Research Progress on Epigenetics of Diabetic Cardiomyopathy in Type 2 Diabetes

Diabetic cardiomyopathy (DCM) is characterized by diastolic relaxation abnormalities in its initial stages and by clinical heart failure (HF) without dyslipidemia, hypertension, and coronary artery disease in its last stages. DCM contributes to the high mortality and morbidity rates observed in diabetic populations. Diabetes is a polygenic, heritable, and complex condition that is exacerbated by environmental factors. Recent studies have demonstrated that epigenetics directly or indirectly contribute to pathogenesis. While epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs, have been recognized as key players in the pathogenesis of DCM, some of their impacts remain not well understood. Furthering our understanding of the roles played by epigenetics in DCM will provide novel avenues for DCM therapeutics and prevention strategies.

Mid-Diastolic Events (L Events): A Critical Review

Mid-diastolic events (L events) include three phenomena appreciable on echocardiography occurring during diastasis: mid-diastolic transmitral flow velocity (L wave), mid-diastolic mitral valve motion (L motion), and mid-diastolic mitral annular velocity (L’ wave). L wave is a known marker of advanced diastolic dysfunction in different pathological clinical settings such as left ventricle and atrial remodeling, overloaded states, and cardiomyopathies. Patients with L events have poor outcomes with a higher risk of developing heart failure symptoms and arrhythmic complications, including sudden cardiac death. The exact mechanism underlying the genesis of mid-diastolic events is not fully understood, just as the significance of these events in healthy young people or their presence at the tricuspid valve level. We also report an explicative case of a patient with L events studied using speckle tracking imaging of the left atrium and ventricle at the same reference heartbeat supporting the hypothesis of a post-early diastolic relaxation or a “two-step” ventricular relaxation for L wave genesis. Our paper seeks to extend knowledge about the pathophysiological mechanisms on mid-diastolic events and summarizes the current knowledge.

Abstract P274: Inhibition Of Abnormal Exosome Release Prevents Excessive Aortic Stiffness And Relaxation Dysfunction In Diet-induced Obesity

Interactions between over-nutrition and abnormal exosome release impact insulin sensitivity and the development of cardiovascular disease (CVD). Recent data have shown that exosomes can be released from various cell types, including adipocytes and vascular cells, and that they exist in body fluids and tissues functioning as mediators of cell-cell communication. However, the specific role of exosomes in diet-induced excessive vascular stiffness and hypertension has not been explored. Accordingly, we hypothesized that abnormal release of exosomes contributes to western diet (WD)- induced aortic stiffening and impaired vascular diastolic relaxation. We further posited that GW4869, an antagonist of neutral sphingomyelinase 2 (nSMase2) which promotes exosome production and release, would prevent WD-induced aortic stiffening and impaired vascular relaxation. Six week-old female C57BL/6L mice were fed a mouse chow (CD) or WD containing excess fat (46%) and fructose (17.5%) for 16 weeks with or without GW4849. To this point, 200 μl of 0.3 mg/mL GW4869 in 0.9% normal saline (60 μg/mouse; 2-2.5 μg/g body weight) was injected intraperitoneally every 48 hours for 12 weeks. 16 weeks of WD induced an increase of aortic stiffness as examined by pulse wave velocity (PWV) and impaired the aortic vasodilation responses to acetylcholine (Ach) and sodium nitroprusside (SNP) (10 -9 -10 -4 mol/L). However, GW4869 treatment prevented the WD-induced excessive aortic stiffness, as well as impairment of endothelium dependent/independent vascular relaxation. There were no significant differences in blood pressure between each group examined by tail cuff blood pressure measurement. These findings support the hypothesis that abnormal release of exosomes play an important role in WD-induced excessive aortic stiffness, impaired vascular relaxation and CVD in diet-induced obesity.

Graves’ Disease and Cardiac Complications

Graves’ disease is an autoimmune thyroid disease and a common cause of hyperthyroidism. Thyroid hormones have multiple adverse effect on cardiovascular system through many direct and indirect mechanisms. They increases heart rate, cardiac contractility, systolic and mean pulmonary artery pressure, cardiac output, diastolic relaxation, and myocardial oxygen consumption, whereas decrease systemic vascular resistance and diastolic pressure. All these hemodynamic changes in cardiovascular system can eventually lead to heart failure, tachyarrhythmias, systemic and pulmonary hypertension, if left untreated. Cardiovascular complications of Graves’ disease are frequent and important cause of increased morbidity and mortality. This chapter reviews the cardiovascular complications of Graves’ hyperthyroidism with underlying mechanisms and treatment.

Abstract 15057: Electromechanical Discoordination is Present in Patients With Duchenne Muscular Dystrophy Independent of Tissue Fibrosis

Introduction: Progressive ventricular dysfunction is a cardinal symptom in Duchenne Muscular Dystrophy (DMD). Some of the earliest signs of cardiomyopathy in DMD are myocardial fibrotic deposition and LV strain defects. Electromechanical discoordination, as measured by Systolic Stretch Fraction (SSF) and Diastolic Relaxation Fraction (DRF), has been shown to be a sensitive marker of ventricular dysfunction. The presence of this discoordination in relation to fibrotic deposition in DMD has yet to be elucidated. Hypothesis: Patients with DMD will have abnormal SSF and DRF on cardiac MRI (CMR) tissue tracking analysis and associated with fibrotic deposition. Methods: Patients with DMD (n=31)(mean age: 14 ± 4 yrs) and controls (n=20) (mean age: 15 ± 3 yrs) underwent CMR for volumetric and functional analysis as well as Gadolinium (Gd) enhancement to evaluate the presence of fibrosis. Circumferential strain and strain rate indices from each segment were used to calculate electromechanical discoordination. Strain rate data was used to calculate SSF and DRF. Results: Patients with DMD showed increased median LV SSF compared to controls [0.027 (IQR: 0.015-0.041) vs 0.007 (IQR:0.005-0.013), P = 0.002] as well as increased median LV DRF [0.371 (IQR: 0.310-0.473) vs 0.300 (IQR: 0.264-0.325), P < 0.001] (Figure). When comparing Gd(+) (n=14) vs Gd(-) (n=17) DMD patients, there was no difference between groups in either SSF [0.027 (IQR: 0.016-0.042) vs 0.026 (IQR: 0.008-0.040), P= 0.929] or DRF [0.371 (IQR: 0.309-0.537) vs 0.379 (IQR: 0.322-0.464), P= 0.931]. The SSF was associated with ESVi (R=0.71, P<0.001), EDVi (R=0.65, P< 0.001) and inversely associated with EF (R=-0.63, P<0.001). Conclusion: Patients with DMD showed increased levels of LV electromechanical discoordination independent of qualitative presence of fibrosis noted by Gd enhancement. This allows speculation that changes in electromechanical discoordination may precede visible fibrotic change in DMD.

Abstract 14479: Fontan Patients With Dominant Left Ventricular Morphology Have Severe Ventricular Electromechanical Discoordination Associated With Worse Exercise Capacity

Introduction: Fontan patients with a single left ventricle (SLV) develop late systolic and diastolic dysfunction. The development of SLV dysfunction has been associated with abnormal loading conditions, myocardial ischemia and fibrosis, and compromised ventricular-aortic coupling. However, electromechanical discoordination, a prime determinant of ventricular performance, has not been adequately evaluated in patients with SLV. Hypothesis: Patients with SLV and Fontan circulation will have abnormal electromechanical discoordination compared to controls, and this will be associated with their functional status. Methods: Patients with SLV (n=20) and healthy controls (n=20) underwent MRI-based tissue deformation analysis. Circumferential strain and strain rate data were used to calculate systolic stretch fraction (SSF) and diastolic relaxation fraction (DRF) (Figure 1). SSF is the proportion of myocardial segments undergoing relaxation in systole, while the DRF is the proportion of myocardial segments undergoing contraction in diastole. SSF and DRF were correlated with standard MRI indices and standard exercise tests. Results: Global circumferential strain was decreased in SLV compared to controls (16.4±2.7 vs 19.9±1.7, P<0.001). SLV had increased median SSF when compared to the LV of controls [(0.023 (IQR: 0.006-0.036) vs. 0.007 (IQR: 0.006-0.013), P=0.023] and increased median DRF [0.39 (IQR: 0.30-0.44) vs. 0.30 (IQR: 0.26-0.32), P=0.002]. SSF correlated with the peak VO 2 index (R=-0.56, P=0.027) and DRF correlated with ejection fraction (R=-0.56, P=0.010). Conclusion: Fontan patients with SLV exhibit systolic and diastolic electromechanical discoordination, which is associated with lower peak VO 2 and reduced ejection fraction, respectively. Electromechanical discoordination might contribute to global SLV dysfunction by limiting both effective contractility and preload generation.

The Giraffe as a Natural Animal Model for Resistance to Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a leading form of human cardiovascular disease and commonly associated with systemic hypertension. Unique evolved adaptations in giraffe myocardia may be a natural animal model of resistance to HFpEF. In humans, pressure-overload induced left ventricular thickening (PLVT) impairs diastolic relaxation, elevates left atrial pressures and may progress to heart failure with symptoms including exercise intolerance. In healthy giraffe, the left ventricle thickens as developmental neck lengthening widens the vertical distance between the heart and head increasing pressures needed to maintain constant brain perfusion. Yet, diastolic relaxation and exercise capacity are unimpaired, a critical adaptation for prey species such as giraffe. The proximate mechanisms underlying this unique cardiovascular physiology are not yet characterized. Developmental PLVT in giraffe emerges as a species-specific evolved adaptation which offers a roadmap for identifying innovations in therapeutic and prevention strategies for HFpEF.

Abstract 299: Cardiac Fibroblast-derived FGF21 is a Novel Therapeutic Target for Cardiac Pathological Remodeling

Background: Fibroblast Growth factor 21(FGF21) is an endocrine factor, secreted mainly by the liver, that exerts metabolic actions. It has been shown that FGF21 has an anti-hypertrophic action for cardiac hypertrophy. We previously reported that murine cardiac FGF21 expression was upregulated by pressure-overload. The objective of this study was to clarify the role of cardiac fibroblast-derived FGF21 in cardiac pathological remodeling. Methods and Results: We generated fibroblast-specific/tamoxifen-inducible FGF21 knockout mice crossing by FGF21flox mice and Col1a2-CreERT mice (FB-FGF21KO). FGF21flox control mice and KO mice were induced cardiac hypertrophy by transverse aortic constriction (TAC). After 3-weeks TAC surgery, we evaluated the cardiac function by echocardiography or conductance catheter. TAC-mediated cardiac hypertrophy or impairment of systolic function were exacerbated in FB-FGF21KO mice. Conductance catheter showed that Tau, diastolic relaxation marker, was exacerbated in FB-FGF21KO mice with TAC. FB-FGF21KO heart with TAC showed significant upregulation in profibrotic genes and down-regulation in Ca2+ ATPase in comparison with control TAC heart. Cardiac Sirt1, which plays a central role in energy metabolism or oxidative stress, increased by TAC was significantly attenuated in FB-FGF21KO heart. Conclusion: Deletion of FGF21 in cardiac fibroblasts exacerbates cardiac dysfunction in response to pressure overload suggesting that cardiac fibroblasts regulates pathological remodeling via FGF21 regulation.

Novel measures of left ventricular electromechanical discoordination predict clinical outcomes in children with pulmonary arterial hypertension

Adverse ventricle-ventricle interaction and resultant left ventricular (LV) dysfunction are a recognized pathophysiological component of disease progression in pulmonary arterial hypertension (PAH) and can be associated with electrical and mechanical dyssynchrony. The purpose of this study was to investigate the clinical and mechanistic implications of LV electromechanical dyssynchrony in children with PAH by using novel systolic stretch and diastolic relaxation discoordination indexes derived noninvasively from cardiac MRI (CMR). In children with PAH referred for CMR ( n = 64) and healthy controls ( n = 20), we calculated two novel markers of ventricular discoordination, systolic stretch fraction (SSF) and diastolic relaxation fraction (DRF). SSF and DRF were evaluated with respect to 1) electrical dyssynchrony, 2) functional status, and 3) composite clinical outcomes. SSF was increased in patients with PAH compared with controls ( P = 0.004). There was no difference in DRF between PAH and control groups. There were no differences between groups in standard mechanical dyssynchrony and LV global circumferential strain. Increased SSF was associated with greater electrical dyssynchrony (QRS duration) as well as worse WHO functional class. SSF, DRF, mechanical dyssynchrony, and right ventricular (RV) volumes were prognostic for worse clinical outcomes. LV dyssynchrony indexes are altered in pediatric patients with PAH compared with controls in proportion with greater degrees of RV dilation. Patients with PAH with greater dyssynchrony have worse clinical outcomes. RV-induced increased LV electromechanical dyssynchrony therefore may be an important link in the causal pathway from PAH to clinically significant LV dysfunction. Since dyssynchrony could precede overt LV dysfunction, addition of ventricular synchrony analysis to CMR postprocessing protocols may be of clinical benefit. NEW & NOTEWORTHY We demonstrate that left ventricular discoordination indexes are altered in pediatric patients with pulmonary arterial hypertension compared with controls and pediatric patients with pulmonary arterial hypertension with greater dyssynchrony have worse clinical outcomes. Furthermore, there is evidence for the mechanism of right ventricular-induced left ventricular discoordination to include a combination of delayed early systolic electromechanical activation, late-systolic septal shift, and prolonged, postsystolic septal thickening.

Left ventricular vortex and intraventricular pressure difference in dogs under various loading conditions

Restrictions on the conventional evaluation of diastolic function have been recognized, especially under various loading conditions. Recently, new noninvasive ventricular vortex indexes have been introduced and are expected to reflect the cardiac function. Physiologically, there is a hypothesis that the intraventricular pressure difference (IVPD) is related to the formation of vortexes. IVPD and vortex indexes were simultaneously measured, and the relationship between the two was investigated. To verify the possibility of diastolic vorticity as an index of diastolic relaxation, a correlation between diastolic vorticity and the load dependency of vorticity [time constant (τ)] was examined. Six healthy dogs were studied using transthoracic echocardiography, pressure, and a conductance catheter. Vorticity was analyzed using vector flow mapping (VFM). IVPD was determined using Euler’s equation with color M-mode Doppler images. Data were obtained at baseline, at balloon dilatation in the thoracic aorta to alter afterload, at hydroxyethyl starch infusion to alter preload, and at milrinone administration to alter ventricular relaxation. Peak vorticity at early diastole (E-Vor) and IVPD of the midventricle (MIVPD) decreased under pressure loading, were unchanged under volume loading, and increased during milrinone administration. In multivariate analysis, the independent predictors of τ were global longitudinal strain, strain rate at early diastole, and E-Vor. MIVPD was strongly correlated with E-Vor ( r = 0.84). VFM-derived peak E vorticity was strongly related to IVPD, especially MIVPD, under various loading conditions. Both of these novel indexes are promising as reliable indexes of ventricular relaxation, independent from preload. NEW & NOTEWORTHY We showed the close relationship of vortex and intraventricular pressure difference and showed that both of them can become new markers of the left ventricular relaxation property. Our present study creates a paradigm for future studies in the field of intraventircular flow physiology and clinical diastology.