Maladaptive Left Ventricular Remodeling Research Articles

Biologically derived epicardial patch induces macrophage mediated pathophysiologic repair in chronically infarcted swine hearts

There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF.

Abstract 17096: Immune Modulation to Treat Ischemic Heart Failure

Introduction: Clinical use of induced pluripotent derived cardiomyocytes (iPSC-CMs) has been slow because their mechanism is not well defined. Our lab developed a cardiac patch composed of iPSC-CMs and human neonatal dermal fibroblast (NDF) seeded on a bioresorbable matrix. Implantation on the epicardium of the infarcted heart in immune competent animal models of ischemic CHF (mice, rats, swine) repaired the damaged heart, improved cardiac function/structure with increased viable myocardium, increased myocardial blood flow, improved left ventricular (LV) contractility, and reversal of maladaptive LV remodeling. Preliminary analysis indicates that the patch created a novel host derived immune response not observed in untreated animals. Hypothesis: The iPSC-CMs and NDFs coordinate an immunomodulatory response that results in reduction of inflammatory cytokine producing M1 macrophages with concomitant polarization to the M2 state. Methods: Spatial transcriptomics and histological analysis was utilized for investigation of patch driven immunomodulatory responses in WT BL6 mice. All animals underwent two procedures; 1) Infarct via left coronary ligation 2) Left lateral sternotomy with patch placement (N=5) (no patch for controls, N=3) 3 weeks post MI. Patch secretions underwent quantitative mass spectroscopy to identify drivers of immunomodulation. Results: Histology demonstrated reduction of left chamber dimension and presence of viable cardiomyocytes in the LV wall. IF demonstrated a novel immune response in the treated group absent in the controls. This response is isolated to the epicardial infarct-patch interface. Cellular deconvolution of the infarct region revealed macrophages and dendritic cells compose this response. Macrophage phenotype was assessed via expression of classical M1(CD68, NOS2, AXL) as well as M2 markers (RETNLA, MRC1, ADGRE1) which were found to be significantly elevated in treated groups. Proteomic analysis of the patch secretome indicates the patch has a role in coordinating this response by upregulation of Il-4/Il-13 signaling and wound healing that stimulates enrichment of pathways associated with reorganization of the ECM.

Nanowired human cardiac organoid transplantation enables highly efficient and effective recovery of infarcted hearts.

Human cardiac organoids hold remarkable potential for cardiovascular disease modeling and human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) transplantation. Here, we show cardiac organoids engineered with electrically conductive silicon nanowires (e-SiNWs) significantly enhance the therapeutic efficacy of hPSC-CMs to treat infarcted hearts. We first demonstrated the biocompatibility of e-SiNWs and their capacity to improve cardiac microtissue engraftment in healthy rat myocardium. Nanowired human cardiac organoids were then engineered with hPSC-CMs, nonmyocyte supporting cells, and e-SiNWs. Nonmyocyte supporting cells promoted greater ischemia tolerance of cardiac organoids, and e-SiNWs significantly improved electrical pacing capacity. After transplantation into ischemia/reperfusion-injured rat hearts, nanowired cardiac organoids significantly improved contractile development of engrafted hPSC-CMs, induced potent cardiac functional recovery, and reduced maladaptive left ventricular remodeling. Compared to contemporary studies with an identical injury model, greater functional recovery was achieved with a 20-fold lower dose of hPSC-CMs, revealing therapeutic synergy between conductive nanomaterials and human cardiac organoids for efficient heart repair.

Chronic high‑salt intake induces cardiomyocyte autophagic vacuolization during left ventricular maladaptive remodeling in spontaneously hypertensive rats.

The role of autophagy in high-salt (HS) intake associated hypertensive left ventricular (LV) remodeling remains unclear. The present study investigated the LV autophagic change and its association with the hypertensive LV remodeling induced by chronic HS intake in spontaneously hypertensive rats (SHR). Wistar Kyoto (WKY) rats and SHR were fed low-salt (LS; 0.5% NaCl) and HS (8.0% NaCl) diets and were subjected to invasive LV hemodynamic analysis after 8, 12 and 16 weeks of dietary intervention. Reverse transcription-quantitative PCR and western blot analysis were performed to investigate the expression of autophagy-associated key components. The LV morphologic staining was performed at the end of the study. The rat H9c2 ventricular myoblast cell-associated experiments were performed to explore the mechanism of HS induced autophagic change. A global autophagy-associated key component, as well as increased cardiomyocyte autophagic vacuolization, was observed after 12 weeks of HS intake. During this period, the heart from HS-diet-fed SHR exhibited a transition from compensated LV hypertrophy to decompensation, as shown by progressive impairment of LV function and interstitial fibrosis. Myocardial extracellular [Na+] and the expression of tonicity-responsive enhancer binding protein (TonEBP) was significantly increased in HS-fed rats, indicating myocardial interstitial hypertonicity by chronic HS intake. The global autophagic change and overt deterioration of LV function were not observed in LS-fed SHR and HS-fed WKY rats. The study of rat H9c2 cardiomyocytes demonstrated a cytosolic [Na+] elevation-mediated, reactive oxygen species-dependent the autophagic change occurred when exposed to an increased extracellular [Na+]. The present findings demonstrated that a myocardial autophagic change participates in the maladaptive LV remodeling induced by chronic HS intake in SHR, which provides a possible target for future intervention studies on HS-induced hypertensive LV remodeling.

Abstract 15210: Association of Circulating Biomarkers With Progressive Left Ventricular Remodeling and Hypertrophy in Patients With Aortic Stenosis: Results From the Progressa Study

Introduction: Aortic stenosis (AS) is associated with progressive left ventricular (LV) remodeling and hypertrophy, ultimately leading to cardiac decompensation. Measurement of circulating biomarkers may be useful to identify AS patients with higher risk of maladaptive LV remodeling, a potent marker of the transition to heart failure. We hypothesized that multiple circulating biomarkers are associated with faster progression of LV hypertrophy in patients with AS. Methods: One hundred and forty-six asymptomatic AS patients (66±13years, 75% male) prospectively enrolled in the PROGRESSA study (NCT01679431) were included in this sub-analysis. All patients underwent Doppler-echocardiography to measure AS severity, LV mass indexed to body surface area (LVMi) and LV relative wall thickness (RWT). The annualized changes in LVMi and RWT were calculated between baseline and last follow-up visit (mean follow-up of 2.5±1.88 years). Results: At baseline, 16% of patients had mild (i.e. peak aortic jet velocity [Vpeak] 2.0-2.9 m/s),76% moderate (Vpeak 3.0-3.9 m/s), and 8% severe (Vpeak ≥4.0 m/s) AS, mean LVMi and RWT were 106±23 g/m 2 and 0.47±0.07 respectively. Among biomarkers, baseline level of triglycerides, D-dimer and tumor antigen 125(Ca-125) were significantly associated with LVMi progression rate (β:0.16,p≤0.05), (β:0.18,p≤0.05) and(β:-0.20,p≤0.05) respectively. Soluble (ST2) protein and alkaline phosphatase (ALP) were the only factors independently associated with the annualized change in RWT. In multivariate analysis adjusted for age, gender, comorbidities, AS severity, cardiac biomarkers; triglycerides and D-dimers remained significantly associated with faster progression rate of LVMi (all, p≤0.05), while lower level of CA125 remained significantly associated with LVMi annualized change (β=-0.21, p=0.01). After similar multivariate adjustment, higher levels of ST2 and ALP remained significantly associated with faster progression rate of RWT (all, p≤0.05). Conclusion: Several blood biomarkers were independently associated with faster progression of LV remodeling and hypertrophy in patients with AS. A multiple biomarker approach may be useful to assess LV health and predict the risk of early phases of heart failure in AS.

Immune and Inflammatory Networks in Myocardial Infarction: Current Research and Its Potential Implications for the Clinic.

Despite recent scientific and technological advances, myocardial infarction (MI) still represents a major global health problem, leading to high morbidity and mortality worldwide. During the post-MI wound healing process, dysregulated immune inflammatory pathways and failure to resolve inflammation are associated with maladaptive left ventricular remodeling, progressive heart failure, and eventually poor outcomes. Given the roles of immune cells in the host response against tissue injury, understanding the involved cellular subsets, sources, and functions is essential for discovering novel therapeutic strategies that preserve the protective immune system and promote optimal healing. This review discusses the cellular effectors and molecular signals across multi-organ systems, which regulate the inflammatory and reparative responses after MI. Additionally, we summarize the recent clinical and preclinical data that propel conceptual revolutions in cardiovascular immunotherapy.

Comparison of cardiovascular magnetic resonance features and clinical consequences in patients with left ventricular non-compaction with and without mitral regurgitation-a multi-institutional study of the retrospective cohort study.

Mitral regurgitation (MR) is common in patients with ischemic or idiopathic cardiomyopathies and may be associated with a poor prognosis; however, the impact of different degrees of MR on cardiovascular magnetic resonance images, left ventricular features, and clinical outcomes of left ventricular noncompaction are unknown. We aimed to investigate and compare cardiovascular magnetic resonance characteristics and clinical consequences in patients with left ventricular non-compaction (LVNC) with and without MR. A cohort of 75 patients with left ventricular noncompaction were retrospectively studied from three institutions; all had undergone cardiovascular magnetic resonance examination with subsequent clinical follow-up. MR was evaluated by echocardiography. Left ventricular myocardial strains including global radial, circumferential, and longitudinal peak strains and left ventricular geometric and functional parameters, including left ventricular ejection fraction, end-diastolic volume, end-systolic volume, left ventricular mass, left ventricular sphericity index, longitudinal shorten, and late gadolinium enhancement (LGE) were measured and compared among groups. The primary endpoint was a composite of heart transplantation, implantable cardioverter-defibrillator insertion, and cardiac death. Compared with the no MR group, the MR groups showed significant deterioration in left ventricular myocardial strains (all P<0.05), and impaired left ventricular geometry and function, including lower left ventricular ejection fraction and greater left ventricular end-systolic volume and left ventricular mass (P<0.05). In the subgroup of moderate-severe MR, patients showed more impaired cardiovascular magnetic resonance features, including left ventricular sphericity index, left ventricular end-diastolic volume, and longitudinal shorten (P<0.05). In this subgroup, Kaplan-Meier analysis showed a significant difference in clinical outcomes (log-rank χ2=4.516, P=0.034; log-rank χ2=4.419, P=0.036, respectively). Additionally, multivariate analyses showed a 6.5-fold higher [hazard ratio, 6.5 (95% CI, 1.015-41.881)] risk of cardiac death with LGE in the moderate-severe MR cohort. In patients with left ventricular noncompaction, MR induced more maladaptive left ventricular remodeling. The incidence of adverse outcomes may be related to the degree of MR. In moderate-severe MR patients, coexisting of LGE may have an additive deleterious effect on clinical outcomes.

Perspective on the development of a bioengineered patch to treat heart failure: rationale and proposed design of phase I clinical trial

This perspective focuses on the development of tissue engineered (TE) cell-based therapies to treat left ventricular (LV) dysfunction and chronic heart failure (CHF). The development of induced pluripotent stem cells enabled investigators to seed or co-culture human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) alone and in combination with other cells onto bioengineered scaffolds applied to the epicardial surface of the damaged left ventricle. Using our work as an example, we show how a xenograft implant of a bioengineered scaffold embedded with human neonatal fibroblasts and seeded with hiPSC-CMs partially reversed maladaptive LV remodeling and improved LV systolic/diastolic function in an immune-competent rat model of CHF. The fibroblasts lay down an extracellular matrix and secrete growth factors that increase myocardial blood flow. This approach provides an improved cell payload that covers a larger area of the damaged left ventricle as opposed to direct cell injections into the heart or down the coronary arteries. These studies combined with ongoing studies in immune-competent Yucatan mini swine treated with the same xenograft led to the preliminary design of a proposed Phase I clinical trial that will be presented to the Federal Drug Administration. For the proposed Phase I clinical, this TE patch will be implanted onto the epicardial surface of non-immunosuppressed patients undergoing elective Coronary Artery Bypass Grafting with Ejection Fractions ≥ 20% and ≤ 45%. The primary endpoints will be adverse events/severe adverse events associated with placing the TE patch on the heart. While Phase I trials are primarily safety trials, this proposed trial is designed to obtain some potential efficacy endpoints to help with the design of future Phase II/III clinical trials. These endpoints include changes in LV remodeling that were seen in the pre-clinical animal models as well as including endpoints that focus on patient well-being.

Abstract 10069: Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Left Ventricular Structure and Function in Duchenne Muscular Dystrophy Carriers

Introduction: Duchenne muscular dystrophy (DMD) is a rare X-linked neuromuscular disorder affecting 1:5,000 males that results in terminal injury to the skeletal muscle and the heart. Recent evidence suggests that DMD female carriers are also at increased risk of developing cardiomyopathy. Renin-angiotensin-aldosterone system (RAAS) antagonists reduce morbidity and mortality and inhibit adverse left ventricular remodeling in patients with heart failure with reduced ejection fraction. The benefit of RAAS inhibition in DMD carriers has not been studied to date. Hypothesis: We hypothesize that RAAS inhibition will improve left ventricular function and induce favorable left ventricular structural changes in DMD carriers over time. Methods: A retrospective, single-center cohort study was undertaken to compare cardiac magnetic resonance imaging (cMRI) parameters in DMD carriers at the time of RAAS inhibitor initiation and after treatment with RAAS inhibitors for at least 12 months. RAAS inhibitors included angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor neprilysin inhibitors. Through EMR review, demographic data and cMRI parameters were collected retrospectively on 20 consecutive DMD carriers. Results: The average time elapsed between cMRIs was 39 months. Overall, left ventricular ejection fraction (LVEF) increased in DMD carriers over time, though the improvement in LVEF did not reach significance (57% + 8 vs 59% + 6, p=0.2). However, subgroup analysis of 16 DMD carriers with reduced LVEF (defined as LVEF &lt;62%) demonstrated significant improvement in LVEF following RAAS inhibition (54% + 6 vs 58% + 7; p= 0.004). DMD carriers with reduced LVEF additionally demonstrated a significant decrease in left ventricular end systolic volume index (LVESVi) after RAAS inhibition (38 + 10 vs 32 + 10 ml/m2; p= 0.013). Conclusions: DMD carriers with reduced LVEF showed significant improvement in LVEF and LVESVi following RAAS inhibition. Collectively, the data suggest that RAAS inhibition significantly improves left ventricular systolic function and significantly reduces maladaptive left ventricular remodeling and dilation in this population.

Immunopathological reactions, endothelial dysfunction and pathological angiogenesis as independent mechanisms of maladaptive left ventricular remodeling in ischemic and nonischemic heart failure patients

Regardless of the great progress in studying the heart failure (HF) pathophysiology, the question about involvement of immune cells activation, systemic inflammation, inflammatory cytokine dysregulation and endothelial dysfunction in maladaptive left ventricular (LV) remodeling in ischemic and nonischemic HF patients is still open to discussion. The aim was to study the characteristics of immunopathological reactions (immunoinflammatory and autoimmune), endothelial dysfunction and pathologic angiogenesis in maladaptive LV remodeling in ischemic and nonischemic HF patients. Materials and methods. A total of 20 healthy volunteers, 31 ischemic HF patients (group 1) and 43 nonischemic HF patients (group 2) were enrolled in the study. All the patients underwent coronarography, ventriculography, echocardigraphic examination. The main lymphocyte subset counts (flow cytometry), serum concentration of C-reactive protein (CRP), vascular endothelial growth factor A (VEGF), TNFα, endothelin-1 (enzyme-linked immunosorbent assay (ELISA)), autoantibodies to myocardium and vessels were detected. Results. Regardless of the HF etiology, all the examined patients demonstrated echocardiographic features of maladaptive LV remodeling and severe intracardiac hemodynamic disorders that was associated with immune system activation, namely increased total and subset lymphocyte counts, chronic systemic inflammation (CRP), autoimmune process with an increase in autoantibodies to myocardium and vessels, and endothelial dysfunction (increased endothelin-1 and VEGF). Under-expression of TNF-α combined with over-expression of VEGF seemed to indicate pathological angiogenesis in ischemic and nonischemic HF patients Conclusions. Significantly increased VEGF levels in heart failure patients can be considered as additional integral key marker of immune inflammation, endothelial dysfunction and pathological angiogenesis and may indicate maladaptive cardiac remodeling in severe heart failure.

The association of glutathione S-transferase T1 and M1 deletions with myocardial infarction

Glutathione S-transferases (GSTs) are the family of enzymes involved in the second line of defense against oxidative stress (OS). The lack of GSTT1/GSTM1 enzyme quantity or activity, due to the presence of homozygous deletion compromises antioxidative defense resulting in OS. OS is the critical mechanism in the pathophysiology of atherosclerosis, coronary artery disease, and myocardial infarction (MI). The increase in reactive oxygen species together with the process of apoptosis plays a role in left ventricular remodeling (LVR) after MI. The associations of GSTT1 and GSTM1 gene polymorphisms with the risk of MI are inconsistent. The aim was to analyze the association of GSTT1/GSTM1 null genotypes with first MI and LVR 8 months after the MI. The study involved 330 controls and 438 consecutive patients with symptoms and signs of first MI. The subgroup of 150 MI patients was prospectively followed up for 6 months. Evidence of maladaptive LVR was obtained by 2D Doppler echocardiography 3–5 days and 6 months after the MI. A multiplex polymerase chain reaction was used to detect the deletion in GSTT1 and GSTM1 genes. GSTM1 null genotype was significantly and independently associated with first MI (adjusted OR = 1.45 95% CI 1.03–2.03, p = 0.03). Association of double null genotypes with maladaptive LVR in patients 6 months after the first MI was no longer significant after adjustment for factors that differed significantly between patients with and without maladaptive LVR. This study demonstrated the association of GSTM1 null genotypes with the risk of MI in the Serbian population.

Abstract 15784: Left Ventricular Structural Remodeling and Cardiomyopathy in Duchenne Muscular Dystrophy Carriers

Introduction: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder. DMD-associated cardiomyopathy is the primary mode of premature death in the majority of male DMD patients, but the prevalence of cardiomyopathy and its clinical significance in female DMD carriers is less well characterized. Hypothesis: We hypothesized that a significant proportion of DMD carriers develop maladaptive left ventricular (LV) structural remodeling and cardiomyopathy over time. Methods: A cross-sectional study was undertaken comparing cardiac magnetic resonance imaging (cMRI) and cardiopulmonary stress test (CPX) parameters between DMD carriers and healthy age- and sex-matched controls from the Dallas Heart Study (DHS). Demographic data, cMRI parameters, and CPX parameters were collected retrospectively on 30 consecutive DMD carriers and 26 control DHS subjects. Results: Overall, DMD carriers had a significantly lower LVEF compared to DHS controls (58+8% vs 70+7%, p&lt; 0.0001). The overall prevalence of reduced LVEF in DMD carriers (defined as LVEF &lt;60%) was 63% compared to 8% in DHS controls. The volumetric variables indexed to body surface area (LVEDVi and LVESVi) were significantly higher in DMD carriers compared to control subjects (72+14 ml/m 2 vs 58+7, p&lt; 0.0001; 31+10 ml/m 2 vs 17+5, p&lt; 0.0001; respectively). LV concentricity was also significantly lower among all DMD carriers compared to DHS controls (3.10+0.65 g/mL 0.67 vs 3.73+0.79, p =0.002). LV concentricity was significantly lower in DMD carriers with reduced EF compared to controls (3.09+0.51 g/mL 0.67 vs 3.73+0.79, p = 0.012), while DMD carriers with preserved EF also had reduced concentricity compared to controls (3.12+0.86 vs 3.73+0.79, p = 0.054). Finally, peak VO 2 was lower in DMD carriers compared to DHS controls (23+6 ml/kg/min vs 25+4, p =0.076), though this difference did not reach statistical significance. Conclusions: Collectively, the data suggest that middle-aged female DMD carriers are at greater risk of developing left ventricular systolic dysfunction and cardiomyopathy associated with decreased exercise capacity. A possible mechanism driving the development of this cardiomyopathy is progressive, maladaptive left ventricular dilatation and cardiac atrophy.

Coronavirus Disease 2019 and Hypertension: The Role of Angiotensin-Converting Enzyme 2 and the Renin-Angiotensin System.

Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.

Зв’язок окремих компонентів антифосфоліпідного синдрому з різними типами ремоделювання лівого шлуночка в пацієнтів з післяінфарктним кардіосклерозом та артеріальною гіпертензією

Мета роботи – встановити особливості ремоделювання міокарда лівого шлуночка в чоловіків з післяінфарктним кардіосклерозом залежно від компонентів антифосфоліпідного синдрому.Матеріали і методи. Обстежено 164 хворих на стабільну ішемічну хворобу серця з післяінфарктним кардіосклерозом (100 % чоловіки віком (53,00±9,14) року). Вміст сумарних антифосфоліпідних антитіл (АФЛ) до кардіоліпіну, фосфатидилсерину, фосфатидилінозитолу, антитіл до β2-глікопротеїну 1 (анти-β2-ГП1) класів IgG та IgM визначали методом ELISA. Ехокардіографію проводили за загальноприйнятою методикою, тип геометрії лівого шлуночка (ЛШ) визначали за Ganau. Результати та обговорення. Позитивні рівні АФЛ та анти-β2-ГП1 класу IgG виявили у 56,7 % хворих, у тому числі у 33,5 % – подвійну позитивність за цими антитілами. Позитивність за АФЛ IgG та анти-β2-ГП1 IgG асоціювалася з більш значущими ехокардіографічними ознаками систолічної і діастолічної дисфункції ЛШ. У хворих із позитивними рівнями АФЛ та анти-β2-ГП1 класу IgG частота гіпертрофії ЛШ була вищою (у 2,5–3,0 разу; p&lt;0,05), ніж у хворих із негативними рівнями антитіл. Підвищений рівень анти-β2-ГП1 IgG виявився незалежним предиктором збільшення індексу маси міокарда ЛШ (β=0,344; р&lt;0,0001) у чоловіків з післяінфарктним кардіосклерозом.Висновки. У чоловіків з післяінфарктним кардіосклерозом за наявності позитивних рівнів АФЛ IgG та анти-β2-ГП1 IgG спостерігається порушення систолічної і діастолічної функцій ЛШ, що асоціюється з високим ризиком дезадаптивних варіантів післяінфарктного ремоделювання ЛШ.

Epigenetic modulation of tenascin C in the heart: implications on myocardial ischemia, hypertrophy and metabolism.

Tenascin C (TN-C) is considered to play a pathophysiological role in maladaptive left ventricular remodeling. Yet, the mechanism underlying TN-C-dependent cardiac dysfunction remains elusive. The present study was designed to investigate the effect of hypoxia and hypertrophic stimuli on TN-C expression in H9c2 cells and its putative regulation by epigenetic mechanisms, namely DNA promoter methylation and microRNAs. In addition, rats subjected to myocardial infarction (MI) were investigated. H9c2 cells were subjected to oxygen and glucose deprivation; incubated with angiotensin II (Ang II); or human TN-C (hTN-C) purified protein. Hypertrophic and fibrotic markers, TN-C promoter methylation as well as mir-335 expression were assessed by reverse transcription and quantitative polymerase chain reaction while TN-C protein levels were assessed by ELISA. Tn-C mRNA expression was markedly increased by both oxygen and glucose deprivation and Ang II (P < 0.01, respectively). In addition, Ang-II-dependent TN-C upregulation was explained by reduced promoter methylation (P < 0.05). Cells treated with hTN-C displayed upregulation of Bnp, Mmp2, β-Mhc, integrin α6 and integrin β1. Furthermore, hTN-C treated cells showed a significant reduction in adenosine monophosphate and adenosine triphosphate levels. In vivo, plasma and myocardial TN-C levels were increased 7 days post MI (P < 0.05, respectively). This increment in TN-C was accompanied by upregulation of mir-335 (P < 0.01). In conclusion, both hypoxic and hypertrophic stimuli lead to epigenetically driven TN-C upregulation and subsequent impairment of cellular energy metabolism in cardiomyoblasts. These findings might enlighten our understanding on maladaptive left ventricular remodeling and direct towards a strong involvement of TN-C.

IMPAIRED MYOCARDIAL FLOW RESERVE AND LEFT VENTRICULAR REMODELING IN AORTIC STENOSIS

Coronary microvascular dysfunction (CMD) has been implicated in maladaptive left ventricular (LV) remodeling in aortic stenosis (AS). In a retrospective cohort of control patients and patients with aortic sclerosis or stenosis with normal perfusion on rest/stress 82Rubidium PET and LV ejection

ROLE OF WINGLESS-REGULATORY MOLECULES DICKKOPF-RELATED PROTEIN 1 AND PODOCAN ON LEFT VENTRICULAR REMODELING IN PATIENTS WITH AORTIC STENOSIS

Aortic Stenosis (AS) may result in maladaptive left ventricular (LV) remodeling. Wingless (Wnt) modulators have been shown to impact LV ejection fraction (LVEF) in patients with AS. In this study we investigated the additional role of podocan and its relationship with the Wnt-regulatory molecule

Left ventricular remodeling after the first myocardial infarction in association with LGALS-3 neighbouring variants rs2274273 and rs17128183 and its relative mRNA expression: a prospective study

Post-infarct left ventricular remodeling (LVR) process increases the risk of heart failure (HF). Circulating galectin-3 has been associated with fibrosis, inflammation and cardiac dysfunction during the remodeling process after myocardial infarction (MI). The aims of this prospective case study were to investigate the association of potentially functional variants in the vicinity of LGALS-3 locus, rs2274273 and rs17128183 with maladaptive LVR and whether these variants could affect LGALS-3 mRNA expression in peripheral blood mononuclear cells of patients 6months after the first MI. This study encompassed 167 patients with acute MI that were followed up for 6months. Evidence of LVR was obtained by repeated 2D Doppler echocardiography. Rs2274273, rs17128183 and LGALS-3 mRNA expression were detected by TaqMan® technology. Rs2274273 and rs17128183 rare allele bearing genotypes, according to the dominant model (CT+TT vs. CC and AG+GG vs. AA, respectively), were significantly and independently associated with maladaptive LVR (adjusted OR = 3.02, P = 0.016; adjusted OR = 3.14, P = 0.019, respectively) and higher LGALS-3 mRNA expression (fold induction 1.203, P = 0.03 and 1.214, P = 0.03, respectively). Our exploratory results suggest that rs2274273 and rs17128183 variants affect LGALS-3 mRNA and bear the risk for maladaptive LVR post-MI remodeling. Further replication and validation in a larger group of patients is inevitable.

Abstract 205: Cryopreserved Cardiac Tissue Graft (MyCardia) Improved Cardiac Function in Rats With Heart Failure

Introduction: There are currently 2M patients with NYHA Class II-IV heart failure of ischemic etiology in the United States. Cell-based therapies hold tremendous potential to provide therapeutic benefit for treating degenerative diseases such as chronic heart failure (CHF). Therapeutic adoption of engineered grafts will require ease of use and demonstration of cost-effectiveness. Here we describe for the first time the ability to cryopreserve an engineered tissue (MyCardia™) and demonstrate functional recovery in a rat model of CHF. Methods: MyCardia grafts were cultured with human dermal fibroblasts (hNDF) and human iPSC derived cardiomyocytes (hiPSC-CMs) (FCDI) into a bioabsorbable mesh (Novus Scientific). Grafts were cryopreserved at -196C for 2-4weeks, thawed, reconstituted and implanted into rats with CHF. Myocardial infarction (MI) were generated in immune competent rats by ligating the left coronary artery. Three weeks after MI, rats received graft implants via median sternotomy. Echocardiography was performed at 3 and 7 weeks post graft implantation. In addition, terminal hemodynamics were performed. Results: MyCardia maintained spontaneous and synchronous contractions pre-freeze (65±10bpm) and post thaw (60±10bpm). Grafts were maintained to 40 days post thaw with no deterioration in composition or beat rate. MyCardia reversed maladaptive left ventricular (LV) remodeling by decreasing (p&lt;0.05) LV volume systole/diastole, LV diameter systole/diastole with trending improvement in EF and FS from 3 and 7 weeks post implantation as compared to CHF controls. Grafts decreased LV end diastolic pressure, 24±6 mmHg vs. 18±3mmHg and showed trending improvements in LV dP/dt(-) and dP/dt(+) as compared to controls. In addition, MyCardia results in 36% reduction in LV EDP operating volume as demonstrated by a leftward shift of the diastolic pressure-volume relationship. Conclusion: MyCardia can be cryopreserved, reconstituted and implanted in rats with CHF. Treated rats demonstrated reversal of maladaptive LV remodeling and continued functional improvement from 3 to 7 weeks post treatment. We anticipate that the ability to cryopreserve will allow long-term storage after large batch manufacture, providing cost and utility advantages.

Maladaptive left ventricular remodeling in women: An analysis from the Women's Ischemia Syndrome Evaluation–Coronary Vascular Dysfunction study

BackgroundWomen represent approximately half of heart failure hospitalizations and are disproportionately affected by heart failure with preserved ejection fraction (HFpEF). Women with signs and symptoms of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive coronary artery disease (CAD) often have elevated left ventricular end-diastolic pressure (LVEDP). However, isolated elevated LVEDP in the absence of coronary microvascular dysfunction (CMD) is not understood. MethodsAmong 244 women with signs and symptoms of ischemia, no obstructive CAD, and preserved LVEF who underwent invasive coronary reactivity testing (CRT), 43 (18%) women had no evidence of CMD. LVEDP was measured at time of CRT, and left ventricular (LV) volumes and mass were assessed by cardiac magnetic resonance (CMR) imaging. ResultsOf the 43 women without CMD, 24 (56%) had elevated LVEDP [mean 18 mm Hg (SD = 3)] compared to 19 (44%) with normal LVEDP [11 mm Hg (SD = 3)]. The elevated LVEDP group had a comparatively higher systolic and diastolic blood pressure, lower LV end-diastolic volume index (EDVI), and higher mass-to-volume ratio. Other functional parameters were not significantly different. ConclusionsAmong women with signs and symptoms of ischemia without obstructive CAD, absence of CMD, and preserved LVEF, isolated elevated LVEDP is associated with a significantly higher systolic and diastolic blood pressure, higher LV mass-to-volume ratio and lower LV EDVI. These results suggest these women have maladaptive remodeling to blood pressure. Given the relatively high prevalence of HFpEF in women, these hypothesis-generating results suggest that further study of ventricular remodeling is warranted.