Long-term levosimendan treatment improves systolic function and myocardial relaxation in mice with cardiomyocyte-specific disruption of the Serca2 gene

2013 ◽  
Vol 115 (10) ◽  
pp. 1572-1580 ◽  
Author(s):  
Vigdis Hillestad ◽  
Frank Kramer ◽  
Stefan Golz ◽  
Andreas Knorr ◽  
Kristin B. Andersson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiac Function ◽  
Diastolic Dysfunction ◽  
Systolic Function ◽  
Cytosolic Calcium ◽  
Left Ventricular ◽  
Pressure Measurements ◽  
Human Heart Failure

In human heart failure (HF), reduced cardiac function has, at least partly, been ascribed to altered calcium homeostasis in cardiomyocytes. The effects of the calcium sensitizer levosimendan on diastolic dysfunction caused by reduced removal of calcium from cytosol in early diastole are not well known. In this study, we investigated the effect of long-term levosimendan treatment in a murine model of HF where the sarco(endo)plasmatic reticulum ATPase ( Serca) gene is specifically disrupted in the cardiomyocytes, leading to reduced removal of cytosolic calcium. After induction of Serca2 gene disruption, these mice develop marked diastolic dysfunction as well as impaired contractility. SERCA2 knockout (SERCA2KO) mice were treated with levosimendan or vehicle from the time of KO induction. At the 7-wk end point, cardiac function was assessed by echocardiography and pressure measurements. Vehicle-treated SERCA2KO mice showed significantly diminished left-ventricular (LV) contractility, as shown by decreased ejection fraction, stroke volume, and cardiac output. LV pressure measurements revealed a marked increase in the time constant (τ) of isovolumetric pressure decay, showing impaired relaxation. Levosimendan treatment significantly improved all three systolic parameters. Moreover, a significant reduction in τ toward normalization indicated improved relaxation. Gene-expression analysis, however, revealed an increase in genes related to production of the ECM in animals treated with levosimendan. In conclusion, long-term levosimendan treatment improves both contractility and relaxation in a heart-failure model with marked diastolic dysfunction due to reduced calcium transients. However, altered gene expression related to fibrosis was observed.

Abstract 5361: PDK1 Plays Crucial Roles in β-Adrenergic Response and Cell Survival in the Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kaoru Ito ◽  
Hiroshi Akazawa ◽  
Noritaka Yasuda ◽  
Haruaki Nakaya ◽  
Issei Komuro
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Gene Disruption ◽  
Systolic Function ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Cardiomyocyte Apoptosis ◽  
Adrenergic Stimulation ◽  
Human Heart Failure ◽  
Bax Protein

Background: The 3-phosphoinositide-dependent protein kinase-1 (PDK1) plays a homeostatic role in the regulation of cellular function in multiple organs, by working downstream of phosphatidylinositol-3 kinase (PI3-K) through activating several kinases including Akt and p70 S6 kinase. We found that myocardial expression of PDK1 was decreased in murine models of heart failure. Although previous studies have reported that PDK1 is important for the regulation of cardiomyocyte size, the precise role of PDK1 in the heart remains to be fully characterized. Methods and Results: To elucidate the roles of PDK1 in the postnatal heart, we generated tamoxifen-inducible heart specific PDK1 knockout (PDK1-KO) mice. Deletion of PDK1 at the age of 10 weeks caused severe heart failure. At 1 week after Pdk1 gene disruption, left ventricular systolic function was already deteriorated without reduction in cardiomyocyte size. Langendorff-perfused hearts from PDK1-KO mice exhibited impaired responsiveness to isoproterenol in spite of preserved responsiveness to forskolin. In PDK1-KO hearts, PI3-K γ activity was enhanced and the expression levels of β1-adrenergic receptor (β1AR) in membrane fraction were decreased. Overexpression of PIK-domain of PI3-K γ blocked β1AR internalization by competitively inhibiting the association between PI3-K γ and G-protein coupled receptor kinase 2, and improved cardiac function in PDK1-KO hearts. In addition, we found that cardiomyocyte apoptosis was significantly increased 1 week after Pdk1 gene disruption. PDK1-KO hearts showed reduction of Akt and SGK activities, upregulation of Bax protein and endoplasmic reticulum stress signals, which were the potential causes of cardiomyocyte apoptosis. Overexpression of Bcl-2 in PDK1-KO hearts prevented cardiomyocyte apoptosis and partially improved cardiac function in PDK1-KO mice. Conclusions : These results suggest that PDK1 is essential for normal cardiac function by not only preserving responsiveness to β-adrenergic stimulation but also preventing cardiomyocyte apoptosis. Since PDK1-KO mice reproduces many aspects of human heart failure, we propose that PDK1 may be a promising molecule targeted for the treatment of heart failure.

Abstract 16485: The Nitroxyl Donor 1-Nitrosocyclohexyl Acetate Limits Cardiac Superoxide Upregulation and Diastolic Dysfunction in a Mouse Model of Diabetic Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rebecca H Ritchie ◽  
Nga Cao ◽  
Yung George Wong ◽  
Sarah Rosli ◽  
Helen Kiriazis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Ex Vivo ◽  
Systolic Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Diastolic Dysfunction ◽  
The Impact

Nitroxyl (HNO), a redox congener of NO•, is a novel regulator of cardiovascular function combining vasodilator and positive inotropic properties. Our previous studies have demonstrated these properties occur concomitantly in the intact heart; HNO moreover also exhibits antihypertrophic and superoxide-suppressing actions. HNO donors may thus offer favorable actions in heart failure. The impact of chronic HNO donor administration has however yet to be reported in this context. We tested the hypothesis that the HNO donor 1-nitrosocyclohexyl acetate (1-NCA) limits cardiomyocyte hypertrophy and left ventricular (LV) diastolic dysfunction in a mouse model of diabetic cardiomyopathy in vivo. Male 6 week-old FVB/N mice received either streptozotocin (55 mg/kg/day i.p. for 5 days, n=17), to induce type 1 diabetes, or citrate vehicle (n=16). After 4 weeks of hyperglycemia, mice were allocated to 1-NCA therapy (83mg/kg/day i.p.) or vehicle, and followed for a further 4 weeks. As shown in the table, blood glucose was unaffected by 1-NCA. LV diastolic dysfunction was evident in diabetic mice, measured as echocardiography-derived A wave velocity, deceleration time and E:A ratio; LV systolic function was preserved. Diabetes-induced diastolic dysfunction was accompanied by increased LV cardiomyocyte size, hypertrophic and pro-fibrotic gene expression, and upregulation of LV superoxide. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as a donor of HNO versus NO• was demonstrated by the sensitivity of the coronary vasodilation response of 1-NCA to the HNO scavenger L-cysteine (4mM), but not to the NO• scavenger hydroxocobalamin (50μM), in the normal rat heart ex vivo (n=3-7). Collectively, our studies provide the first evidence that HNO donors may represent a promising new strategy for the treatment of diabetic cardiomyopathy, and implies their therapeutic efficacy in settings of chronic heart failure.

scholarly journals Diastolic Cardiac Function by MRI—Imaging Capabilities and Clinical Applications

Tomography ◽  
2021 ◽  
Vol 7 (4) ◽  
pp. 893-914
Author(s):  
El-Sayed H. Ibrahim ◽  
Jennifer Dennison ◽  
Luba Frank ◽  
Jadranka Stojanovska
Keyword(s):  
Cardiac Function ◽  
Diastolic Dysfunction ◽  
Systolic Function ◽  
Heart Diseases ◽  
Left Ventricular ◽  
Clinical Applications ◽  
Mri Imaging ◽  
Spatial And Temporal Patterns ◽  
Myocardial Relaxation ◽  
Diastolic Cardiac Function

Most cardiac studies focus on evaluating left ventricular (LV) systolic function. However, the assessment of diastolic cardiac function is becoming more appreciated, especially with the increasing prevalence of pathologies associated with diastolic dysfunction like heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction is an indication of abnormal mechanical properties of the myocardium, characterized by slow or delayed myocardial relaxation, abnormal LV distensibility, and/or impaired LV filling. Diastolic dysfunction has been shown to be associated with age and other cardiovascular risk factors such as hypertension and diabetes mellitus. In this context, cardiac magnetic resonance imaging (MRI) has the capability for differentiating between normal and abnormal myocardial relaxation patterns, and therefore offers the prospect of early detection of diastolic dysfunction. Although diastolic cardiac function can be assessed from the ratio between early and atrial filling peaks (E/A ratio), measuring different parameters of heart contractility during diastole allows for evaluating spatial and temporal patterns of cardiac function with the potential for illustrating subtle changes related to age, gender, or other differences among different patient populations. In this article, we review different MRI techniques for evaluating diastolic function along with clinical applications and findings in different heart diseases.

scholarly journals Long-Term Outcomes of Adults With Heart Failure by Left Ventricular Systolic Function Status

2018 ◽  
Vol 122 (6) ◽  
pp. 1008-1016 ◽  
Author(s):  
Harshith R. Avula ◽  
Thomas K. Leong ◽  
Keane K. Lee ◽  
Sue Hee Sung ◽  
Alan S. Go
Keyword(s):  
Heart Failure ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Long Term Outcomes ◽  
Ventricular Systolic Function

scholarly journals Peripartum Cardiomyopathy Presenting with Predominant Left Ventricular Diastolic Dysfunction: Efficacy of Bromocriptine

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Piercarlo Ballo ◽  
Irene Betti ◽  
Giuseppe Mangialavori ◽  
Leandro Chiodi ◽  
Gherardo Rapisardi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Peripartum Cardiomyopathy ◽  
Lv Function ◽  
Lv Diastolic Dysfunction ◽  
Lv Diastolic Function

Management of patients with peripartum cardiomyopathy (PPCM) is still a major clinical problem, as only half of them or slightly more show complete recovery of left ventricular (LV) function despite conventional evidence-based treatment for heart failure. Recent observations suggested that bromocriptine might favor recovery of LV systolic function in patients with PPCM. However, no evidence exists regarding its effect on LV diastolic dysfunction, which is commonly observed in these patients. Tissue Doppler (TD) is an echocardiographic technique that provides unique information on LV diastolic performance. We report the case of a 37-year-old white woman with heart failure (NYHA class II), moderate LV systolic dysfunction (ejection fraction 35%), and severe LV diastolic dysfunction secondary to PPCM, who showed no improvement after 2 weeks of treatment with ramipril, bisoprolol, and furosemide. At 6-week followup after addition of bromocriptine, despite persistence of LV systolic dysfunction, normalization of LV diastolic function was shown by TD, together with improvement in functional status (NYHA I). At 18-month followup, the improvement in LV diastolic function was maintained, and normalization of systolic function was observed. This paper might support the clinical utility of bromocriptine in patients with PPCM by suggesting a potential benefit on LV diastolic dysfunction.

Link between diabetes and diastolic dysfunction and the diagnostic role of echocardiography

2009 ◽  
Vol 150 (45) ◽  
pp. 2060-2067 ◽  
Author(s):  
András Nagy ◽  
Zsuzsanna Cserép
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Systolic Function ◽  
Diastolic Heart Failure ◽  
Systolic Dysfunction ◽  
Mitral Annulus ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Doppler Study

Diabetes mellitus, a disease that has been reaching epidemic proportions, is an important risk factor to the development of cardiovascular complication. The left ventricular diastolic dysfunction represents the earliest pre-clinical manifestation of diabetic cardiomyopathy, preceding systolic dysfunction and being able to evolve to symptomatic heart failure. In early stages, these changes appear reversible with tight metabolic control, but as pathologic processes become organized, the changes are irreversible and contribute to an excess risk of heart failure among diabetic patients. Doppler echocardiography provides reliable data in the stages of diastolic function, as well as for systolic function. Combination of pulsed tissue Doppler study of mitral annulus with transmitral inflow may be clinically valuable for obtaining information about left ventricular filling pressure and unmasking Doppler inflow pseudonormal pattern, a hinge point for the progression toward advanced heart failure. Subsequently we give an overview about diabetes and its complications, their clinical relevance and the role of echocardiography in detection of diastolic heart failure in diabetes.

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