS and control participants showed no age and gender differences (Table 1). MetS participants had a greater waist circumference (Hedge's g = 2.2; P < 0.001), systolic blood pressure (g = 0.9; P < 0.001), triglycerides (g = 0.9; P < 0.001), and fasting blood glucose levels (g = 1.2; P < 0.001), as well as lower HDL (g = 1.0; P < 0.001) than controls. All inflammatory cytokines, with the exception of pro-BNP, were greater in MetS participants than controls.
Table 1. Clinical and inflammatory characteristics of MetS and control participants
|Demographic parameters|| || || |
|Age (years)||58 ± 5||59 ± 5||NS|
|Medication (number of treatments)|| || || |
|Hypertension||0||65 (16 β-blockers)||<0.001|
|Clinical and laboratory parameters|| || || |
|BMI (kg m−2)||24.1 ± 3.1||33.4 ± 3.9||<0.001|
|Systolic blood pressure (mmHg)||117 ± 12||130 ± 15||<0.001|
|Diastolic blood pressure (mmHg)||73 ± 8||77 ± 10||NS|
|Lean mass (kg)||50.7 ± 11.2||58.2 ± 10.6||<0.001|
|Fat mass (kg)||16.5 ± 4.1||30.9 ± 7.8||<0.001|
|Central fat (kg)||1.2 ± 0.6||3.1 ± 0.7||<0.001|
|Waist circumference (cm)||82.4 ± 7.7||102.2 ± 9.4||<0.001|
|Fasting glucose (mmol L−1)||4.2 ± 0.5||5.6 ± 1.4||<0.001|
|HbA1c (%)||5.5 ± 0.4||6.2 ± 0.8||<0.001|
|LDL cholesterol (mmol L−1)||3.6 ± 0.8||3.4 ± 0.9||NS|
|HDL cholesterol (mmol L−1)||1.6 ± 0.5||1.2 ± 0.3||<0.001|
|Triglycerides (mmol L−1)||1.2 ± 0.4||1.9 ± 0.9||<0.001|
|HOMA-IRa||2.5 ± 1.4||4.0 ± 2.1||<0.001|
|Inflammatory blood markers|| || || |
|High sensitivity CRP (mg L−1)a||1.3 ± 1.4||3.6 ± 2.5||<0.001|
|TNFα (pg mL−1)a||3.6 ± 3.4||11.5 ± 8.0||<0.001|
|Leptin (ng mL−1)a||11.8 ± 10.4||30.3 ± 15.9||<0.001|
|IL-6 (pg mL−1)a||1.3 ± 1.3||3.0 ± 2.5||<0.001|
|PAI-1 active (ng mL−1)a||8.0 ± 4.9||19.7 ± 11.4||<0.001|
|Adiponectin (µg mL−1)a||31.9 ± 21.7||19.1 ± 13.5||<0.001|
|Pro-BNP (pg mL−1)a||21.7 ± 36.0||29.5 ± 58.7||NS|
Conventional and tissue doppler echocardiography
MetS participants revealed greater LV mass, parietal dimensions, and LA diastolic diameter than controls (Table 2). They also demonstrated lower E/A ratio (g = 0.59; P < 0.001) and Em (g = 1.2; P < 0.001) than controls (Table 2). However, when using a combined approach to assess diastolic dysfunction (), 60.4% of MetS participants revealed normal diastolic function. LV ejection fraction, peak Sm, and end-systolic wall stress did not differ between MetS participants and controls. Although E/Em was more elevated in MetS participants compared with controls (g = 0.7; P < 0.001), absolute values for both populations remained within normal limits.
Table 2. Global echocardiographic parameters of MetS and control participants
|Cardiac morphology|| || || |
|LV mass (g)||201 ± 50||267 ± 65||<0.001|
|LV mass indexed (g m−2.7)||46.9 ± 14.0||66.1 ± 22.4||<0.001|
|LVED diameter (mm)||47.7 ± 5.1||50.2 ± 5.7||<0.05|
|LVES diameter (mm)||29.2 ± 4.7||30.4 ± 5.5||NS|
|LA diastolic diameter (mm)||31.5 ± 4.1||36.4 ± 4.0||<0.001|
|IV septum diastolic (mm)||10.0 ± 1.3||11.4 ± 1.5||<0.001|
|Posterior wall diastolic (mm)||10.0 ± 1.1||11.6 ± 1.4||<0.001|
|Relative wall thickness (mm)||0.42 ± 0.06||0.46 ± 0.08||<0.05|
|End systolic wall stress (g cm−2)||54.4 ± 13.5||51.2 ± 16.6||NS|
|Pulsed Doppler cardiac function|| || || |
|LV ejection fraction (%)||61.4 ± 5.6||61.6 ± 6.7||NS|
|Resting heart rate (beats min−1)||61 ± 5||72 ± 11||<0.001|
|E velocity (cm s−1)||63.8 ± 12.0||64.7 ± 14.9||NS|
|A velocity (cm s−1)||51.4 ± 14.2||62.9 ± 17.5||<0.001|
|E/A||1.3 ± 0.4||1.1 ± 0.3||<0.001|
|Deceleration time of E (ms)||205 ± 33||210 ± 37||NS|
|IVRT (ms)||119 ± 18||120 ± 19||NS|
|Tissue Doppler imaging|| || || |
|Sm velocity (cm s−1)||8.6 ± 1.7||8.2 ± 1.3||NS|
|Em velocity (cm s−1)||10.6 ± 1.8||8.7 ± 1.5||<0.001|
|Am velocity (cm s−1)||9.6 ± 1.7||10.6 ± 4.9||NS|
|E/Em lateral wall||5.7 ± 1.5||6.9 ± 1.9||<0.001|
|Intra-LV dyssynchrony|| || || |
|TDI Sm: Max-Min diff of four sites (>65 ms: yes/no)||25.3 ± 11.9 (0/48)||43.4 ± 21.6 (19/68)||<0.001|
|TDI Em: Max-Min diff of four sites (>65 ms: yes/no)||21.9 ± 10.2 (0/48)||25.6 ± 11.9 (3/68)||NS|
Vector velocity imaging
MetS participants had lower longitudinal strain (g = 1.6; P < 0.001), longitudinal diastolic (g = 1.6; P < 0.001) and systolic (g = 1.4; P < 0.001) SR, and earlier time to peak longitudinal strain than controls, even after normalization to heart rate (Table 3). All circumferential strain, SR, and respective time to peak parameters at basal and apical levels were not different between MetS and control participants.
Table 3. STE-derived parameters of myocardial function in MetS and control participants
|Longitudinal axis of LV|| || || |
|L strain (%)||−21.2 ± 2.6||−16.8 ± 2.8||<0.001|
|Time to peak L strain (ms)||99.9 ± 6.1||97.6 ± 5.4||<0.05|
|L systolic SR (strain s−1)||−1.2 ± 0.2||−1.0 ± 0.1||<0.001|
|Time to peak L systolic SR (ms)||53.6 ± 6.2||52.0 ± 7.1||NS|
|L diastolic SR (strain s−1)||1.5 ± 0.3||1.1 ± 0.2||<0.001|
|Time to peak L diastolic SR (ms)||132.2 ± 7.0||132.2 ± 11.9||NS|
|Circumferential apex of LV|| || || |
|Apical C strain (%)||−31.6 ± 4.7||−30.9 ± 5.3||NS|
|Time to peak apical C strain (ms)||95.9 ± 4.8||94.0 ± 5.4||NS|
|Apical C systolic SR (strain s−1)||1.9 ± 0.4||−2.0 ± 0.4||NS|
|Time to peak apical C systolic SR (ms)||59.1 ± 6.9||57.2 ± 7.3||NS|
|Apical C diastolic SR (strain s−1)||2.4 ± 0.5||2.3 ± 0.6||NS|
|Time to peak apical C diastolic SR (ms)||131.9 ± 5.1||130.8 ± 9.5||NS|
|Circumferential base of LV|| || || |
|Basal C strain (%)||−26.5 ± 4.1||−25.3 ± 4.8||NS|
|Time to peak basal C strain (ms)||104.4 ± 6.7||103.7 ± 7.9||NS|
|Basal C systolic SR (strain s−1)||−1.8 ± 0.3||−1.8 ± 0.4||NS|
|Time to peak basal C systolic SR (ms)||55.8 ± 8.2||55.2 ± 8.4||NS|
|Basal C diastolic SR (strain s−1)||2.3 ± 0.5||2.0 ± 0.5||NS|
|Time to peak basal C diastolic SR (ms)||130.7 ± 9.1||133.8 ± 12.1||NS|
|Rotational mechanics of LV|| || || |
|Apical rotation (°)||4.5 ± 2.2||4.6 ± 2.1||NS|
|Basal rotation (°)||−4.2 ± 1.7||−4.5 ± 1.9||NS|
|Twist (°)||8.1 ± 2.5||8.6 ± 2.4||NS|
|Twist rate (° s−1)||48.7 ± 12.5||58.4 ± 16.4||<0.05|
|Untwist rate (° s−1)||−58.1 ± 16.0||−69.7 ± 25.4||<0.05|
No differences were found between MetS and control participants in apical and basal rotation, as well as resultant twist. Compared with controls, MetS participants had higher twist (g = 0.6; P < 0.05) and untwist (g = 0.5; P < 0.05) rates, but no difference remained after co-varying for heart rate. A positive association between the number of accumulated MetS parameters and longitudinal strain was observed (Table 4). Specifically, MetS with five risk factors had lower longitudinal strain than MetS participants with three and four factors (P < 0.05).
Table 4. Cumulative impact of MetS on longitudinal myocardial function
|L strain (%)||−21.2 ± 2.6||−17.2 ± 2.5a||−17.5 ± 2.6a||−14.7 ± 2.1a, b|
|L systolic SR (strain s−1)||−1.22 ± 0.17||−1.04 ± 0.16a||−1.03 ± 0.11a||−0.92 ± 0.12a, b|
|L diastolic SR (strain s−1)||1.47 ± 0.30||1.12 ± 0.14a||1.18 ± 0.18a||0.97 ± 0.18a, b|
Significant differences were found between MetS participants and controls regarding TDI-derived intra-LV systolic, but not diastolic, dyssynchrony indices (Table 2). Additional chi-square analyses showed that intra-LV systolic, but not diastolic, dyssynchrony was more prevalent in MetS participants (19 of 68) than controls (0 of 44), according to previously validated criteria (TDI Sm Max-Min difference >65 ms) ().
Independent effects of diabetes and hypertension within MetS population
Nondiabetic MetS participants showed lower longitudinal strain (g = 1.5; P < 0.001), systolic (g = 1.1; P < 0.001), and diastolic (g = 1.2; P < 0.001) SR than controls. Diabetes exacerbated this alteration in MetS participants, leading to lower longitudinal strain (g = 2.6; P < 0.05) than observed in nondiabetic MetS participants. Diabetes did not impair circumferential strain, SR, and twist in MetS participants. No difference in longitudinal or circumferential parameters was observed between hypertensive and normotensive MetS participants.
Relationships between longitudinal myocardial dysfunction and clinical data
Linear regression and correlation analyses were performed to examine the relationships between longitudinal strain and clinical, inflammatory, and functional cardiac parameters. Only moderate-strong correlates of longitudinal strain (r > 0.40) were entered into regression analyses (Table 5). The forward stepwise method was used to predict variability in longitudinal strain. A significant regression model emerged with a tolerance >0.05 to avoid colinearity (F4, 92 = 23.5, P < 0.001. Adjusted R2 = 0.484). Standardized residuals were normally distributed. The most significant independent predictors of longitudinal strain were central fat, HbA1c, TNF-α, and TDI Sm: max-min difference of four sites (Table 6).
Table 5. Relationships between longitudinal myocardial deformation and clinical, inflammatory, and morphological cardiac parameters
|Systolic blood pressure||0.48||<0.001|
|Left ventricular mass||0.47||<0.001|
|Posterior wall diastolic thickness||0.47||<0.001|
|High sensitivity CRP||0.45||<0.001|
|TDI Sm: Max-Min diff of four sites||0.40||<0.001|
Table 6. Independent predictors of longitudinal strain following multiple regression analyses
|Longitudinal strain: R2 = 0.48 (P < 0.001)|
|TDI Sm: Max-Min diff of four sites||0.200||<0.05|
The major findings of the present study were as follows: () Asymptomatic patients with MetS revealed myocardial functional impairments in the longitudinal axis only, while other major components of myocardial performance, such as circumferential deformation and twist/untwist mechanics, remained preserved. () Diastolic, as well as systolic longitudinal myocardial abnormalities were identified; the latter was detected only using recent STE technology. () In association with abdominal obesity; inflammation, glucose intolerance, and systolic intra-LV dyssynchrony emerged as major contributors to longitudinal dysfunction.
Effect of MetS on myocardial mechanics
Several studies using conventional echocardiography and TDI have shown evidence of isolated diastolic dysfunction in MetS patients, irrespective of grading criteria, but with preserved systolic function ([5, 7]). Our findings agree; showing attenuated TDI-derived indices of diastolic function along with normal ejection fraction and systolic longitudinal velocities in MetS participants, compared with controls (Table 2). Of note in the present study; when diastolic function was assessed using previously validated grading criteria (), 60.4% of MetS participants revealed normal diastolic function. A major limitation of conventional echocardiography and TDI is a lack of sensitivity (dependency on loading conditions, tethering effect) in detecting subtle myocardial changes (). This is of particular concern when evaluating systolic abnormalities. Whether systolic myocardial function is normal or not in MetS remains hitherto unclear. Additionally, due to insonation angle-dependency, TDI-based indices of myocardial performance are usually restricted to basal and median segments in the longitudinal axis, therefore allowing only partial evaluation of myocardial performance, and ignoring the important role of both circumferential deformation and twist/untwist mechanics (). STE offers a comprehensive and sensitive evaluation of myocardial function (). In contrast to TDI, it enables the assessment of all segments in the parietal walls, thus limiting erroneous readings from translational cardiac movement. In addition, STE assesses not only longitudinal, but also circumferential function and torsional mechanics, and has previously been used to detect early dysfunction in various pathologies, including diabetes () and obesity (). Impaired longitudinal strain as well as diastolic and systolic SR in our MetS patients concurs with, and extends previous findings in MetS patients that used color-TDI to assess strain and SR in LV basal segments ([7, 12, 13]). The absence of impairment in circumferential function and twist/untwist in MetS patients, despite revealing decreased longitudinal function, was another major and novel finding of our study. The reason for the decreased longitudinal but preserved circumferential function and twist/untwist mechanics cannot be ascertained, but may be related to myofiber spatial-organization within the LV. Subendocardial fibers, running parallel to the LV long-axis and governing longitudinal function, have greater sensitivity to ischemia and fibrosis than other layers (). We hypothesize that inferiorly located myofibers may be more susceptible to MetS-related inflammation and interstitial tissue damage (see Discussion below), leading to earlier impairment of longitudinal function ([26, 27]). Meanwhile, mid to superior myocardial/epicardial fiber layers, which predominantly govern circumferential function, may be preserved despite sharing the same stage of pathology. Of note, in more advanced pathologies, such as type-2 diabetes, circumferential function often decreases while twist increases ([28, 29]). Furthermore, using STE, both myocardial diastolic and systolic dysfunction in the longitudinal axis was detected in MetS patients. This highlights the importance of evaluating diastolic and systolic coupling using the same, more sensitive, technique to gain insight into overall myocardial function.
Mechanisms responsible for depressed longitudinal function in MetS patients
Myocardial deformation is affected by increased cardiac preload and afterload (). However, no differences between MetS participants and controls were found in the preload dependent E velocity measure and the afterload dependent end-systolic wall stress index; indicating that loading conditions were unlikely to have influenced longitudinal strain and SR. Growing evidence in the literature highlights a link between cardiac abnormalities and metabolic risk factors (). However, their associations with LV myocardial dysfunction in MetS patients remain incompletely understood. In the present study, we observed that abdominal obesity, biological markers of systemic inflammation and glucose intolerance, as well as myocardial systolic dyssynchrony, were independent predictors of longitudinal strain in MetS patients. While the exact mechanisms behind impaired longitudinal but preserved circumferential function are still unknown, this finding has been replicated in other metabolic disease states ([11, 25]). Several hypotheses, which align with the present study's findings, may help elucidate these mechanisms.
Increasing evidence supports the role of abdominal adiposity in active endocrinological functions, via dysfunctional adipocytes (). Increased adipokine levels were observed in our MetS participants (Table 1), and significant relationships were shown between some markers of systemic inflammation, such as TNF-α and high sensitivity CRP, and longitudinal strain (Table 4). Elevated pro-inflammatory cytokines and oxidative-stress in our MetS patients could explain the depressed myocardial longitudinal strain, and diastolic and systolic SR. This may be via the known deleterious impact of adipokines on () macro and micro-circulatory structure and function, leading to reduced coronary myocardial blood flow and subendocardial hypo-perfusion, () cell apoptosis and tissue fibrosis, impairing signal conductance and increasing LV dyssynchrony, or () calcium-handling, leading to excitation–contraction coupling abnormalities ([14, 32]).
It is well established that exposure to an increasing number of MetS factors causes stepwise deterioration in global diastolic function ([4, 7, 33, 34]). We also found a stepwise deterioration in longitudinal strain in MetS participants with an increasing number of factors. Moreover, diabetes had a similar exacerbating effect on longitudinal function. The aforementioned mechanisms and deleterious effects of chronic hyperglycaemia on cardiomyocyte calcium cycling may explain this finding (). Other studies have reported evidence of LV-dyssynchrony in participants with obesity () and type-2 diabetes (). Our results extend previous findings; showing systolic LV-dyssynchrony was an independent predictor of longitudinal myocardial function in MetS participants. The mechanisms underlying this finding are speculative, but may be related to the inflammation and obesity-related LV remodeling (), and the vulnerability of subendocardial fibers to ischemic tissue damage, as discussed earlier (). More studies in humans are needed to clarify this, and other underlying mechanisms responsible for the impairment in LV longitudinal function in MetS participants.
The results may be confounded by a large portion of the participants being hypertensive (78%). However, we found no significant difference in longitudinal myocardial function between hypertensive and normotensive MetS participants. Within the MetS population, 17% were medicated using beta-blockers; a drug which may mask myocardial dysfunction, or reverse LV remodeling (). Nonetheless, no differences in LV mass index or longitudinal and circumferential strain, SR, and twist were observed between MetS participants taking beta-blockers and nondrug-taking counterparts. Lastly, we were limited to a somewhat small sample size due to strict inclusion criteria, and difficulty in acquiring adequate quality images from all participants. Generalizing the results and assuming causality in the findings should be done with caution.
In conclusion, MetS participants without a history of incompatible diseases such as CVD showed impairments in both LV diastolic and systolic myocardial function in the longitudinal axis, while circumferential myocardial function was preserved. Abdominal obesity, combined with key inflammatory, clinical, and systolic dyssynchrony markers were strongly associated with this deterioration. Participants with diabetes and a greater number of metabolic risk factors demonstrated the most severe myocardial dysfunction, but only in the longitudinal axis. More research is needed to understand the mechanisms through which MetS affects longitudinal LV function. However, we contend that early identification of subclinical myocardial dysfunction in MetS participants, using more precise STE methods, may allow better comprehension of the pathophysiology of MetS.
We express our sincere thanks to the men and women who participated in the study and to ESAOTE Company for technical support. The help from Anne Camus in the management of participants was also greatly appreciated.