This study investigated the difference in LV function and deformation damage in RCM patients with or without DM, and explored the independent predictors of LV dysfunction and deformation injury. The main findings of this study are as follows: (1) RCM patients presented impaired LV function and deformation. Moreover, DM further deteriorated LV function, LV GPS in all three directions and LV peak diastolic strain rate in the longitudinal direction; (2) For RCM patients, DM was found to be an independent determinant of impaired LVEF and LV GPS in all three directions; (3) Patients with RCM comorbid with DM displayed a decreased LV peak diastolic strain rate in the longitudinal direction, in which DM plays the predominant role. Our study demonstrated that DM aggravated LV dysfunction and deformation injury in RCM patients, especially exacerbating the injury of the LV diastolic deformation rate in RCM patients. Therefore, RCM patients with comorbid DM may have a hidden high-risk that needs more advanced and personalized management.
RCM is a heterogeneous group of diseases characterized by nondilated left or right ventricle with diastolic dysfunction[7]. Patients with RCM have an increased myocardial stiffness LV with impaired diastolic filling and high filling pressures. Chronically elevated LV diastolic pressures commonly induce pulmonary hypertension and right heart failure, even the whole heart failure[16]. As a cardiomyopathy with poor prognosis, early intervention and control of risk factors for RCM can delay the further deterioration of cardiac function to a certain extent. DM, as a growing health concern, is the most common chronic metabolic disease and the major risk factor for cardiovascular complications and adverse cardiovascular events[19]. Previous research has confirmed that diastolic dysfunction is an important damage stage in patients with DM, and with the progression of the disease there are varying degrees of diffuse myocardial fibrosis[20–22]. We conducted this study to explore changes in LV dysfunction in RCM patients with DM. Our study demonstrated that conventional LV volume parameters (i.e., LVEDVi and LVESVi) were increased in RCM patients than the controls, but similar between the two RCM groups. RCM patients with comorbid DM augmented the impaired LVSVi and LVGFI in RCM patients. LVGFI is a measure of LV cardiac performance that integrates LV structure into LV functional assessment, which can provide incremental prognostic value. Compared with LVEF, LVGFI mainly reflects structure-related LV function impairment. We speculated that DM may increase the stiffness of the LV, leading to a decrease in LVSVi and LVGFI without significant volume changes.
The underlying cause of cardiac alterations in RCM patients with DM is a combination of multiple mechanisms. Myocardial metabolism disorder is the characteristic of patients with DM, and the underlying mechanisms of how DM affects LV function may be due to the synthesis effect of metabolic disorders, excitation–contraction coupling impairment, microvasculature dysfunction and extracellular matrix fibrosis[23, 24]. Several studies on the myocardial damage related to DM have reported that DM can lead to more severe LV global deformation injury[12, 25]. Similarly, this study found that comorbid DM augmented the impairment of LV global peak strain in all three directions by CMR-FT in RCM patients, and DM was an independent determinant of LV global peak strain, especially in the longitudinal direction in patients with RCM. The cardiac phenotypes of RCM are complex, with infiltrative cardiomyopathy such as cardiac amyloidosis being the most common type, and infiltration starting in the sub-endocardium predominantly consisting of longitudinal fibers[26, 27]. Furthermore, the myocardial fiber in the sub-endocardium is the most susceptible to microvascular ischemia by DM [28, 29]. Therefore, the LV GLPS has a closed independent correlation with DM among the three directions. These pathomechanisms may partly explain the additive effect of DM on LV deformation in RCM patients.
In the early stages of RCM, LV diastolic dysfunction may occur due to increased myocardial stiffness, which causes a rapid rise in ventricular pressure at the beginning of the diastolic stage, while LV systolic function is typically preserved[7, 16]. In our study, the LV longitudinal PDSR was significantly decreased in the RCM(DM+) group, and multivariable regression analysis showed that DM was independently associated with longitudinal PDSR in RCM patients, which suggesting a possible mechanistic link between DM and myocardial diastolic dysfunction in patients with RCM. Previous studies have shown that diastolic dysfunction can be detected in asymptomatic DM patients with normal LVEF level, which is related to the complex mechanism of myocardium injury in diabetes[30, 31]. For patients with RCM, impaired diastolic dysfunction may be further aggravated with DM, which chronically elevated LV filling pressure and resulted in an almost fixed or decreased stroke volume. Under these conditions, the increase in heart rate is the only adaptive response to increase cardiac output, which is also consistent with the structure of our study.
Furthermore, our study showed that NT-proBNP levels were significantly higher in RCM(DM+) patients than in RCM(DM-) patients, and were an independent determinant of LV global strains and longitudinal PDSR in RCM patients. LGE has been shown to be associated with myocardial interstitial infiltration, which is the s the most dominant cardiac phenotypes of RCM, and diffuse LGE was independently predictive of increased late mortality in RCM patients[18, 32]. Although, there were no differences in the LGE type between RCM patients with and without DM, similar to NT-proBNP levels, the LGE type was also an independent determinant of LV deformation. The relationship of NT-proBNP and LGE type with LV deformation was stronger than that of DM, however, with the addition of DM, the multi-parameter combination obtained a larger AUC in the ROC curves of GLPS and longitudinal PDSR. In addition to the biochemical and imaging indicators of conventional cardiac function injury, DM, as a cardiovascular risk factor with increasing incidence, should be given more attention to achieve early prevention and treatment in RCM patients.
Limitation
The study had several limitations. First, this was a retrospective single-center study, so there may be some selection bias in the results. Second, not all patients received biopsies to confirm the cause of their restrictive cardiomyopathy, so we based the inclusion criteria on the clinical biopsy results or combined clinical, ECG, and imaging findings, according to the ESC review [6]; Third, RCM patients usually have several cardiovascular risk factors, including hypertension, hyperlipidemia and coronary heart disease, which may have potential adverse effects on LV function. In order to avoid ischemic myocardial damage caused by coronary heart disease, we excluded these patients. We included hypertension and hyperlipidemia in the multivariable regression analysis and found that DM was still an independent determinant of LV function.