scholarly journals Cardiomyocyte-specific deletion of leptin receptors causes lethal heart failure in Cre-recombinase-mediated cardiotoxicity

2012 ◽  
Vol 303 (12) ◽  
pp. R1241-R1250 ◽  
Author(s):  
Michael E. Hall ◽  
Grant Smith ◽  
John E. Hall ◽  
David E. Stec
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Leptin Receptor ◽  
Systolic Function ◽  
Mammalian Target Of Rapamycin ◽  
Left Ventricular Systolic Function ◽  
Cre Recombinase ◽  
Left Ventricular ◽  
Leptin Receptors ◽  
Specific Deletion

Although disruption of leptin signaling is associated with obesity as well as cardiac lipid accumulation and dysfunction, it has been difficult to separate the direct effects of leptin on the heart from those associated with the effects of leptin on body weight and fat mass. Using Cre-loxP recombinase technology, we developed tamoxifen-inducible, cardiomyocyte-specific leptin receptor-deficient mice to assess the role of leptin in regulating cardiac function. Cre recombinase activation in the heart resulted in transient reduction in left ventricular systolic function which recovered to normal levels by day 10. However, when cardiomyocyte leptin receptors were deleted in the setting of Cre recombinase-induced left ventricular dysfunction, irreversible lethal heart failure was observed in less than 10 days in all mice. Heart failure after leptin receptor deletion was associated with marked decreases of cardiac mitochondrial ATP, phosphorylated mammalian target of rapamycin (mTOR), and AMP-activated kinase (pAMPK). Our results demonstrate that specific deletion of cardiomyocyte leptin receptors, in the presence of increased Cre recombinase expression, causes lethal heart failure associated with decreased cardiac energy production. These observations indicate that leptin plays an important role in regulating cardiac function in the setting of cardiac stress caused by Cre-recombinase expression, likely through actions on cardiomyocyte energy metabolism.

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 3356: Does Severe Obesity Cause Progressive Impairment of Left Ventricular Systolic Function?

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Theophilus Owan ◽  
Kimberly Morley ◽  
Travis G Ault ◽  
Ronny Jiji ◽  
Nathaniel Hall ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Entire Group ◽  
Obese Patients ◽  
Cross Sectional ◽  
Increased Risk ◽  
Severely Obese ◽  
The Mean

Background: Obesity is associated with an increased risk of developing heart failure. Based on cross sectional studies, it has been hypothesized that the duration of obesity is the key factor leading to impaired cardiac function. However, longitudinal data to confirm this hypothesis are not available. Methods: We prospectively studied 62 severely obese patients at baseline, 2 and 5 years after randomization to nonsurgical therapy (NonSurg, n = 25) or Rouxen-Y gastric bypass surgery (GBS, n = 37). Echocardiography was used to measure left ventricular (LV) size and ejection fraction (EF). Results: At enrollment, the mean BMI was 46±9 and the mean age was 47±11 years (range 25– 66). GBS subjects lost 96± 26 vs. 6±18 lbs at 2 years and 78±42 vs. 17±42 lbs at 5 years compared to NonSurg (p<0.0001 for both). At baseline LVEF was not different between GBS and nonsurg (67±9 vs. 64±8%) and it did not change at 2 years (64±9 vs. 63±9%) or 5 years (63±9 vs. 63±10%). LV diastolic dimension did not change over time in control (4.3±1.0 vs. 4.2±0.6 vs. 4.5±0.3) or GBS patients (4.4±0.6 vs. 4.3±0.7 vs. 4.4±0.4). Stratifying the entire group by quartiles of age or duration of obesity (quartile 1 avg duration = 16 years, quartile 4 average duration = 56 years), we found no evidence of time-dependent changes in LV size or function. Conclusion: In this, prospective study of severely obese patients we found no evidence of progressive changes in LV size or EF over a period of 5 years. Moreover, we find no relationship between age or duration of obesity and LV size or LVEF. These data argue strongly that other factors such as the development of coronary disease are the most likely causes of heart failure in obese patients.

scholarly journals Comparison between ivabradine and low-dose digoxin in the therapy of diastolic heart failure with preserved left ventricular systolic function

2013 ◽  
Vol 3 (2) ◽  
pp. 29 ◽  
Author(s):  
Giuseppe Cocco ◽  
Paul Jerie
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Heart Rate ◽  
Low Dose ◽  
Systolic Function ◽  
Diastolic Heart Failure ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Ventricular Systolic Function ◽  
Coronary Patients

Multicenter trials have demonstrated that in patients with sinus rhythm ivabradine is effective in the therapy of ischemic heart disease and of impaired left ventricular systolic function. Ivabradine is ineffective in atrial fibrillation. Many patients with symptomatic heart failure have diastolic dysfunction with preserved left ventricular systolic function, and many have asymptomatic paroxysmal atrial fibrillation. Ivabradine is not indicated in these conditions, but it happens that it is <em>erroneously</em> used. Digoxin is now considered an outdated and potentially dangerous drug and while effective in the mentioned conditions, is rarely used. The aim of the study was to compare the therapeutic effects of ivabradine in diastolic heart failure with preserved left ventricular systolic function. Patients were assigned to ivabradine or digoxin according to a randomization cross-over design. Data were single-blind analyzed. The analysis was performed using an intention-to-treat method. Forty-two coronary patients were selected. In spite of maximally tolerated therapy with renin-antagonists, diuretics and ?-blockers, they had congestive diastolic heart failure with preserved systolic function. Both ivabradine and digoxin had positive effects on dyspnea, Nterminal natriuretic peptide, heart rate, duration of 6-min. walk-test and signs of diastolic dysfunction, but digoxin was high-statistically more effective. Side-effects were irrelevant. Data were obtained in a single-center and from 42 patients with ischemic etiology of heart failure. The number of patients is small and does not allow assessing mortality. In coronary patients with symptomatic diastolic heart failure with preserved systolic function low-dose digoxin was significantly more effective than ivabradine and is much cheaper. One should be more critical about ivabradine and low-dose digoxin in diastolic heart failure. To avoid possible negative effects on the cardiac function and a severe reduction of the cardiac output the resting heart rate should not be decreased to &lt;65 beats/min.

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