Introduction

Hypertrophic cardiomyopathy (HCM) was once considered a malignant disease with limited effective treatment options but is now considered a relatively common contemporary and highly treatable disease with a normal life expectancy benefiting from substantially evolved understanding and management of the disease, particularly in the last two decades [1, 2]. As the clinical course of HCM extended, ageing-related cardiovascular risks are increasing. Comorbidities such as type 2 diabetes mellitus (T2DM) can worsen the clinical features of HCM. Previous studies have shown that HCM patients with T2DM (HCM-DM) had a higher New York Heart Association class, a higher prevalence of comorbidities, and a higher risk of adverse events including end-stage renal disease progression, stroke, heart failure and cardiovascular death [3,4,5,6]. T2DM is associated with left ventricular (LV) hypertrophy, diastolic dysfunction as well as left atrial (LA) enlargement, and overt systolic impairment can occur in advanced stages [7,8,9,10,11,12]. However, the mechanism for the adverse prognostic impact of T2DM on HCM remains incompletely understood.

Cardiac magnetic resonance (CMR) is an established, noninvasive and comprehensive imaging strategy used for the evaluation and follow-up of patients with HCM [13]. CMR feature tracking, an emerging method for strain analysis, has been widely applied to evaluate myocardial deformation in all cardiac chambers including the relatively thin-walled atrium [14]. Compared with conventional functional analysis, strain analysis can provide incremental information for clinical management by detecting early dysfunction and subtle changes in disease progression. We supposed that diabetes-related adverse cardiac alterations may worsen the clinical manifestations of HCM, but few studies have focused on the effects of T2DM on cardiac remodelling in patients with HCM thus far. Therefore, the present study aimed to determine the impact of T2DM on LV and LA function in patients with HCM using CMR feature tracking.

Methods

Study population

A total of 45 consecutive HCM-DM patients who underwent CMR evaluation between January 2012 and December 2022 were retrospectively included. Isolated HCM controls (HCM patients without diabetes) were matched to HCM-DM patients according to maximal wall thickness, age, and gender distribution. The diagnosis of HCM was based on the presence of unexplained LV hypertrophy on CMR (a maximal end-diastolic wall thickness ≥ 15 mm, or ≥ 13 mm with a family history of HCM or with a positive genetic test) [15]. The diagnosis of T2DM was based on the clinical chart at the time of CMR examination in accordance with the 2019 European Society of Cardiology guidelines [16]. The exclusion criteria were as follows: (1) a history of myocardial infarction on medical documentation, or significant coronary arterial stenosis (≥ 50%) on invasive coronary angiography or coronary computed tomography angiography; (2) history of septal reduction therapy; (3) concomitant uncontrolled hypertension; (4) congenital heart diseases; (5) infiltrative cardiomyopathies; (6) severe valvular heart diseases; (7) persistent atrial fibrillation; and (8) uninterpretable CMR images. The study was approved by the Biomedical Research Ethics Committee of the local hospital, and the requirement for informed consent was waived because of the retrospective design.

CMR examination and analysis

CMR examinations were performed with 3.0 T scanners (Magnetom Skyra or Tim Trio; Siemens, Erlangen, Germany) with 32-channel phased array coils, using electrocardiographic and respiratory gating. A standardized protocol was used as previous described [17], mainly including balanced steady-state free precession sequences for cine images (temporal resolution = 37–42 ms, echo time = 1.2 ms) and segmented phase-sensitive inversion recovery sequences for late gadolinium enhancement (LGE) images acquired in short-axis views and three LV long-axis views 10–15 min after gadolinium-based contrast agent injection (inversion time = 330–380 ms).

The structural and functional parameters of the LA and LV were assessed by using the commercial software CVI42 (Circle Cardiovascular Imaging, Calgary, Canada). The LV volumes and ejection fraction (LVEF) were quantified on short-axis cine stacks by manually outlining the endocardial and epicardial contours at end diastole and end systole. Papillary muscles and trabeculae were assigned to the blood pool. LGE was measured by manually drawing the endocardial and epicardial contours on the short-axis view and selecting a region of interest in the normal (dark) zone to define the reference signal intensity. The myocardium with a signal intensity ≥ 6 standard deviations above the mean of the reference region was identified as enhanced myocardium. The extent of LGE was recorded as a percentage of the total LV mass.

Feature tracking strain analysis was conducted on cine images for LA and LV (Fig. 1). After manually delineating the contours at end diastole, the automatically tracked borders of the myocardium in each phase were carefully checked and adjusted if necessary. The LV peak strains in three directions were derived from three long-axis cines and short-axis cines, including the global radial strain (GRS), global circumferential strain (GCS), and global longitudinal strain (GLS). The LA parameters were analysed on LV 2-chamber and 4-chamber views with pulmonary veins and atrial appendage excluded, including phasic volume, longitudinal strain and strain rate measurements: maximal volume (Vmax), pre-atrial contractile volume (Vpac), minimal volume (Vmin), reservoir strain (εs), conduit strain (εe), booster‒pump strain (εa), peak positive strain rate (SRs), peak early negative strain rate (SRe), and peak late negative strain rate (SRa). The phasic LA EF parameters were computed as follows: LA total EF = (LA Vmax − LA Vmin)/LA Vmax; LA passive EF = (LA Vmax − LA Vpac)/LA Vmax; LA booster EF = (LA Vpac − LA Vmin)/LA Vpac [18, 19].

Fig. 1
figure 1

Measurements of left ventricular and atrial strain. LV left ventricular, GRS global radial strain, GCS global circumferential strain, GLS global longitudinal strain, LA left atrial, εs reservoir strain, εe conduit strain, εa booster-pump strain, SRs peak positive strain rate, SRe peak early negative strain rate, SRa peak late negative strain rate

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Inter- and intraobserver variability in strain parameters were independently assessed in 12 randomly selected patients by 2 radiologists with 6 and 10 years of CMR experience (S.Y and K.S), respectively. One of the radiologists repeated the analysis 2 months later to determine the intraobserver variability.

Statistical analysis

Statistical analyses were performed using MedCalc 16.8.4 (Ostend, Belgium). The normality of continuous variables was tested using the Shapiro-Wilk test, histograms, and Q–Q plots. Continuous data are expressed as means ± standard deviations or medians with interquartile ranges (IQRs) appropriately, and differences between HCM patients and HCM-DM patients were compared using the t-test or Mann–Whitney U test. Categorical variables are presented as numbers with percentages, and datasets were compared using the chi-square test or Fisher’s exact test. Univariable and multivariable linear regression analyses (stepwise methods) were performed to determine the associations of variables with LA/LV dysfunction. Only variables with two-sided P values < 0.05 according to the univariate analysis were included in the multivariate analysis. The intraclass correlation coefficient was used to evaluate the inter- and intraobserver variability. A two-tailed P value < 0.05 was considered statistically significant.

Results

Study population

The baseline demographic and clinical characteristics are summarized for each group and compared in Table 1. HCM patients with T2DM presented with higher body mass index, cardiac troponin T (cTnT) levels and blood glucose levels than those without T2DM did (P = 0.02, P = 0.01 and P < 0.001, respectively). Most HCM-DM patients (89%, 40 of 45) were treated with non-insulin medications, mainly metformin (56%, 25 of 45), and only 11% (5 of 45) of the patients were treated with insulin.

Table 1 Clinical characteristics
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LV and LA CMR parameters

In terms of LV parameters, the patients with T2DM had smaller end-diastolic volume (132.2 ± 26.9 ml vs. 142.5 ± 21.4 ml) and stroke volume (83.1 ± 17.7 ml vs. 98.4 ± 15.0 ml), lower ejection fraction (63.2% ± 7.2 vs. 69.2% ± 4.9), and larger mass/volume ratio (MVR; 0.9 ± 0.3 vs. 0.8 ± 0.2) than those without T2DM (all P < 0.05; Table 2). Compared with patients without T2DM, those with T2DM had worse LV strain parameters in all three directions (GRS: 26.7% ± 9.0 vs. 33.3% ± 8.9; GCS: − 16.0% ± 3.8 vs. − 18.5% ± 3.1; GLS: − 10.6% ± 3.0 vs. − 12.8% ± 2.8; all P < 0.001). In addition, the extent of LGE was greater in HCM-DM patients than in isolated HCM patients (2.5% [IQR, 1.0%~6.2%] vs. 1.2% [IQR, 0.3%~3.4%]; P = 0.047).

Table 2 Cardiac magnetic resonance imaging characteristics
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Although the average LA volumes were not significantly different between HCM patients with and without T2DM (all P > 0.05), impaired LA reservoir and conduit function were detected by strain analyses in patients with T2DM compared with those without T2DM(Table 2; εs: 23.2% ± 11.0 vs. 28.2% ± 7.9; εe: 9.0% [IQR, 4.6%~13.5%] vs. 12.3% [IQR, 10.1%~14.7%]; SRs: 1.2 ± 0.5 s−1 vs. 1.5 ± 0.8 s−1; SRe: − 0.7 s−1 [IQR, − 1.2 ~ − 0.5 s−1] vs. − 0.9 s−1 [IQR, − 1.2 ~ − 0.7 s−1]; all P < 0.05). The LA booster-pump function was similar between the two groups (LA booster EF: 32.3% ± 14.6 vs. 34.9% ± 9.9; εa: 13.1% ± 6.8 vs. 15.4% ± 6.1; SRa: − 1.5 ± 0.8 s−1 vs. − 1.7 ± 0.7 s−1; all P > 0.05). Representative cases from the two groups are shown in Fig. 2.

Fig. 2
figure 2

Representative examples of LGE (A, E), left ventricular (B, F) and atrial (C, D, G, H) strain in hypertrophic cardiomyopathy patients with (E–H, from a 55-year-old man) and without diabetes (A–D, from a 57-year-old man). LGE late gadolinium enhancement, LV left ventricular, LA left atrial

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Association between T2DM and LV/LA dysfunction

The factors associated with LV/LA dysfunction are displayed in Tables 3 and 4.. Among all HCM patients, comorbidity with T2DM was significantly associated with LVEF (r = − 6.05, P < 0.001), GRS(r = − 6.66, P < 0.001), GCS (r = 2.51, P < 0.001), GLS (r = 2.28, P < 0.001), εs (r = − 4.97, P = 0.02), SRs (r = − 0.31, P = 0.02) and εe (r = − 2.66, P = 0.03) in the univariate analysis. In the multivariate analysis, the coexistence of T2DM remained an independent predictor of a low LVEF (β = − 6.05, P < 0.001) and impaired GLS (β = 1.40, P = 0.007). In addition, the extent of LGE was independently associated with impaired GRS (β = − 45.81, P = 0.008), GCS (β = 18.25, P = 0.003), εs (β = − 59.20, P < 0.001), εe (β = − 21.29, P = 0.02) and SRs (β = − 2.90, P = 0.002) when adjusted for confounding factors.

Table 3 Univariable and multivariable linear regression analysis of LV parameters in all HCM patients
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Table 4 Univariable and multivariable linear regression analysis of LA parameters in all HCM patients
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Intra- and interobserver variability

The intra- and interobserver reproducibility of the LV and LA strain parameters are presented in Table 5. The intraclass correlation coefficient ranged from 0.827 to 0.981 for intraobserver agreement and from 0.818 to 0.970 for interobserver agreement, which indicated good reproducibility.

Table 5 Interobserver and intraobserver variability of strain measurements
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Discussion

The current study investigated the effects of T2DM on LV and LA remodelling in HCM patients using CMR, featuring the largest sample size described to date. Several important observations are evident: (1) the LVEF and LV strains in all three directions were impaired in HCM patients with T2DM compared with those without T2DM; (2) CMR strain analysis revealed an early reduction in LA reservoir and conduit function in the HCM-DM group; (3) T2DM was independently associated with LVEF and GLS; and (4) HCM-DM patients presented with greater myocardial scar indicated by LGE, which was an independent predictor of GRS, GCS, εs and SRs, respectively.

The presence of diabetes was associated with adverse LV remodelling in HCM patients. Our results showed lower LV volumes and larger mass/volume ratio in HCM-DM patients than HCM-alone patients. This finding was consistent with a Mendelian randomization study which demonstrated an association between insulin resistance and adverse changes in LV structure [20]. Similar to our results, a prospective study revealed a greater reduction in LV contractile function and a greater degree of fibrosis burden in 20 HCM-DM patients [21]. In addition, our data showed a higher myocardial injury degree in HCM-DM patients indicated by a higher level of cTnT, which was independently associated with GRS and GCS, respectively. Diabetes-related microvascular dysfunction may be a possible explanation. This was theoretically supported by Jex et al., who described more impaired stress myocardial perfusion in HCM-DM patients than in patients with isolated HCM [21]. Further study was expected to investigate the impact of diabetes-related microvascular dysfunction on LV contractile abnormalities in HCM patients. In addition, our study showed a greater degree of LV fibrosis in the HCM-DM patients than in the isolated HCM controls, which could be the result of diabetes-related microvascular dysfunction.

Recently, literatures have reported a higher prevalence of atrial fibrillation in HCM patients with diabetes comorbidity than in those without [3, 4, 22]. The current study provided insights into an early condition for the pathophysiological alteration. We observed impaired LA reservoir and conduit function in HCM-DM patients, whereas the LA size was similar between patients with and without coexisting diabetes. LA reservoir and conduit functions contribute to LV filling and are useful indicators of LV diastolic function. The increased LV diastolic stiffness, reflected by impaired LA reservoir and conduit function, can lead to symptoms of heart failure and provide an elucidation of the higher New York Heart Association class in HCM-DM patients. This was also consistent with an echocardiographic study that revealed the prognostic value of LA reservoir strain for predicting incident heart failure events in HCM patients [23]. In addition, a greater degree of LV fibrosis burden in HCM-DM patients was independently associated with LA reservoir function in the present study, which could provide a mechanism for the intimate relationship between LV myocardial fibrosis and future atrial fibrillation in a previous HCM study [24].

Previous findings suggested the presence of myocardial microvascular dysfunction, myocardial hypertrophy and fibrosis, left ventricular diastolic dysfunction primarily and systolic impairment later in diabetes, independent of diabetes-related cardiovascular diseases [25,26,27]. Similarly, our results added that T2DM was an independent determinant of LVEF and GLS in HCM patients, respectively. Diabetes-induced microvascular ischaemia may be the underlying mechanism since subendocardial fibres lying in a longitudinal orientation contribute to the main myocardial contraction and are most vulnerable to pathological changes of ischaemia [11, 28, 29]. We also found that a greater extent of LGE in HCM-DM patients was an independent predictor of GRS, GCS, εs and SRs. The possible mechanisms are as follows: (1) Diabetes can aggravate fibrosis progression in HCM patients since myocardial fibrosis is a well-recognized pathological change in diabetes [25, 26, 30]; (2) LGE on the images of HCM patients typically manifests as a patchy midwall pattern in areas of hypertrophy and the insertion points of the septum [31], which can affect radial and circumferential myocardial motion; and (3) LV fibrosis in HCM-DM patients can further increase myocardial stiffness, which could lead to diastolic dysfunction reflected by impaired LA strain. In summary, the present study demonstrated the association between adverse LV/LA remodelling and T2DM in HCM patients. The results support the active prevention and close surveillance of T2DM throughout life as an integral part of the management of HCM. A prospective study might be warranted to confirm the clinical value of CMR for monitoring the adverse impact of T2DM on HCM patients and guiding early therapy to prevent adverse events.

The limitations of the current study were as follows: (1) quantitative stress perfusion was not available in this retrospective analysis, and the association between microvascular dysfunction and adverse cardiac function should be elucidated in future studies; (2) the present study was limited to conducting subgroup analysis by diabetes features because of incomplete data regarding the duration of T2DM; (3) there is potential bias, as patients were recruited from a single tertiary referral center; and (4) the relatively small population size and low adverse event rate in the HCM patients limited prognostic analysis. Further studies with large sample sizes are supposed to provide a more detailed analysis of the associations between impaired imaging parameters and poor outcomes.

Conclusions

T2DM worsened LV and LA function in HCM patients and was independently associated with impaired LVEF and GLS. Compared with the isolated HCM controls, the HCM-DM patients presented with a greater extent of LGE, which was an independent predictor of impaired GRS, GCS, εs and SRs. These findings may help elucidate the mechanism underlying the adverse prognostic impact of T2DM on HCM and support the prevention and management of T2DM in HCM patients.