Myocardial Stiffness Evaluation Using Noninvasive Shear Wave Imaging in Healthy and Hypertrophic Cardiomyopathic Adults

OBJECTIVES The goal of our study was to investigate the potential of myocardial shear wave imaging (SWI) to quantify the diastolic myocardial stiffness (MS) (kPa) noninvasively in adult healthy volunteers (HVs) and its physiological variation with age, and in hypertrophic cardiomyopathy (HCM) populations with heart failure and preserved ejection function (HFpEF). BACKGROUND MS is an important prognostic and diagnostic parameter of the diastolic function. MS is affected by physiological changes but also by pathological alterations of extracellular and cellular tissues. However, the clinical assessment of MS and the diastolic function remains challenging. SWI is a novel ultrasound-based technique that has the potential to provide intrinsic MS noninvasively. METHODS Weprospectivelyincluded80adults:60HV(dividedinto3groups:20-to39-yearoldpatients[n ¼ 20];40-to 59-year-old patients [n ¼ 20]; and 60- to 79-year-old patients [n ¼ 20]) and 20 HCM-HFpEF patients. Echocardiography, cardiac magnetic resonance imaging and biological explorations were achieved. MS evaluation was performed using an ultrafast ultrasound scanner with cardiac phased array. The fractional anisotropy of MS was also estimated. (cid:2) 1.06 kPa for the 20- to 40-year-old, 40- to 60-year-old, and 60- to 80-year-old patient groups, respectively; p < 0.01 between each group). MS was signi ﬁ cantly higher in HCM-HFpEF patients than in HV patients (mean MS ¼ 12.68 (cid:2) 2.91 kPa vs. 4.47 (cid:2) 1.68 kPa, respectively; p < 0.01), with a cut-off at 8 kPa (area under the curve ¼ 0.993; sensitivity ¼ 95%, speci ﬁ city ¼ 100%). The fractional anisotropy was lower in HCM-HFpEF (mean ¼ 0.133 (cid:2) 0.073) than in HV (0.238 (cid:2) 0.068) (p < 0.01). Positive correlations were found between MS and diastolic parameters in echocardiography (early diastolic peak/early diastolic mitral annular velocity, r ¼ 0.783; early diastolic peak/transmitral ﬂ ow propagation velocity, r ¼ 0.616; left atrial volume index, r ¼ 0.623) and with ﬁ brosis markers in cardiac magnetic resonance (late gadolinium enhancement, r ¼ 0.804; myocardial T1 pre-contrast, r ¼ 0.711). CONCLUSIONS MS was found to increase with age in healthy adults and was signi ﬁ cantly higher in HCM-HFpEF patients. Myocardial SWI has the potential to become a clinical tool for the diagnostic of diastolic dysfunction.

M yocardial stiffness (MS) is known to play a key role in diastolic left ventricular (LV) function (1). Abnormalities in LV relaxation and MS are one of the key pathophysiological mechanisms (2) in heart failure patients with preserved ejection fraction (HFpEF). Hypertrophic cardiomyopathy (HCM) is also associated to severe diastolic dysfunction mainly due to fibrosis and fiber disarray (3). Moreover, MS is also affected by aging due to progressive physiological changes and cellular and extracellular matrix alterations. However, as the clinical assessment of MS and of the diastolic function is still challenging (4), the study of MS remained limited to invasive explorations (5).
In a general view, the assessments of diastolic function can be divided into those that reflect the process of active/auxotonic relaxation (depending on filling load and afterload) and those that reflect passive stiffness (independent of load conditions) (6).
In clinical practice, biological parameters are correlated with ventricular filling pressures (e.g., brain natriuretic protein [BNP]) (7), echocardiographic parameters are identified to assess the auxotonic relaxation and/or the filling pressure, and cardiac magnetic resonance (CMR) imaging offers tools to evaluate myocardial fibrosis (late enhancement gadolinium [LGE]) (8), or the collagen volume fraction (pre-post contrast T1 mapping or extracellular volume fraction [ECV]) (9,10). However, noninvasive estimation of passive stiffness remains challenging. To date, cardiac catheterization is the only validated option to assess the passive stiffness clinically, through the compliance estimation thanks to the pressure-volume loops (11). But the risks for the patients, the necessary equipment, and the costs of these interventions make this examination unfeasible in daily clinical practice.
Shear wave imaging (SWI) is an ultrasound-based technique for quantitative, local, and noninvasive mapping of soft tissue's stiffness. The clinical impact of SWI has been shown during the last decade in the field of breast lesions (12) and liver (13) imaging.
Quantification of MS using SWI has also been investigated extensively on animal models in previous studies (14). SWI was compared to invasive gold standard parameters (15) derived from pressurevolume loops and was shown to quantify the enddiastolic MS (i.e., passive stiffness) accurately. More recently, the clinical feasibility and reproducibility of transthoracic SWI was shown on a small group of healthy volunteers (HVs) (16) and on pediatric patients (17). The next step is to show the clinical interest and contribution of this technology for the assessment of diastolic MS in adults and its impact on diastolic LV function. Unlike other imaging techniques, echocardiography is inexpensive, widely available, and can be performed in real-time at the patient bedside allowing monitoring of the heart structure and function.    This modality has already been described in previous works (14,15), and is also described in more details in the Supplemental Appendix. In this study, a phased Fractional anisotropy. Similar to any fiber-composed muscular tissue, the myocardium presents a significant anisotropy of its elastic properties. Consequently, MS is expected to be higher when measured along the fibers, which are mainly oriented along the The study was performed on 60 healthy volunteer and 20 HCM patients. CMR ¼ cardiac magnetic resonance; HCM ¼ hypertrophic cardiomyopathy; HFpEF ¼ heart failure with preserved ejection fraction.
Villemain et al.  was tested by the Bland-Altman limits of agreement.
The reproducibility coefficient was calculated as 1.96 Â the SD of the differences, as proposed by Bland and Altman (25). All the analyses were conducted using Medcalc (MedCalc Software, Mariakerke, Belgium).  Values are mean AE SD or n/N (%).
There is no statistical difference between the HV group and the HCM-HFpEF group in terms of age (p ¼

DISCUSSION
In this study, MS was assessed quantitatively using noninvasive SWI in HV and HCM patients with HFpEF.
To our knowledge, this is the first study to assess MS quantitatively and noninvasively in both HV and pathological cases (HCM-HFpEF). This study showed that SWI allows us to establish values of MS in a HV population, MS increases strongly with age in the normal heart, and there is a large difference in MS between HV and HCM-HFpEF groups (cutoff ¼ 8 kPa).
In this study we were able to quantify MS aging. In the NORRE (Normal Reference Ranges for Echocardiography) study, Caballero et al. (26) also found a gradual change with age of the main echocardiographic parameters of the diastolic function. In this study, which analyzed 449 HV echocardiographs, the E/e 0 ratio increased from an average of 6.9 AE 1.6 in 20to 39-year-old subjects to an average of 9.7 AE 2.8 in 60to 79-year-old subjects, a change of approximately 50% with a fairly linear evolution. Myocardial aging was also evaluated by CMR on a human population (27) or by invasive estimation on animal study (28). In 1991, Weger et al. (29) have well demonstrated that the age-induced physiological myocardial fibrosis impacts on the cardiac function, including the ability of the ventricle to relax during the diastolic filling (auxotonic relaxation). Regarding HV patients who participated in our study, we also found a linear evolution of MS, allowing us to establish the change of MS with age.
We also showed an MS difference between HV and HCM-HFpEF noninvasively. Zile et al. (30) have shown on myocardial histologic explorations of HFpEF patients that an increase in passive MS is due to an architectural modification (increase of collagen and    Transthoracic Myocardial Stiffness Assessment in Adults J U L Y 2 0 1 9 : 1 1 3 5 -4 5