Abstract 1247: Heart Function is Transiently Sustained Despite a Near Loss of SERCA2 Protein in Cardiomyocyte-specific Serca2 null Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kristin B Andersson ◽  
Alexandra V Finsen ◽  
Ivar Sjaastad ◽  
Yibin Wang ◽  
Ju Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Output ◽  
Diastolic Pressure ◽  
Heart Function ◽  
Clinical Signs ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Lung Weight ◽  
Adult Mice

The SERCA2 Ca 2+ ATPase is of central importance for refilling of the sarcoplasmic reticulum (SR) Ca 2+ store and cardiac contractility. Reduced SERCA2 function is associated with heart failure. We hypothesized that loss of SERCA2 would result in immediate severe myocardial contractile dysfunction and death. Transgenic mice were generated with a Cre-loxP strategy in which tamoxifen induces Serca2 ( Atp2a2 ) gene excision in the cardiomyocytes (SERCA2KO) of adult mice. In SERCA2KO mice, SERCA2 protein was rapidly reduced in left ventricular myocardium with a half-life < 3 days. After 4 weeks, SERCA2 protein was reduced to < 5% of control values. In isolated cardiomyocytes, SERCA2a, SERCA2b, SERCA1 and SERCA3 proteins were not detectable. Strikingly, SERCA2KO mice did not present clinical signs of circulatory failure at 4 weeks. Fractional shortening was preserved, and cardiac output was reduced to 80% of control values. The left atrial diameter, lung weight and left ventricular end-diastolic pressure (LVEDP) were slightly increased in SERCA2KO mice compared with controls, and the maximal rates of pressure development and decline in the left ventricle were affected with a prolongation of the ventricular relaxation time. After seven weeks, SERCA2KO mice developed severe congestive heart failure with dilated chambers, elevated LVEDP and pronounced increases in lung and atrial weights. Cardiac output was reduced to 70% of control values. There were no indications of major cardiomyocyte disarray in the myocardium at the 4 or 7 week timepoints. The abundance of Na + ,Ca 2+ exchanger, L-type Ca 2+ channel 1c and alpha2delta1 subunit proteins and Pmca1 mRNA were all increased at 4 and 7 weeks. The expression of calsequestrin protein and Ryr2 mRNA were unchanged. L-type Ca 2+ channel alpha2delta1 subunit and PMCA1 expression were further enhanced at 7 weeks in SERCA2KO mice. Thus, cardiac function is supported in SERCA2KO mice for several weeks despite the near absence of SERCA2 protein. Alterations in the expression of Ca 2+ transporting proteins suggest that Ca 2+ transients are generated over the plasma membrane rather than the SR. However, the adaptations induced by loss of SERCA2 are not sufficient for long-term support of heart function in adult mice.

scholarly journals Effect of Valsartan on Sarcoplasmic Reticulum Ca2+-ATPase Pump of the Left Ventricular Myocardium in Rats with Heart Failure with Preserved Ejection Fraction

2016 ◽  
Vol 1 (2) ◽  
pp. 1-9
Author(s):  
Xiao Ying ◽  
Long Weiqing ◽  
Lu Guihua ◽  
Zhang Juhong ◽  
Zhibin Huang
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Preserved Ejection Fraction ◽  
Relaxation Time Constant ◽  
Ventricular Relaxation ◽  
Constant Quantity

Objectives: The aim was to investigate the effects of valsartan on the sarcoplasmic reticulum Ca2+-ATPase pump (SERCA) and L-type Ca2+ channel current (ICaL) of the left ventricular myocardium in rats with heart failure with preserved ejection fraction. Methods: The 30-week-old male spontaneously hypertensive rats (SHRs) are randomly divided into the non-Valsartan and Valsartan groups, and the 30-week-old male Wistar-Kyoto rats served as control rats. The expression of SERCA is measured by Western blot. The ICaL is measured by whole-cell patch clamp. The left ventricular end-diastolic pressure and left ventricular relaxation time constant quantity are measured at the same time. Results: The left ventricular end-diastolic pressure is much higher in SHRs compared with that in control rats (p < 0.01). The left ventricular relaxation time constant quantity is markedly extended in SHRs compared with control rats (p < 0.01). Valsartan cannot increase the expression of SERCA nor decrease the density of ICaL compared with the non-Valsartan group (p > 0.05). Conclusions: Valsartan has no effect on SERCA and ICaL of the left ventricular myocardium in rats with heart failure with preserved ejection fraction.

scholarly journals Remodeling of t-system and proteins underlying excitation-contraction coupling in aging versus failing human heart

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yankun Lyu ◽  
Vipin K. Verma ◽  
Younjee Lee ◽  
Iosif Taleb ◽  
Rachit Badolia ◽  
...  
Keyword(s):  
Heart Function ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Excitation Contraction Coupling ◽  
Transverse Tubular System ◽  
Contraction Coupling ◽  
Senescent Phenotype ◽  
Cellular Microstructure ◽  
T System

AbstractIt is well established that the aging heart progressively remodels towards a senescent phenotype, but alterations of cellular microstructure and their differences to chronic heart failure (HF) associated remodeling remain ill-defined. Here, we show that the transverse tubular system (t-system) and proteins underlying excitation-contraction coupling in cardiomyocytes are characteristically remodeled with age. We shed light on mechanisms of this remodeling and identified similarities and differences to chronic HF. Using left ventricular myocardium from donors and HF patients with ages between 19 and 75 years, we established a library of 3D reconstructions of the t-system as well as ryanodine receptor (RyR) and junctophilin 2 (JPH2) clusters. Aging was characterized by t-system alterations and sarcolemmal dissociation of RyR clusters. This remodeling was less pronounced than in HF and accompanied by major alterations of JPH2 arrangement. Our study indicates that targeting sarcolemmal association of JPH2 might ameliorate age-associated deficiencies of heart function.

DNA enzyme targeting TNF-α mRNA improves hemodynamic performance in rats with postinfarction heart failure

2001 ◽  
Vol 281 (5) ◽  
pp. H2211-H2217 ◽  
Author(s):  
Per Ole Iversen ◽  
Gunnar Nicolaysen ◽  
Mouldy Sioud
Keyword(s):  
Heart Failure ◽  
Therapeutic Potential ◽  
Diastolic Pressure ◽  
Substantial Reduction ◽  
Left Ventricular ◽  
Lung Weight ◽  
Cleavage Activity ◽  
Arterial Blood ◽  
Modified Dna ◽  
Tnf Α

Tumor necrosis factor-α (TNF-α) probably affects the pathogenesis of heart failure. Here we have investigated the therapeutic potential of a nuclease-resistant DNA enzyme that specifically cleaves TNF-α mRNA. A phosphorothioate-modified DNA enzyme was designed to retain similar cleavage activity as its unmodified version, and that inhibited the expression of TNF-α in vitro. To test its efficacy in vivo, postinfarction congestive heart failure was induced in anesthetized rats by ligation of the left coronary artery. A 4-wk treatment with the DNA enzyme induced a substantial reduction in left ventricular end-diastolic pressure and lung weight concomitant with an increase in arterial blood pressure and myocardial blood flow compared with controls. The concentration of TNF-α in coronary sinus blood was markedly lowered on treatment, and myocardial TNF-α mRNA was substantially reduced. Recovery studies showed that the DNA enzyme cleavage activity was present within the myocardium throughout the observation period and had no apparent toxic effects. Our findings indicate that DNA enzyme-based therapy may hold promise in the treatment of this debilitating disease.

scholarly journals Exertional dyspnea after myocardial infarction: thinking beyond the diagnosis of heart failure

2018 ◽  
Vol 46 (11) ◽  
pp. 4769-4774
Author(s):  
Konstantinos Koutsampasopoulos ◽  
Savvas Grigoriadis ◽  
Ioannis Vogiatzis
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Aneurysm ◽  
Left Ventricular Myocardium ◽  
Inferior Wall ◽  
Delayed Presentation ◽  
Exertional Dyspnea ◽  
St Elevation

Introduction We herein present an unusual case of a pseudoaneurysm of the left ventricular myocardium, which is a rare and fatal complication of myocardial infarction. Case report A 64-year-old man with a history of bipolar disorder and arterial hypertension was hospitalized for delayed presentation ST-elevation myocardial infarction. He was admitted to our hospital 24 hours after symptom onset. Diagnostic coronary angiography revealed 95% stenosis at the distal third of the right coronary artery, and he underwent a primary percutaneous coronary intervention to the culprit lesion. Despite administration of a diuretic and optimization of other pharmaceutical treatment, his heart failure deteriorated. Electrocardiography showed a sinus rhythm with Q-wave formation in the inferior wall leads (II, III, aVF), T-wave inversion in the same leads, and borderline QT prolongation (QTc of 490 ms). No ST elevation suggestive of left ventricular aneurysm formation was noticed. Forty days later, cardiac ultrasound revealed a dyskinetic cavity (pseudoaneurysm) in continuity with the posterior–inferior wall of the myocardium, resulting in severe mitral valve regurgitation. Unfortunately, the patient died while awaiting surgical treatment. Conclusion Although most patients with left ventricular pseudoaneurysm have a relatively benign outcome, those with symptoms of heart failure must be urgently diagnosed and treated.

Deloading of the Left Ventricle by Ventricular Assist Device Normalizes Increased Expression of Endothelin ET A Receptors But Not Endothelin-Converting Enzyme-1 in Patients With End-Stage Heart Failure

Circulation ◽  
2000 ◽  
Vol 102 (suppl_3) ◽  
Author(s):  
Henning Morawietz ◽  
Marten Szibor ◽  
Winfried Goettsch ◽  
Babett Bartling ◽  
Matthias Barton ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Transplantation ◽  
Ace Inhibitor ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Converting Enzyme ◽  
Ventricular Assist ◽  
End Stage Heart Failure ◽  
End Stage

Background —Ventricular assist devices (VAD) are implanted in patients with end-stage heart failure for bridging the time until heart transplantation, resulting in hemodynamic unloading of the failing heart, improved cardiac contractile and mitochondrial function, and reversal of cardiac hypertrophy. It is unknown whether VAD unloading may affect the cardiac endothelin (ET) system, which has been proposed as one of the putative pathomechanisms of heart failure. Methods and Results —With the use of standard-calibrated, competitive reverse-transcription–polymerase chain reaction mRNA expression of components of the ET system was analyzed in left ventricular myocardium from nonfailing donor hearts, from failing hearts without and with ACE inhibitor therapy, and from patients with end-stage heart failure at the time of VAD implantation and 103±15 days after VAD implantation during removal with subsequent heart transplantation. ET receptor A (ET A ) was markedly upregulated in failing human myocardium. This increased ET A expression was not affected by ACE inhibitor treatment but was normalized by VAD unloading. ET A expression before or after VAD implantation did not correlate with duration of VAD implantation or suppression of Pro-ANP mRNA. ET B mRNA expression was unaffected by heart failure or VAD. In contrast, increased ET-converting enzyme-1 mRNA and ET-1 peptide levels in failing myocardium were partially normalized by ACE inhibition but not by VAD unloading. Conclusions —We conclude that VAD implantation normalizes ET A expression in failing human left ventricular myocardium, probably as the result of the beneficial effects of VAD unloading.

Abstract 370: Type 2 Diabetes Is Associated with the Exacerbation of Heart Failure via Increasing Myocardial NAD(P)H Oxidase-Derived Superoxide Production

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shintaro Kinugawa ◽  
Shouji Matsushima ◽  
Takashi Yokota ◽  
Yukihiro Ohta ◽  
Naoki Inoue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Lung Weight ◽  
Tissue Mass ◽  
Tibial Length ◽  
Lv Remodeling

Type 2 diabetes mellitus (DM) adversely affects the outcomes in patients with myocardial infarction (MI), which is associated with the development of left ventricular (LV) remodeling and failure. NAD(P)H oxidase-derived superoxide (O 2 − ) production is increased in DM. However, its pathophysiological significance in advanced post-MI LV failure associated with DM remains unestablished. We thus determined whether an inhibitor of NAD(P)H oxidase activation, apocynin, could attenuate the exacerbated LV remodeling and heart failure after MI in high-fat diet (HFD)-induced obese mice with DM. Male C57BL/6J mice were fed on either HFD or normal diet (ND) for 8 weeks. At 4 weeks of feeding, MI was created in all mice by ligating left coronary artery. MI mice were treated with either apocynin (10 mmol/l in drinking water; n = 10 for ND and n = 11 for HFD) or vehicle (n = 15 for ND and n = 13 for HFD). HFD significantly increased body weight (BW), adipose tissue mass, fasting plasma glucose and insulin levels compared to ND after 4 and 8 weeks. HFD + MI had significantly greater LV end-diastolic diameter (LVEDD; 5.7 ± 0.1 vs. 5.3 ± 0.2 mm) by echocardiography, end-diastolic pressure (EDP; 12 ± 2 vs. 8 ± 1 mmHg) and lung weight/tibial length (10.1 ± 0.3 vs. 8.7 ± 0.7 mg/mm) than ND + MI, which was accompanied by an increased interstitial fibrosis of non-infarcted LV. Treatment of HFD + MI with apocynin significantly decreased LVEDD (5.4 ± 0.1 mm), LVEDP (9.7 ± 0.8 mmHg), lung weight/tibial length (9.0 ± 0.3 mg/mm), and concomitantly interstitial fibrosis of non-infarcted LV to ND + MI level without affecting BW, glucose metabolism, infarct size and aortic pressure. On the other hand, treatment of ND + MI with apocynin did not affect LV remodeling and failure. NAD(P)H oxidase activity, O 2 − production measured by lucigenin chemiluminescence, and thiobarbituric acid-reactive substances were increased in non-infarcted LV tissues from HFD + MI, all of which were also attenuated by apocynin to ND + MI level. Type 2 DM was associated with the exacerbation of LV remodeling and failure after MI via increasing NAD(P)H oxidase derived O 2 − production, which may be a novel important therapeutic target in advanced heart failure with DM.

Sign in / Sign up

Export Citation Format

Share Document