Assessing cardiac stiffness using ultrasound shear wave elastography

Shear wave elastography offers a new dimension to echocardiography: it measures myocardial stiffness. Therefore, it could provide additional insights into the pathophysiology of cardiac diseases affecting myocardial stiffness and potentially improve diagnosis or guide patient treatment. The technique detects fast mechanical waves on the heart wall with high frame rate echography, and converts their propagation velocity into a stiffness value. A proper interpretation of shear wave data is required as the shear wave interacts with the intrinsic, yet dynamically changing geometrical and material characteristics of the heart under pressure. This dramatically alters the wave physics of the propagating wave, demanding adapted processing methods compared to other shear wave elastography applications as breast tumor and liver stiffness staging. Furthermore, several advanced analysis methods have been proposed to extract supplementary material features such as viscosity and anisotropy, potentially offering additional diagnostic value. This review explains the general mechanical concepts underlying cardiac shear wave elastography and provides an overview of the preclinical and clinical studies within the field. We also identify the mechanical and technical challenges ahead to make shear wave elastography a valuable tool for clinical practice.

N-acetyl Cysteine, Selenium, and Ascorbic Acid Rescue Diabetic Cardiac Hypertrophy via Mitochondrial-Associated Redox Regulators

Metabolic disorders often lead to cardiac complications. Metabolic deregulations during diabetic conditions are linked to mitochondrial dysfunctions, which are the key contributing factors in cardiac hypertrophy. However, the underlying mechanisms involved in diabetes-induced cardiac hypertrophy are poorly understood. In the current study, we initially established a diabetic rat model by alloxan-administration, which was validated by peripheral glucose measurement. Diabetic rats displayed myocardial stiffness and fibrosis, changes in heart weight/body weight, heart weight/tibia length ratios, and enhanced size of myocytes, which altogether demonstrated the establishment of diabetic cardiac hypertrophy (DCH). Furthermore, we examined the expression of genes associated with mitochondrial signaling impairment. Our data show that the expression of PGC-1α, cytochrome c, MFN-2, and Drp-1 was deregulated. Mitochondrial-signaling impairment was further validated by redox-system dysregulation, which showed a significant increase in ROS and thiobarbituric acid reactive substances, both in serum and heart tissue, whereas the superoxide dismutase, catalase, and glutathione levels were decreased. Additionally, the expression levels of pro-apoptotic gene PUMA and stress marker GATA-4 genes were elevated, whereas ARC, PPARα, and Bcl-2 expression levels were decreased in the heart tissues of diabetic rats. Importantly, these alloxan-induced impairments were rescued by N-acetyl cysteine, ascorbic acid, and selenium treatment. This was demonstrated by the amelioration of myocardial stiffness, fibrosis, mitochondrial gene expression, lipid profile, restoration of myocyte size, reduced oxidative stress, and the activation of enzymes associated with antioxidant activities. Altogether, these data indicate that the improvement of mitochondrial dysfunction by protective agents such as N-acetyl cysteine, selenium, and ascorbic acid could rescue diabetes-associated cardiac complications, including DCH.

Myocardial stiffness assessed by natural shear wave elastography is related to pressure-volume loop derived parameters

Background Several cardiovascular disorders are accompanied by a stiffening of the myocardium and may result in diastolic heart failure. The non-invasive assessment of myocardial stiffness could therefore improve the understanding of the pathophysiology and guide treatment. Shear wave elastography (SWE) is a recent technique with tremendous potential for evaluating myocardial stiffness in a non-invasive way. Using high frame rate echocardiography, the propagation speed of shear waves is evaluated, which is directly related to the stiffness of the myocardium. These waves are induced by for instance mitral valve closure (MVC) and propagate throughout the cardiac muscle. However, validation of SWE against an invasive gold standard method is lacking. Purpose The aim of this study was to compare echocardiographic shear wave elastography against invasive pressure-volume loops, a gold standard reference method for assessing chamber stiffness. Methods In 15 pigs (31.2±4.1 kg) stiffness of the myocardium was acutely changed by inducing ischemia/reperfusion (I/R) injury. For this, the proximal LAD was balloon occluded for 90 minutes with subsequent reperfusion for 40 minutes. Conventional and high frame rate echocardiographic images were acquired simultaneously with pressure-volume loops during baseline conditions and after the induction of the I/R injury. Preload was reduced in order to acquire a set of pressure-volume loops to derive the end-diastolic pressure volume relation (EDPVR). From the EDPVR, the stiffness coefficient β and the operating chamber stiffness dP/dV were obtained. High frame rate echocardiographic datasets of the parasternal long axis view were acquired with an experimental ultrasound scanner (HD-PULSE) at an average frame rate of 1304±115 Hz. Tissue acceleration maps were obtained by drawing an M-mode line along the interventricular septum in order to visualize shear waves after MVC (at end-diastole). The propagation speed was assessed by semi-automatically measuring the slope (Figure A). Results I/R injury led to an elevated chamber stiffness constant β (0.09±0.03 1/ml vs. 0.05±0.01 1/ml; p<0.001) and operating chamber stiffness dP/dV (1.09±0.38 mmHg/ml vs. 0.50±0.18 mmHg/ml; p<0.01). Likewise, shear wave speed after MVC increased after the induction of the I/R injury in comparison to baseline (6.1±1.2 m/s vs. 3.2±0.8 m/s; p<0.001). Shear wave speed had a moderate positive correlation with β (r=0.63; p<0.001) (Figure B) and a strong positive correlation with dP/dV (r=0.81; p<0.001) (Figure C). Conclusion End-diastolic shear wave speed is strongly related to chamber stiffness, assessed invasively by pressure-volume loops. These results indicate that shear wave propagation speed could be used as a novel non-invasive measurement of the mechanical properties of the ventricle. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): FWO - Research Foundation Flanders

One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction

Background: Individuals with left ventricular (LV) hypertrophy and elevated cardiac biomarkers in middle age are at increased risk for the development of heart failure with preserved ejection fraction. Prolonged exercise training reverses the LV stiffening associated with healthy but sedentary aging; however, whether it can also normalize LV myocardial stiffness in patients at high risk for heart failure with preserved ejection fraction is unknown. In a prospective, randomized controlled trial, we hypothesized that 1-year prolonged exercise training would reduce LV myocardial stiffness in patients with LV hypertrophy. Methods: Forty-six patients with LV hypertrophy (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomly assigned to either 1 year of high-intensity exercise training (n=30) or attention control (n=16). Right-heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using both lower body negative pressure and rapid saline infusion to define the LV end-diastolic pressure-volume relationship. A constant representing LV myocardial stiffness was calculated from the following: P=S×[Exp {a (V–V 0 )}–1], where “P” is transmural pressure (pulmonary capillary wedge pressure – right atrial pressure), “S” is the pressure asymptote of the curve, “V” is the LV end-diastolic volume index, “V 0 ” is equilibrium volume, and “a” is the constant that characterizes LV myocardial stiffness. Results: Thirty-one participants (exercise group [n=20]: 54±6 years, 65% male; and controls (n=11): 51±6 years, 55% male) completed the study. One year of exercise training increased max by 21% (baseline 26.0±5.3 to 1 year later 31.3±5.8 mL·min –1 ·kg –1 , P <0.0001, interaction P =0.0004), whereas there was no significant change in max in controls (baseline 24.6±3.4 to 1 year later 24.2±4.1 mL·min –1 ·kg –1 , P =0.986). LV myocardial stiffness was reduced (right and downward shift in the end-diastolic pressure-volume relationship; LV myocardial stiffness: baseline 0.062±0.020 to 1 year later 0.031±0.009), whereas there was no significant change in controls (baseline 0.061±0.033 to 1 year later 0.066±0.031, interaction P =0.001). Conclusions: In patients with LV hypertrophy and elevated cardiac biomarkers (stage B heart failure with preserved ejection fraction), 1 year of exercise training reduced LV myocardial stiffness. Thus, exercise training may provide protection against the future risk of heart failure with preserved ejection fraction in such patients. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03476785.

Sensing and Responding of Cardiomyocytes to Changes of Tissue Stiffness in the Diseased Heart

Cardiomyocytes are permanently exposed to mechanical stimulation due to cardiac contractility. Passive myocardial stiffness is a crucial factor, which defines the physiological ventricular compliance and volume of diastolic filling with blood. Heart diseases often present with increased myocardial stiffness, for instance when fibrotic changes modify the composition of the cardiac extracellular matrix (ECM). Consequently, the ventricle loses its compliance, and the diastolic blood volume is reduced. Recent advances in the field of cardiac mechanobiology revealed that disease-related environmental stiffness changes cause severe alterations in cardiomyocyte cellular behavior and function. Here, we review the molecular mechanotransduction pathways that enable cardiomyocytes to sense stiffness changes and translate those into an altered gene expression. We will also summarize current knowledge about when myocardial stiffness increases in the diseased heart. Sophisticated in vitro studies revealed functional changes, when cardiomyocytes faced a stiffer matrix. Finally, we will highlight recent studies that described modulations of cardiac stiffness and thus myocardial performance in vivo. Mechanobiology research is just at the cusp of systematic investigations related to mechanical changes in the diseased heart but what is known already makes way for new therapeutic approaches in regenerative biology.