The additive effects of type 2 diabetes mellitus on left ventricular deformation and myocardial perfusion in essential hypertension: a 3.0 T cardiac magnetic resonance study

Background Type 2 diabetes mellitus (T2DM) increases the risks of heart failure and mortality in patients with hypertension, however the underlying mechanism is unclear. This study aims to investigate the impact of coexisting T2DM on left ventricular (LV) deformation and myocardial perfusion in hypertensive individuals. Materials and methods Seventy hypertensive patients without T2DM [HTN(T2DM−)], forty patients with T2DM [HTN(T2DM+)] and 37 age- and sex-matched controls underwent cardiac magnetic resonance examination. Left ventricular (LV) myocardial strains, including global radial (GRPS), circumferential (GCPS) and longitudinal peak strain (GLPS), and resting myocardial perfusion indices, including upslope, time to maximum signal intensity (TTM), and max signal intensity (MaxSI), were measured and compared among groups by analysis of covariance after adjusting for age, sex, body mass index (BMI) and heart rate followed by Bonferroni’s post hoc test. Backwards stepwise multivariable linear regression analyses were performed to determine the effects of T2DM on LV strains and myocardial perfusion indices in patients with hypertension. Results Both GRPS and GLPS deteriorated significantly from controls, through HTN(T2DM−), to HTN(T2DM+) group; GCPS in HTN(T2DM+) group was lower than those in both HTN(T2DM−) and control groups. Compared with controls, HTN(T2DM−) group showed higher myocardial perfusion, and HTN(T2DM+) group exhibited lower perfusion than HTN(T2DM−) group and controls. Multiple regression analyses considering covariates of systolic blood pressure, age, sex, BMI, heart rate, smoking, indexed LV mass and eGFR demonstrated that T2DM was independently associated with LV strains (GRPS: p = 0.002, model R2= 0.383; GCPS: p < 0.001, model R2= 0.472; and GLPS: p = 0.002, model R2= 0.424, respectively) and perfusion indices (upslope: p < 0.001, model R2= 0.293; TTM: p < 0.001, model R2= 0.299; and MaxSI: p < 0.001, model R2= 0.268, respectively) in hypertension. When both T2DM and perfusion indices were included in the regression analyses, both T2DM and TTM were independently associated with GRPS (p = 0.044 and 0.017, model R2= 0.390) and GCPS (p = 0.002 and 0.001, model R2= 0.424), and T2DM but not perfusion indices was independently associated with GLPS (p = 0.002, model R2= 0.424). Conclusion In patients with hypertension, T2DM had an additive deleterious effect on subclinical LV systolic dysfunction and myocardial perfusion, and impaired myocardial perfusion by coexisting T2DM was associated with deteriorated LV systolic dysfunction.


Introduction
Given their common risk factors, essential hypertension and type 2 diabetes mellitus (T2DM) frequently coexist. Approximately 70% of patients with T2DM have hypertension, and the development of T2DM is almost 2.5 times more likely in patients with precedent hypertension [1,2]. It is well known that both hypertension and T2DM are well-established risk factors for cardiovascular disease morbidity and mortality regardless of the presence of each factor [3]. In addition, T2DM in hypertensive patients further increases the risks of heart failure and all-cause and cardiovascular mortality [4,5]. Once established, heart failure is associated with worse clinical outcomes. Therefore, early detection of subclinical left ventricular (LV) myocardial dysfunction allows for earlier intervention, which may potentially prevent heart failure and improve patient outcomes.
Cardiac magnetic resonance (CMR) has less shortcomings of echocardiography, such as acoustic window limitations, low spatial resolution and high operator dependency, and can evaluate cardiac anatomy and function as well as myocardial perfusion in a single examination [6]. The commonly used global volumetric measurement of left ventricular ejection fraction (LVEF) cannot provide a detailed assessment of cardiac mechanics, and it has been demonstrated to be an insensitive and late marker of contractile impairment [7]. Recently, CMR feature tracking using routinely acquired cine images has become a more sensitive technique for evaluating global and regional myocardial deformation as an indicator of subclinical myocardial dysfunction [8]. In addition, CMR-derived first-pass myocardial perfusion has been increasingly used to noninvasively evaluate myocardial microcirculation function with high reproducibility [9,10].
Although limited echocardiographic studies have observed more severe subclinical systolic dysfunction in patients with coexisting hypertension and T2DM than in those with T2DM alone [11][12][13][14], none have evaluated the impact of T2DM on LV deformation and myocardial microcirculation function in patients with hypertension. Accordingly, the aim of this study was to investigate the impact of coexisting T2DM on subclinical LV systolic dysfunction and myocardial microcirculation function using CMR in patients with hypertension.

Study population
From January 2016 to January 2020, 179 Adult Chinese Han race essential hypertensive patients with or without T2DM [HTN(T2DM+) and HTN(T2DM−), respectively] who underwent CMR at our institution were consecutively included. Hypertension was defined as a clinical systolic blood pressure (SBP) ≥ 140 mmHg and/ or a diastolic blood pressure (DBP) ≥ 90 mmHg or a history of antihypertensive medications. The diagnosis of T2DM was based on the current American Diabetes Association guideline recommendations [15]. The exclusion criteria (Fig. 1) included patients with symptoms of heart failure (n = 3), LVEF < 50% (n = 8), known coronary artery disease (n = 10), myocardial infarction (n = 4), moderate to severe valvular disease (n = 3), cardiomyopathy (n = 3), bundle branch block (n = 5), atrial fibrillation (n = 2), serious liver and lung dysfunction (n = 6), estimated glomerular filtration rate (eGFR) < 30 mL/ min/1.73 m 2 (n = 8) and poor image quality (n = 2). In addition, patients unmatched for age and sex (n = 15) were also excluded. Finally, 110 patients including 70 (35 men and 35 women; mean age, 55.0 ± 14.1 years) and 40 (20 men and 20 women; mean age, 55.7 ± 9.8 years) age-and sex-matched patients with HTN (T2DM−) and HTN (T2DM+), were eligible for this study. Another 37 healthy individuals (18 men and 19 women; mean age, 54.2 ± 10.5 years) matched for age and sex were selected from our healthy volunteer database to serve as the control group, and they underwent the same CMR examination.
This study was approved by the Biomedical Research Ethics Committee of our hospital and conducted in accordance with the Declaration of Helsinki (2013 EDITION).

CMR protocol
All the CMR examinations were performed using a 3.0 T whole-body scanner (Trio Tim; Siemens Medical Solutions, Erlangen, Germany) in the supine position. Data acquisition was performed with a standard ECG-triggering device that monitored each subject's dynamic ECG changes during the end-inspiratory breath hold period. A balanced steady-state free precession (bSSFP) sequence (repetition time [TR]: 39.34 ms, echo time [TE]: 1.22 ms, flip angle: 40°, slice thickness: 8 mm, field of view [FOV]: 250 × 300 mm, and matrix size: 208 × 139) was used to acquire 8 -12 continuous cine images from the base to the apex in the short-axis view, as well as vertical LV two-and four-chamber cine images in the long-axis view. For perfusion imaging, a dose of 0.2 mL/kg gadobenate dimeglumine (MultiHance 0.5 mmol/mL; Bracco, Milan, Italy) was injected into the right antecubital vein with a power injector (Stellant, MEDRAD, Indianola, PA, USA) at a flow rate of 2.5-3.0 mL/s, followed by 20 mL of saline. Rest first-pass perfusion images were acquired in three standard short-axis slices (basal, middle, and apical) and in one four-chamber view slice by inversion recovery prepared echo-planar imaging sequence (TR/TE: 163.0/1.

CMR data analysis
CMR images were evaluated using offline commercially available software (cvi42, v. 5.10.2; Circle Cardiovascular Imaging, Calgary, Canada) by two radiologists with more than 3 years of CMR experience, who were blinded to the clinical data.
The endocardial and epicardial contours of the LV myocardium on the short-axis cine images were manually traced at the end-diastolic and end-systolic phases in the cvi42 short-3D module. Then, LV mass at enddiastole, LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LVEF, stroke volume and cardiac index were computed automatically. The trabeculae and papillary muscles were excluded from the LV mass and included in the LV cavity. LV mass, LVEDV and LVESV indexed for body surface area (BSA) (LVMI, LVEDVI and LVESVI, respectively) were calculated using the Mosteller formula [16]. In addition, LV remodeling index, calculated as LVM/LVEDV, was included for analysis.
The LV global radial (GRPS), circumferential (GCPS) and longitudinal peak strain (GLPS) were obtained by manually delineating the endocardium and epicardium of the cine images at the end-diastole from the short-axis and long-axis two-and four-chamber slice views in the tissue tracking module. Strain was depicted as relative For the evaluation of first-pass myocardial perfusion (Fig. 2), the endocardium and epicardium and a region of interest drawn in the LV chamber were manually determined in the first-pass perfusion images (basal, middle and apical). Then, signal intensity-time curves were generated for the blood pool and each myocardial segment based on the 16-segment heart model. Consequently, semiquantitative segmental perfusion indices including the upslope, time to maximum signal intensity (TTM), and max signal intensity (MaxSI) were acquired automatically, and the global first-pass myocardial perfusion indices for each subject were calculated by averaging the regional values of the 16 myocardial segments. In addition, the presence of LGE was visually evaluated by the two radiologists with consensus.

Reproducibility of LV myocardial strain and perfusion
Intra-and inter-observer variabilities for the LV global myocardial strain and perfusion indices were analyzed in 30 random cases including 20 HTN patients and 10 controls. To determine the intra-observer variability, one observer (XM. L) evaluated the same subjects on two separate measurements 1 month apart. For the interobserver variability evaluation, a second investigator (L. J) who was blinded to the first observer's results and clinical data reanalyzed the measurements.

Statistical analysis
Categorical variables are presented as frequencies (percentages) and were compared using Chi square tests.
Continuous variables were evaluated for normality distribution by the Shapiro-Wilk test and are expressed as the mean ± standard deviation (SD). One-way analysis of variance (one-way ANOVA) was used to compare the baseline characteristics among the normal and HTN groups. Comparisons of the CMR-derived parameters between different groups were evaluated by analysis of covariance (ANCOVA) after adjusting for age, sex, body mass index (BMI) and heart rate followed by Bonferroni's post hoc test. Pearson's correlation coefficient was used to determine the correlation between LV myocardial strain and first-pass myocardial perfusion indices in HTN. Backwards stepwise multivariable linear regression analyses were performed to determine the predictors for LV strains and myocardial perfusion indices in the whole population and patients with HTN. Inter-and intraobserver agreements were determined by the evaluation of intraclass correlation coefficients (ICCs). All analyses were performed in SPSS version 21 (IBM, Armonk, New York, USA), and a two-tailed p < 0.05 was considered significant.

Baseline characteristics
The main clinical characteristics of the study participants are summarized in Table 1. Age, BSA, heart rate, plasma triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and eGFR were not significantly different between the observed groups (all p > 0.05), except for a higher BMI in both the HTN (T2DM−) and HTN (T2DM+) groups than in the control group (all p < 0.01). As expected, fasting blood glucose was significantly higher in the HTN (T2DM+) group than in the HTN (T2DM−) group and control group (all p < 0.001). In addition, both SBP and DBP were significantly higher in the hypertensive groups than in the control group (all p < 0.001).

Comparison of CMR findings among groups
The CMR findings for the observed groups are shown in Table 2. The LVMI (p < 0.001 and = 0.005, respectively) and LV remodeling index (p < 0.001 and = 0.040, respectively) in both the HTN (T2DM−) and HTN (T2DM+) groups were significantly higher than those in the control group, whereas the LVEDVI, LVESVI, LVEF, stroke volume and cardiac index were not significantly different among the groups (all p > 0.05).
Compared with the control group, higher myocardial perfusion was observed in the HTN (T2DM−) group as supported by increased upslope (p = 0.023) and MaxSI (p = 0.005), and lower myocardial perfusion was demonstrated in the HTN (T2DM+) group as supported by decreased upslope (p = 0.036) and increased TTM (p = 0.038). In addition, the HTN (T2DM+) group exhibited worse myocardial perfusion than the HTN (T2DM−) group, which was supported by a reduced upslope and MaxSI (all p < 0.001) and increased TTM (all p = 0.001) values.

Discussion
The main findings of this study are as follows: (1) hypertension impairs LV GLPS, and coexisting T2DM further deteriorates subclinical LV systolic dysfunction; (2) myocardial perfusion is increased in HTN (T2DM−) but decreased in HTN (T2DM+) patients; and (3) impaired myocardial perfusion by T2DM is associated with aggravated LV systolic dysfunction in patients with hypertension. These changes observed in our study indicate the deleterious effect of T2DM on myocardial systolic function and myocardial microcirculation function in patients with hypertension, which may contribute to the increased cardiovascular risk.

T2DM aggravate LV dysfunction in hypertension
Similar to most progressive myocardial diseases, subendocardial fibers are more vulnerable to being affected; thus, longitudinal contractile function representing as GLPS may be impaired earlier and more severely [8], as shown in previous studies with hypertension [17][18][19] and T2DM [13,[20][21][22], as well as in our patients. In hypertension, there is insulin resistance and activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, which may result in diffuse myocardial fibrosis [12]. Diffuse myocardial fibrosis and hemodynamic overload-associated LV hypertrophy are more vulnerable to the involvement of subendocardial Table 4 Multivariable association of diabetes with first-pass myocardial perfusion indices or LV strains in all patients with hypertension adjusted for SBP, age, sex, BMI, heart rate, smoking, LVMI and eGFR Abbreviation of SBP, BMI and eGFR are shown in Table 1; and LVMI, LVEDVI, GRPS, GCPS, GLPS, TTM and MaxSI in Table 2 Model 1: Association between diabetes and perfusion indices

Table 5 Intra-and inter-observer variability of LV strains and perfusion indices
Abbreviation of GRPS, GCPS, GLPS, TTM and MaxSI are shown in Table 2 ICC, intraclass correlation coefficient; CI, confidence interval fibers. In addition, studies in hypertension have found that GCPS was significantly reduced in patients with hypertrophy [17,23]. Recent studies showed the negative effects of acute hyperglycemia on systolic LV global longitudinal strain and multilayer longitudinal and circumferential strain in asymptomatic T2DM and unfavorable subclinical reductions in global and average circumferential strain in obese adolescents with dysglycemia, which may indicate the importance of intensive blood glucose control [24,25]. Moreover, epicardial adipose tissue may be associated with LV structural and functional abnormalities and exercise intolerance in T2DM patients with asymptomatic heart failure [26], and serum levels of omentin-1 and Zinc-α2-glycoprotein have been recently defined as the most important predictors for LV hypertrophy and LV diastolic dysfunction in T2DM patients [27]. Our study demonstrated that T2DM aggravated LV systolic dysfunction as represented by more severe impairment of GLPS and GRPS and the occurrence of impaired GCPS in the HTN (T2DM+) group, even though similar LVEF and LV geometries were observed between the hypertensive subgroups. The reason for this may be the superimposed factors that cause contractile dysfunction in T2DM, such as impairments in excitation-contraction coupling, metabolic derangements, remodeling of the extracellular matrix and abnormalities in microvasculature [28]. Nevertheless, it may be difficult to determine the exact individual contribution, since some of them are usually found together.

The combined effect of T2DM and hypertension on microvascular dysfunction
In both hypertension and T2DM, there are structural and functional abnormalities in coronary microvasculature, including hypertrophic remodeling of small arteries and arterioles, microvascular rarefaction, and functional increases in vasoconstriction due to endothelial dysfunction [2,28,29]. However, resting myocardial perfusion reflecting autoregulated blood flow correlates with myocardial oxygen consumption and is mainly determined by LV wall stress, myocardial contractility and heart rate [1]. Increased myocardial perfusion was observed in our HTN (T2DM−) patients, which was consistent with previous studies [30][31][32]. Kjaer et al. [31] demonstrated a 25% higher baseline myocardial perfusion by positron emission tomography, and Kozakova et al. [30] revealed higher resting coronary flow in the left anterior descending artery by transesophageal Doppler echocardiography.
The increased resting myocardial perfusion in hypertension may reflect an adaptive mechanism, adapting to the increased oxygen demand for the heart to work under increased afterload [29,32]. In T2DM, increased resting myocardial perfusion has been exhibited in some previous studies [33][34][35], while others have reported decreased resting perfusion [20,36]. This discrepancy may be due to different study populations, investigation modalities, and relatively modest sample sizes. Increased plasma insulin, a known vasodilator, by insulin resistance in T2DM may explain the increased myocardial perfusion at rest [34]. Additionally, glucose and lactate oxidation is inhibited, and fatty acid oxidation is increased, which may lead to more oxygen consumption, subsequently resulting in higher resting perfusion [34,35]. To our knowledge, reports about the combined effect of hypertension and T2DM on myocardial microcirculation are still missing. We found that patients with HTN (T2DM+) showed worsened myocardial perfusion than those with HTN (T2DM−) and control group. A possible explanation for this may be that although hypertension and T2DM increase resting myocardial perfusion to meet increased oxygen consumption, their coexistence may amplify the abovementioned abnormalities of microvasculature that have reduced myocardial perfusion at rest.

Association between impaired myocardial perfusion and LV dysfunction
In our study, there was a significant correlation between subclinical LV systolic dysfunction and impaired myocardial perfusion, and impaired myocardial perfusion by T2DM was associated with the deterioration of subclinical LV systolic dysfunction in patients with hypertension. Our results were consistent with the study by Jiang et al. [37], which may suggest that myocardial microcirculation might be associated with myocardial systolic function, giving further support to the importance of efficient energy production in normal myocardial contraction [28]. The aggravated abnormalities of the microvasculature discussed above may compromise nutrient and oxygen delivery and energy production, impair myocardial contractility and eventually lead to LV systolic dysfunction. Therefore, pharmacologic treatment aimed at increasing myocardial microvascular function might be an effective method for improving myocardial contractility and preventing heart failure, which needs further study.

Limitation
Several limitations in this study merit comment. First, this was a cross-sectional single-center study with a relatively small sample size, and further multicenter studies with a larger population should be performed to validate our findings. Second, The PROCEED study revealed that duration of T2DM and systolic blood pressure are determinants of severity of coronary stenosis in asymptomatic diabetes [38]. Although not all our patients underwent coronary computed tomography angiography or invasive coronary angiography, coronary artery disease was considered to be unlikely according to the evaluation of patients by clinical history, laboratory results, echocardiography and electrocardiography which was subsequently supported by the CMR examinations. Third, stress tests were not performed in our participants; thus, myocardial systolic function and perfusion reserve could not be evaluated, and subclinical coronary artery disease was excluded [39]. Even if subclinical coronary artery disease could not be excluded, which may subsequently cause impaired myocardial perfusion and myocardial dysfunction, our results could still reflect the impact of T2DM and hypertension after adjustment for confounders including age. Finally, follow-up observation was not conducted to examine whether changes in myocardial microcirculation over time affect myocardial structure and function, and further longitudinal studies are required to investigate the potential prognostic value of impaired myocardial perfusion and deformation in patients with coexisting hypertension and T2DM.

Conclusion
In patients with hypertension, T2DM had an additive deleterious effect on subclinical LV systolic dysfunction and myocardial perfusion. In addition, impaired myocardial perfusion by coexisting T2DM was associated with deteriorated LV systolic dysfunction, which may contribute to increased adverse outcomes.