4968Increased Gao expression underlies cardiac dysfunction and lethal arrhythmias accompanied with abnormal Ca2+ handling

Abstract Background We previously demonstrated that a transcriptional repressor, neuron restrictive silencer factor (NRSF), maintains normal cardiac function and electrical stability. Transgenic mice expressing a dominant-negative mutant of NRSF in their hearts (dnNRSF-Tg) exhibit systolic dysfunction with cardiac dilation and premature death due to lethal arrhythmias like human dilated cardiomyopathy (DCM). Underlining mechanisms remain to be elucidated, however. Purpose We studied underling mechanisms by which NRSF maintains normal cardiac function to identify novel therapeutic targets for heart failure. Methods and results We generated cardiac-specific NRSF knockout mice (NRSFcKO) and confirmed that cardiac phenotypes of NRSFcKO are similar to those of dnNRSF-Tg. cDNA microarray analysis revealed that cardiac gene expression of GNAO1 that encodes Gαo, a member of inhibitory G protein Gαi family, is increased in both dnNRSF-Tg and NRSFcKO ventricles. We confirmed that GNAO1 is a direct target of NRSF through ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay. In dnNRSF-Tg, pharmacological inhibition of Gαo with pertussis toxin improved systolic dysfunction and knockdown of Gαo by crossing with GNAO1 knockout mice improved not only systolic function but also frequency of ventricular arrhythmias and survival rates. Electrophysiological and biochemical analysis in ventricular myocytes obtained from dnNRSF-Tg demonstrated that genetic reduction of Gαo ameliorated abnormalities in Ca2+ handling, which include increased current density in surface sarcolemmal L-type Ca2+ channel, reduced content of sarcoplasmic reticulum Ca2+ and lowered peak of Ca2+ transient. Furthermore, genetic reduction of Gαo attenuated increased phosphorylation levels of CAMKII in dnNRSF-Tg ventricles, which presumably underlies the improvement in Ca2+ handling. In addition, we identified increased Gαo expression in ventricles of heart failure model mice induced by transverse aortic constriction and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gαo ameliorated cardiac dysfunction. Figure 1 Conclusions We found that increased expression of Gαo, induced by attenuation of NRSF-mediated repression, plays a crucial role in the progression of cardiac dysfunction and lethal arrhythmias by evoking Ca2+ handling abnormality. These data demonstrate that Gαo is a potential therapeutic target for heart failure.

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Abstract MP170: Increased Ga o Expression Regulated by NRSF Plays a Key Role in the Development of Heart Failure Through the Impairment of Ca 2+ Homeostasis

Circulation Research ◽

10.1161/res.127.suppl_1.mp170 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Hideaki Inazumi ◽

Yasuaki Nakagawa ◽

Kenji Moriuchi ◽

Koichiro Kuwahara

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Troponin T ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Cardiac Gene ◽

Normal Cardiac Function

Background: In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac gene program, which leads to pathological cardiac remodeling. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac gene program and maintains normal cardiac function, while pathological stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac function remains to be determined, however. Purpose: To elucidate molecular mechanisms by which NRSF maintains normal cardiac function. Methods and Results: Newly generated cardiac-specific NRSF knockout mice (NRSF-cKO) showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). Expression of Gnao1 gene encoding Gα o , a member of inhibitory G proteins, was commonly increased in ventricles of dnNRSF-Tg and NRSF-cKO. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gα o in dnNRSF-Tg and NRSF-cKO ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Conversely cardiac-specific GNAO1 overexpression was sufficient to show impaired cardiac function. Mechanistically, Gα o increases current density in surface sarcolemmal L-type Ca 2 + channel and then activates CaMKII without affecting protein kinase A activity, which finally leads to impaired Ca 2+ handling and systolic dysfunction. Furthermore, expression of Gα o is also increased in ventricles of transverse aortic constriction model mice and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gα o prevented the progression of cardiac dysfunction. Conclusions: Increased expression of Gα o , induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII and progresses heart failure by impairing Ca 2+ homeostasis. Gα o is a potential therapeutic target for heart failure.

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NRSF-GNAO1-CaMK2 axis exacerbates cardiac remodeling and progresses heart failure by impairing Ca2+ homeostasis

European Heart Journal ◽

10.1093/ehjci/ehaa946.3672 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Inazumi ◽

K Kuwahara ◽

Y Kuwabara ◽

Y Nakagawa ◽

H Kinoshita ◽

...

Keyword(s):

Heart Failure ◽

Transgenic Mice ◽

Knockout Mice ◽

Cardiac Remodeling ◽

Cardiac Dysfunction ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Systolic Function ◽

Dominant Negative Mutant ◽

Funding Source

Abstract Background In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac genes, which leads to maladaptive remodeling and cardiac dysfunction. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac genes and maintains normal cardiac function under normal conditions, while hypertrophic stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac systolic function remains to be determined, however. Purpose To elucidate how NRSF maintains normal cardiac homeostasis and identify the novel therapeutic targets for heart failure. Methods and results We generated cardiac-specific NRSF knockout mice (NRSF cKO), and found that these NRSF cKO showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). By cDNA microarray analysis of dnNRSF-Tg and NRSF-cKO, we identified that expression of Gnao1 gene encoding Gαo, a member of inhibitory G proteins, was commonly increased in ventricles of both types of mice. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gαo in dnNRSF-Tg and NRSF-cKO by crossing these mice with Gnao1 knockout mice ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Transgenic mice expressing a human GNAO1 in their hearts (GNAO1-Tg) showed progressive cardiac dysfunction with cardiac dilation. Ventricles obtained from GNAO1-Tg have increased phosphorylation level of CaMKII and increased expression level of endogenous mouse Gnao1 gene. These data suggest that increased cardiac expression of Gαo is sufficient to induce pathological Ca2+-dependent signaling and cardiac dysfunction, and that Gαo forms a positive regulatory circuit with CaMKII and NRSF. Electrophysiological analysis in ventricular myocytes of dnNRSF-Tg revealed that impaired Ca2+ handling via alterations in localized L-type calcium channel (LTCC) activities; decreased T-tubular and increased surface sarcolemmal LTCC activities, underlies Gαo-mediated cardiac dysfunction. Furthermore, we also identified increased expression of Gαo in ventricles of two different heart failure mice models, mice with transverse aortic constriction and mice carrying a mutant cardiac troponin T, and confirmed that genetic reduction of Gαo prevented the progression of cardiac dysfunction in both types of mice. Conclusions Increased expression of Gαo, induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII. This circuit exacerbates cardiac remodeling and progresses heart failure by impairing Ca2+ homeostasis. Gαo is a potential therapeutic target for heart failure. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grants-in –Aid for Scientific Research from the Japan Society for the Promotion of Science

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Abstract MP26: Endothelial-derived Microvesicles From Andean Highlanders With Excessive Erythrocytosis Induce A Deleterious Cardiomyocyte Phenotype

Hypertension ◽

10.1161/hyp.76.suppl_1.mp26 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

L. Madden Brewster ◽

Hannah Fandl ◽

Anthony Bain ◽

Vinicius P Garcia ◽

Rachel Stone ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

High Altitude ◽

Cardiac Dysfunction ◽

Type I Collagen ◽

Troponin T ◽

Induced Pluripotent Stem Cell ◽

Type I ◽

Healthy Men ◽

Increased Risk

Background: Excessive erythrocytosis (EE), defined as Hb ≥21 g/dL in men and ≥19 g/dL in women, is a pathologic consequence of residing at high altitude (>2500 m) and is common in Andean highlanders. EE is associated with increased cardiovascular risk and cardiac dysfunction. Specifically, EE has been linked to congestive heart failure as well as right ventricular hypertrophy in high altitude dwellers. The mechanisms responsible for diminished cardiac function in adults with EE remain unclear. Endothelial microvesicles (EMVs) play an important role in mediating interaction between the vascular endothelium and cardiac function. The experimental aim of this study was to determine the effects of EMVs isolated from adults with EE on markers of cardiomyocyte fibrosis, hypertrophy and autophagy as well as endothelial nitric oxide synthase (eNOS). Methods: Twenty-four male residents of Cerro de Pasco, Peru (4,340 m) were studied: 12 highlanders without EE (Healthy; age: 40±4 yr; BMI: 26.4±1.7; Hb: 17.4±0.5 g/dL) and 12 highlanders with EE (EE: 45±5 yr; 26.7±1.0; 24.4±0.4 g/dL). All subjects were non-obese, normotensive, normolipidemic and non-diabetic. EMVs (CD31+/CD42b-) were identified, enumerated, and isolated from plasma by flow cytometry. Human induced pluripotent stem cell cardiomyocytes were cultured and treated with EMVs from either healthy or EE men. Results: EMVs from EE men induced significantly greater expression of specific markers of fibrosis: TGF-β (91.1±4.0 vs 52.7±3.8 AU) and alpha-1 type I collagen (85.6±5.6 vs 59.7±4.8 AU) and hypertrophy: troponin T (41.4±2.0 vs 16.9±1.4 AU) and α-actinin (95.3±6.7 vs 62.4±5.0 AU) than EMVs from healthy men. Cell autophagy was not significantly affected by EE EMVs. Intercellular expression of phosphorylated eNOS at the primary activation site, Ser1177 (13.3±1.1 vs 18.9±1.2 AU), and inhibitory site, Thr495 (56.7±3.4 vs 40.8±2.7 AU), were ~35% lower and ~30% higher (both P<0.05), respectively, in cells treated with EMVs from EE compared with healthy men. Conclusions: These data indicate that EMVs from Andean highlanders with EE negatively affect cardiomyocyte function and, therefore, may contribute to the increased risk of heart failure and cardiac dysfunction associated with EE.

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Cardiac p300 Is Involved in Myocyte Growth with Decompensated Heart Failure

Molecular and Cellular Biology ◽

10.1128/mcb.23.10.3593-3606.2003 ◽

2003 ◽

Vol 23 (10) ◽

pp. 3593-3606 ◽

Cited By ~ 154

Author(s):

Tetsuhiko Yanazume ◽

Koji Hasegawa ◽

Tatsuya Morimoto ◽

Teruhisa Kawamura ◽

Hiromichi Wada ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Myocytes ◽

Zinc Finger Protein ◽

Systolic Dysfunction ◽

Critical Role ◽

Decompensated Heart Failure ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Myocyte Hypertrophy

ABSTRACT A variety of stresses on the heart initiate a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and cause myocyte hypertrophy with heart failure. However, common nuclear pathways that lead to this state are unknown. A zinc finger protein, GATA-4, is one of the transcription factors that mediate changes in gene expression during myocardial-cell hypertrophy. p300 not only acts as a transcriptional coactivator of GATA-4, but also possesses an intrinsic histone acetyltransferase activity. In primary cardiac myocytes derived from neonatal rats, we show that stimulation with phenylephrine increased an acetylated form of GATA-4 and its DNA-binding activity, as well as expression of p300. A dominant-negative mutant of p300 suppressed phenylephrine-induced nuclear acetylation, activation of GATA-4-dependent endothelin-1 promoters, and hypertrophic responses, such as increase in cell size and sarcomere organization. In sharp contrast to the activation of cardiac MEK-1, which phosphorylates GATA-4 and causes compensated hypertrophy in vivo, p300-mediated acetylation of mouse cardiac nuclear proteins, including GATA-4, results in marked eccentric dilatation and systolic dysfunction. These findings suggest that p300-mediated nuclear acetylation plays a critical role in the development of myocyte hypertrophy and represents a pathway that leads to decompensated heart failure.

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Exercise cardiac MRI unmasks cardiac dysfunction in childhood and adolescent cancer survivors with reduced cardiopulmonary fitness

European Heart Journal ◽

10.1093/ehjci/ehaa946.3275 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S Foulkes ◽

B Costello ◽

E.J Howden ◽

K Janssens ◽

H Dillon ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cancer Survivors ◽

Pediatric Cancer ◽

Cardiac Dysfunction ◽

Cardiopulmonary Fitness ◽

Cardiac Reserve ◽

Pediatric Cancer Survivors ◽

Increased Risk

Abstract Background Young cancer survivors are at increased risk of impaired cardiopulmonary fitness (VO2peak) and heart failure. Assessment of exercise cardiac reserve may reveal sub-clinical abnormalities that better explain impairments in fitness and long term heart failure risk. Purpose To investigate the presence of impaired VO2peak in pediatric cancer survivors with increased risk of heart failure, and to assess its relationship with resting cardiac function and cardiac reserve Methods Twenty pediatric cancer survivors (aged 8–24 years) treated with anthracycline chemotherapy underwent cardiopulmonary exercise testing to quantify VO2peak, with a value <85% of predicted defined as impaired VO2peak. Resting cardiac function was assessed using 3-dimensional echocardiography, with cardiac reserve quantified from resting and peak exercise heart rate (HR), stroke volume index (SVi) and cardiac index (CI) using exercise cardiac magnetic resonance imaging. Results 12 of 20 survivors (60%) had impaired VO2peak (97±14% vs. 70±16% of age and gender predicted). There were no differences in echocardiographic or CMR measurements of resting cardiac function between survivors with normal or impaired VO2peak. However, those with reduced VO2peak had diminished cardiac reserve, with a lesser increase in CI (Fig. 1A) and SVi (Fig. 1B) during exercise (Interaction P=0.001 for both), whilst the HR response was similar (Fig. 1C; P=0.71). Conclusions Resting measures of cardiac function are insensitive to significant cardiac dysfunction amongst pediatric cancer survivors with reduced VO2peak. Measures of cardiopulmonary fitness and cardiac reserve may aid in early identification of survivors with heightened risk of long-term heart failure. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Heart Foundation

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Very early detection of low dose anti-cancer therapy-related cardiotoxicity in lymphoma patients

European Heart Journal ◽

10.1093/ehjci/ehaa946.3257 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

Y.W Liu ◽

H.Y Chang ◽

C.H Lee ◽

W.C Tsai ◽

P.Y Liu ◽

...

Keyword(s):

Heart Failure ◽

Cancer Therapy ◽

Cardiac Dysfunction ◽

Systolic Dysfunction ◽

Multivariable Analysis ◽

Cardiopulmonary Exercise Test ◽

Left Ventricular ◽

Funding Source ◽

Anti Cancer ◽

All Cause Mortality

Abstract Background and purpose Left ventricular (LV) global peak systolic longitudinal strain (GLS) by speckle-tracking echocardiography is a sensitive modality for the detection of subclinical LV systolic dysfunction and a powerful prognostic predictor. However, the clinical implication of LV GLS in lymphoma patients receiving anti-cancer therapy remains unknown. Methods We prospectively enrolled 74 patients (57.9±17.0 years old, 57% male) with lymphoma who underwent echocardiography prior to chemotherapy, post 3rd and 6th cycle and 1 year after chemotherapy. Cancer therapy-related cardiac dysfunction (CTRCD) is defined as the reduction of absolute GLS value from baseline of ≥15%. All the eligible patients underwent a cardiopulmonary exercise test (CPET) upon completion of 3 cycles of anti-cancer therapy. The primary outcome was defined as a composite of all-cause mortality and heart failure events. Results Among 36 (49%) patients with CTRCD, LV GLS was significantly decreased after the 3rd cycle of chemotherapy (20.1±2.6% vs. 17.5±2.3%, p<0.001). In the multivariable analysis, male sex and anemia (hemoglobin <11 g/dL) were found to be independent risk factors of CTRCD. Objectively, patients with CTRCD had lower minute oxygen consumption/kg (VO2/kg) and lower VO2/kg value at anaerobic threshold in the CPET. The incidence of the primary composite outcome was higher in the CTRCD group than in the non-CTRCD group (hazard ratio 3.21; 95% CI, 1.04–9.97; p=0.03). Conclusion LV GLS is capable of detecting early cardiac dysfunction in lymphoma patients receiving anti-cancer therapy. Patients with CTRCD not only had a reduced exercise capacity but also a higher risk of all-cause mortality and heart failure events. Change of LVEF and GLS after cancer Tx Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Ministry of Science and Technology (MOST), Taiwan

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Abstract 428: Pharmacologic and Activated Fibroblast-specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury

Circulation Research ◽

10.1161/res.119.suppl_1.428 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Joshua G Travers ◽

Fadia A Kamal ◽

Michelle L Nieman ◽

Michelle A Sargent ◽

Jeffery D Molkentin ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Reperfusion Injury ◽

G Protein ◽

Knockout Mice ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Myocardial Dysfunction ◽

Ischemia Reperfusion ◽

Ventricular Compliance

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transform to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately the pathologic activation of G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast activation and cardiac remodeling. To investigate this hypothesis, mice were subjected to ischemia/reperfusion (I/R) injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein. While animals receiving vehicle demonstrated a reduction in overall cardiac function as measured by echocardiography, mice treated with gallein exhibited nearly complete preservation of cardiac function and reduced fibrotic scar formation. We next sought to establish the cell specificity of this compound by treating inducible cardiomyocyte- and activated fibroblast-specific GRK2 knockout mice post-I/R. Although we observed modest restoration in cardiac function in cardiomyocyte-specific GRK2 null mice, treatment of these mice with gallein resulted in further protection against myocardial dysfunction following injury, suggesting a functional role in other cardiac cell types, including fibroblasts. Activated fibroblast-specific GRK2 knockout mice were also subjected to ischemia/reperfusion injury; these animals displayed preserved myocardial function and reduced collagen deposition compared to littermate controls following injury. Furthermore, systemic Gβγ-GRK2 inhibition by gallein did not appear to confer further protection over activated fibroblast-specific GRK2 ablation alone. In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.

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Abstract 1213: Cardiac Overexpression of Epac1 in Transgenic Mice Protects Heart from Lipopolysaccharide-induced Cardiac Dysfunction and Inhibits JAK-STAT Pathway

Circulation ◽

10.1161/circ.116.suppl_16.ii_246-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Satoshi Okumura ◽

Yunzhe Bai ◽

Meihua Jin ◽

Sayaka Suzuki ◽

Akiko Kuwae ◽

...

Keyword(s):

Heart Failure ◽

Cyclic Amp ◽

Transgenic Mice ◽

Cardiac Function ◽

Proinflammatory Cytokines ◽

Cardiac Dysfunction ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Stat Pathway

The sympathetic nervous system and proinflammatory cytokines are believed to play independent roles in the pathophysiology of heart failure. However, the recent identification of Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, have implicated that there may be a potential cross talk between the sympathetic and cytokine signals. In order to examine the role of Epac in cytokine signal to regulate cardiac function, we have generated transgenic mice expressing the human Epac1 gene under the control of alpha-cardiac myosin heavy chain promoter (Epac1-TG), and examined their response in lipopolysaccharide (LPS)-induced cardiac dysfunction, a well established model for sepsis-induced cardiac dysfunction. Sepsis-induced cardiac dysfunction results from the production of proinflammatory cytokines. At baseline, left ventricular ejection fraction (LVEF) was similar (TG vs. NTG, 67±1.7 vs. 69±2.1%, n =7–9). The degree of cardiac hypertrophy (LV(mg)/tibia(mm)) was also similar at 3 months old (TG vs. NTG 4.0±0.1 vs. 4.2±0.1, n =5–6), but it became slightly but significantly greater in Epac1-TG at 5 month old (TG vs. NTG 4.9±0.1 vs. 4.4±0.1, p< 0.05, n =5–7). LPS (5mg/kg) elicited a significant and robust reduction of LVEF in both Epac1-TG and NTG, but the magnitude of this decrease was much less in Epac1-TG at 6 hr after injection (TG vs. NTG 48±2.4 vs. 57±1.8%, p< 0.01, n =6–9). At 24 hr after injection, cardiac function was restored to the baseline in both Epac1-TG and NTG. We also examined the activation of JAK-STAT pathway at 24 hr after injection. The tyrosine phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV, which is an indicator of STAT activation, was reduced to a greater degree in Epac1-TG by 31±8.8% ( p< 0.05, n =4) and 29±5.9% ( p< 0.05, n =7), respectively, relative to that in NTG. Taken together, Epac1 protects the heart from the cytokine-induced cardiac dysfunction, at least in part, through the inhibition of the JAK-STAT pathway, suggesting the beneficial role played by sympathetic signal to antagonize proinflammatory cytokine signal in heart failure.

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Abstract 12153: Impact of a Hybrid Nurse-Led Intervention for the Prevention of Progressive Cardiac Dysfunction in High Risk Individuals: Results From a Pragmatic, Randomized Trial (the NIL-CHF Study)

Circulation ◽

10.1161/circ.130.suppl_2.12153 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Simon Stewart ◽

Melinda Carrington ◽

Yih Kai Chan ◽

Garry Jennings ◽

Chiew Wong ◽

...

Keyword(s):

High Risk ◽

Cardiac Function ◽

Diastolic Dysfunction ◽

Cardiac Dysfunction ◽

Systolic Dysfunction ◽

Cardiac Abnormality ◽

Coronary Syndrome ◽

History Of ◽

Hybrid Program

Background: The natural history of chronic heart failure (CHF) is characterized by initial cardiac insult and/or stressors over time that leaves affected individuals at high risk for progressive cardiac dysfunction and eventual development of the syndrome. Methods: Of a total of 624 subjects at high risk of developing CHF randomized into the NIL-CHF Study comparing a hybrid program of home and clinic-based follow-up (NIL-CHF group) to Standard Care, 454 (73%) underwent serial echocardiography at 1 month post index cardiac hospitalization and at 3 years. At both time points (nil signs/symptoms of CHF at baseline), these were blindly classified as follows: 1) no cardiac abnormality, 2) systolic dysfunction/HFrEF - LVEF ≤ 45% ), 3) diastolic dysfunction/HFpEF as defined by any moderate diastolic dysfunction (with pseudonormalization pattern) or E/E prime ratio ≥ 15, 4) combination of 2 & 3 and 5) other cardiac abnormality (including LVH). Pre-specified criteria were used to determine - i) no change, ii) improvement or iii) deterioration in cardiac function from baseline to 3 years. Results: Mean age was 66±11 years, 71% were male, 70% were hospitalized with an acute coronary syndrome and 62% and 26%, respectively, were being treated for hypertension and diabetes. At baseline 25.2% vs. 28.4% (p=ns), 15.1% vs. 9.1% (p<0.05), 35.1% vs. 32.4% (p=ns) and 34.3% vs. 39.6% had normal cardiac function, HFrEF, HFpEF (13% both HFrEF and HFpEF overall) and LVH (the predominant “other” cardiac abnormality), respectively. At 3 years the proportion of subjects with reversal of pre-existing HFrEF or HFpEF was lower in the NIL-CHF group (23% vs. 16%; p=0.063). Moreover, significantly more NIL-CHF subjects demonstrated any form of cardiac recovery/reversal on echocardiography (39% vs. 25%, p=0.011, 95% CI 1.35, 95% CI 1.04, 1.76). They also demonstrated significantly greater regression to normal LV structure (36% vs. 25%; p=0.047) among those with LVH at baseline. Conclusions: These pre-specified analyses (secondary endpoint) of the recently completed NIL-CHF Study suggests a cardio-protective effect conferred by a long-term, nurse-led, home and clinic-based intervention targeting hospitalized individuals at high risk for developing CHF.

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Abstract 296: Loss of Trpc6 Function in Cardiomyocytes Improves Survival and Attenuates Progression of Cardiac Dysfunction After Mi

Circulation Research ◽

10.1161/res.119.suppl_1.296 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Polina Gross ◽

Xiaoxiao Zhang ◽

Tao Wang ◽

Amir Toib ◽

Markus Wallner ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Dysfunction ◽

Cardiac Myocyte ◽

Transient Receptor Potential ◽

Weight Ratio ◽

Dominant Negative ◽

Heart Weight ◽

Trpc Channels ◽

Pump Function ◽

Hypertrophic Signaling

Ischemic heart disease (IHD) commonly culminates in myocardial infarction (MI), which causes cardiac myocyte death and depressed cardiac pump function. Surviving myocytes can usually maintain pump function by increasing Ca 2+ influx and contractility. However, elevated intracellular Ca 2+ also can activate pathological hypertrophic signaling that promotes cardiac dysfunction and progression into heart failure. Ca 2+ influx through Canonical Transient Receptor Potential (TRPC) channels has been classified as a potential source of hypertrophic signaling. Specifically, TRPC6 gene expression and biological activity is significantly upregulated in cardiac myocytes after MI. Our aim was to determine if TRPC6 loss of function is cardioprotective in MI mouse model. We performed an MI study on cardiac specific dominant negative (dn) TRPC6 transgenic mice that express 3 mutated amino acids (L678A-W680A) in the pore region, which disables TRPC6 channel function. In the course of 6 weeks post MI, dnTRPC6 mice had significantly greater survival (69.2%) than wild-type (WT) mice (47.5%). Cardiac function at 2 weeks post MI was decreased to the same extent in WT and dnTRPC6 mice. Ejection fraction (EF) in WT group was 30.6% vs. 57.1% and in dnTRPC6 EF was 31% vs. 61% (MI vs. sham, respectively). The EF in dnTRPC6 mice 6 weeks post MI suggested attenuation of heart failure progression compared to WT mice (32.5% vs. 26.5%, *P=0.05). Mice in the WT group demonstrated significant elevation in end diastolic and end systolic volumes (EDV and ESV) 6 weeks post MI, while dnTRPC6 had reduced end diastolic and end systolic volumes (116μL vs. 88μL and 106μL vs. 76μL, WT vs. dnTRPC6, EDV and ESV, respectively. ***P<0.0001). Hypertrophy measures of heart weight to body weight ratio and heart weight to tibia length ratio were significantly reduced in dnTRPC6 mice 6 weeks post MI as opposed to WT mice (8.4 vs. 7.3 and 13.4 vs. 11.7, respectively *P<0.05). Hypertrophic markers of ANP, BNP and βMHC followed similar downregulation trend in the dnTRPC6 mice. In conclusion, loss of TRPC6 function slows the progression of cardiac dysfunction and cardiac remodeling in the post MI heart.

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