Abstract 2673: Myoblast Transplantation Improves Cardiac Function Whether the Cells are Implanted Early or Late After Coronary Ligation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Patrick Farahmand ◽  
Richard D Weisel ◽  
Philippe Menasche ◽  
Ren-Ke Li
Keyword(s):  
Cardiac Function ◽  
Left Ventricular ◽  
Border Zone ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Matrix Remodeling ◽  
Stroke Work ◽  
Artery Ligation ◽  
Skeletal Myoblasts ◽  
Myoblast Transplantation

Background: The inability of skeletal myoblasts to transdifferentiate into cardiomyocytes supports the hypothesis that their beneficial effects on cardiac function after a myocardial infarction (MI) are mediated by paracrine effects. In order to explore the role of the timing of cell therapy on the resultant angiogenesis and matrix remodeling, we compared the effects of myoblast transplantation early or late after MI. Methods: MI was generated in Lewis rats by coronary artery ligation. Skeletal myoblasts (5X10 6 ) or control media were injected into the scar and border zone either 5 days (early; n=33) or 30 days (late; n=29) after ligation. Function was assessed by echocardiography before transplantation (Tx), and 14 and 30 days thereafter. Invasive hemodynamics were measured with a Millar catheter at 30 days after Tx, following which explanted hearts were processed to assess LV volumes (computerized planimetry), fibrillar collagen (confocal microscopy), and myoblast engraftment, angiogenesis and extra-cellular matrix characteristics (immunohistochemistry). Results: Load-independent indices of left ventricular (LV) function (Emax, preload recruitable stroke work) were significantly increased in myoblast recipients compared with controls regardless of whether cells were implanted early (p=0.003, p=0.03, respectively) or late (p=0.003, p=0.0007, respectively) after MI. Changes in fractional shortening (by echocardiography) followed a similar pattern. These changes were associated with a significant reduction in LV volume (p=0.04, p=0.01 for early and late Tx groups vs. controls, respectively), and an increase in angiogenesis (p=0.02) whether the myoblasts were injected early or late after MI. The length and width of collagen fibers both in the scar and remote myocardium were also significantly increased (p<0.001) regardless of the timing of myoblast injection. Conclusions: The data suggest that myoblast transplantation improved cardiac function whether cells were injected early or late after MI. In each case, functional recovery was associated with enhanced angiogenesis, favourable effects on extracellular matrix remodeling, and improved LV geometry, supporting the paracrine hypothesis for myoblast transplantation.

Abstract 402: Vitamin C Deficiency Impairs Cardiac Function and Post-infarction Survival in the Mouse

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Adolfo G Mauro ◽  
Donatas Kraskauskas ◽  
Bassem M Mohammed ◽  
Bernard J Fisher ◽  
Eleonora Mezzaroma ◽  
...  
Keyword(s):  
Vitamin C ◽  
Cardiac Function ◽  
Diastolic Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Additional Group ◽  
Gulonolactone Oxidase ◽  
Low Levels ◽  
Systolic And Diastolic Function

Introduction: L-gulonolactone oxidase (Gulo) is the rate limiting enzyme for Vitamin C (VitC) biosynthesis. Humans rely on dietary VitC for collagen synthesis, extracellular matrix formation, and tissue regeneration. VitC deficiency is an unrecognized condition and its role in cardiac homeostasis and post-acute myocardial infarction (AMI) remodeling is unknown. Hypothesis: Low levels of VitC impair cardiac function and tissue repair following AMI. Methods: Adult male Gulo -/- knockout mice (C57BL6 background, N=8) and control C57BL (N=8), which are able to synthesize VitC were used. VitC deficiency was maintained supplying low levels of VitC (30mg/l) to Gulo -/- mice in drinking water. Mice underwent M-mode and Doppler echocardiography to measure left ventricular (LV) diameters and wall thicknesses, fractional shortening (FS), E and A waves, E/A ratio, isovolumetric relaxation time (IRT) and myocardial performance index (MPI). Experimental AMI was induced by coronary artery ligation for 7 days. An additional group of Gulo -/- were mice supplemented with physiological levels of VitC (330 mg/l) and underwent AMI. Results: VitC deficient Gulo -/- mice exhibited significantly reduced LV wall thicknesses, reduced FS, and impaired diastolic function, measured as significantly reduced E/A ratio and longer IRT (Panel A, B & C). Following AMI, 100% (8/8) of deficient Gulo -/- mice died within 5 days. Supplementation with physiological levels of VitC significantly improved survival after AMI (Panel D). Conclusion: VitC deficiency impairs systolic and diastolic function. Moreover, VitC is critical for the post-AMI survival.

Abstract 132: Cardiomyocyte Specific Conditional Overexpression Of Stromal Cell Derived Factor 1 Facilitates Cardiac Regeneration After Permanent Coronary Artery Ligation In Mice.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Detlef Obal ◽  
Kenneth Brittian ◽  
Michael Book ◽  
Aruni Bhatnagar ◽  
Yiru Guo ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Stromal Cell ◽  
Cardiac Regeneration ◽  
Left Ventricular ◽  
Border Zone ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Casein Kinase 1 ◽  
Coronary Ligation ◽  
Stromal Cell Derived Factor

Background: Interruption of cardiac stromal cell derived factor 1 (SDF1)-CXCR4 axis by chronic AMD3100 administration increased myocardial injury after permanent coronary artery ligation demonstrating the important role of this chemokine in cardiac regeneration. Hypothesis: Cardiomyocyte specific conditional overexpression of SDF1 prevents heart failure after permanent coronary ligation and facilitates cardiac regeneration. Methods and Results: Tetracycline-controlled, αMyHC promoter directed overexpression of cardiac SDF1, resulted in a significant increase of SDF1 expression (SDF1: 8.1 ng/mg protein) compared to littermate WT mice (0.02 ng/mg protein) four weeks after doxycycline withdraw. SDF1 overexpression increased AKT and casein kinase 1 levels in the heart. Although there was no difference in cardiac function and scar size 1 week after infarction, SDF1 overexpression improved left ventricular (LV) ejection fraction (SDF1 [n=13]: 47±5% [mean±SEM] vs. WT [n=15]: 29±4%, p<0.05) decreased end-diastolic volume (78±10 vs. 158±30, p<0.05) and reduced infarct size measured by trichrome staining (13±3% vs. 23±3% of LV wall, p<0.05) 4 weeks after permanent ligation. Bromodeoxyuridine (BrdU) staining revealed increased regeneration indicated by a 5-fold increase in BrdU + cardiomyocyte (CM) nuclei in the borderzone of the infarct (22±3% vs. 5±1% CM nuclei, p<0.01). Increased proliferation in SDF1 mice was confirmed by a higher number of KI67 + cells compared to WT mice. Cardiomyocyte cross sectional area in the border zone was significantly reduced in SDF1 mice (365±13 μm 2 vs. 434±10 μm 2 , p<0.001) while capillary density was unchanged (2348±151/ mm 2 vs. 2498±153/ mm 2 ) compared to WT mice. Conclusion: This study demonstrates for the first time that cardiac specific overexpression of SDF1 increases myocardial regeneration and improves LV function 4 weeks after permanent coronary ligation.

Differing cardioprotective efficacy of the Na+/Ca2+ exchanger inhibitors SEA0400 and KB-R7943

2003 ◽  
Vol 284 (3) ◽  
pp. H903-H910 ◽  
Author(s):  
William P. Magee ◽  
Gayatri Deshmukh ◽  
Michael P. Deninno ◽  
Jill C. Sutt ◽  
Justin G. Chapman ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Recovery Of Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Negative Effects ◽  
Artery Ligation ◽  
Regional Ischemia ◽  
Developed Pressure ◽  
Postischemic Recovery

KB-R7943 and SEA0400 are Na+/Ca2+ exchanger (NCX) inhibitors with differing potency and selectivity. The cardioprotective efficacy of these NCX inhibitors was examined in isolated rabbit hearts (Langendorff perfused) subjected to regional ischemia (coronary artery ligation) and reperfusion. KB-R7943 and SEA0400 elicited concentration-dependent reductions in infarct size (SEA0400 EC50: 5.7 nM). SEA0400 was more efficacious than KB-R7943 (reduction in infarct size at 1 μM: SEA0400, 75%; KB-R7943, 40%). Treatment with either inhibitor yielded similar reductions in infarct size whether administered before or after regional ischemia. SEA0400 (1 μM) improved postischemic recovery of function (±dP/d t), whereas KB-R7943 impaired cardiac function at ≥1 μM. At 5–20 μM, KBR-7943 elicited rapid and profound depressions of heart rate, left ventricular developed pressure, and ±dP/d t. Thus the ability of KB-R7943 to provide cardioprotection is modest and limited by negative effects on cardiac function, whereas the more selective NCX inhibitor SEA0400 elicits marked reductions in myocardial ischemic injury and improved ±dP/d t. NCX inhibition represents an attractive approach for achieving clinical cardioprotection.

Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

2005 ◽  
Vol 288 (5) ◽  
pp. H2491-H2497 ◽  
Author(s):  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Cardiac Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mineralocorticoid Receptors ◽  
Artery Ligation ◽  
Sympathetic Hyperactivity ◽  
Air Jet ◽  
Baroreflex Function ◽  
Adrenoceptor Agonist ◽  
The Brain

In rats post-myocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors (MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via Na+ channels, presumably epithelial Na+ channels (ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post-MI, we examined effects of blockade of MR and Na+ channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 ng·kg−1·h−1) or its vehicle, or with benzamil (4 μg·kg−1·h−1) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air-jet stress, intracerebroventricular injection of the α2-adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats (∼31%). In rats treated post-MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain Na+ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction.

scholarly journals Endotoxin impairs cardiac hemodynamics by affecting loading conditions but not by reducing cardiac inotropism

2010 ◽  
Vol 299 (2) ◽  
pp. H492-H501 ◽  
Author(s):  
Li Jianhui ◽  
Nathalie Rosenblatt-Velin ◽  
Noureddine Loukili ◽  
Pal Pacher ◽  
François Feihl ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Myocardial Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Laboratory Animals ◽  
Lv Function ◽  
Stroke Work ◽  
Loading Conditions ◽  
Arterial Elastance ◽  
End Diastolic Volume

Acute myocardial dysfunction is a typical manifestation of septic shock. Experimentally, the administration of endotoxin [lipopolysacharride (LPS)] to laboratory animals is frequently used to study such dysfunction. However, a majority of studies used load-dependent indexes of cardiac function [including ejection fraction (EF) and maximal systolic pressure increment (dP/d tmax)], which do not directly explore cardiac inotropism. Therefore, we evaluated the direct effects of LPS on myocardial contractility, using left ventricular (LV) pressure-volume catheters in mice. Male BALB/c mice received an intraperitoneal injection of E. coli LPS (1, 5, 10, or 20 mg/kg). After 2, 6, or 20 h, cardiac function was analyzed in anesthetized, mechanically ventilated mice. All doses of LPS induced a significant drop in LV stroke volume and a trend toward reduced cardiac output after 6 h. Concomitantly, there was a significant decrease of LV preload (LV end-diastolic volume), with no apparent change in LV afterload (evaluated by effective arterial elastance and systemic vascular resistance). Load-dependent indexes of LV function were markedly reduced at 6 h, including EF, stroke work, and dP/d tmax. In contrast, there was no reduction of load-independent indexes of LV contractility, including end-systolic elastance (ejection phase measure of contractility) and the ratio dP/d tmax/end-diastolic volume (isovolumic phase measure of contractility), the latter showing instead a significant increase after 6 h. All changes were transient, returning to baseline values after 20 h. Therefore, the alterations of cardiac function induced by LPS are entirely due to altered loading conditions, but not to reduced contractility, which may instead be slightly increased.

scholarly journals β1-Adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction

2009 ◽  
Vol 297 (4) ◽  
pp. H1377-H1386 ◽  
Author(s):  
ByungSu Yoo ◽  
Anthony Lemaire ◽  
Supachoke Mangmool ◽  
Matthew J. Wolf ◽  
Antonio Curcio ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Border Zone ◽  
Tunel Staining ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cardiac Inotropy ◽  
Significant Attenuation

The β-adrenergic receptor (βAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca2+ homeostasis. We investigated the role of βAR stimulation in augmenting cardiac function and its role in the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) using various βAR knockouts (KO) including β1ARKO, β2ARKO, and β1/β2AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific βAR subtypes in the activation of CaMKII in vivo in failing myocardium. Cardiac inotropy, chronotropy, and CaMKII activity following short-term isoproterenol stimulation were significantly attenuated in β1ARKO and DKO compared with either the β2ARKO or wild-type (WT) mice, indicating that β1ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), β1ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the β2ARKO or WT mice. CaMKII activity after MI was significantly increased only in the β2ARKO and WT hearts and not in the β1ARKO and DKO hearts. The border zone of the infarct in the β2ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the β1ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the β1AR. Moreover, it appears that β1AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.

Midterm Surgical Outcomes for ALCAPA Repair in Infants and Children

2021 ◽  
Author(s):  
Renjie Hu ◽  
Wen Zhang ◽  
Xiafeng Yu ◽  
Hongbin Zhu ◽  
Haibo Zhang ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Mitral Valve ◽  
Mitral Valve Regurgitation ◽  
Left Ventricular ◽  
Surgical Correction ◽  
Circulatory Support ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Abstract Background Surgical correction of an anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) has been associated with excellent survival during recent years. The purpose of this study was to evaluate the effectiveness of reimplantation of the coronary artery and to investigate the recovery of postoperative cardiac and mitral valve (MV) function. Methods From 2005 to 2015, 80 patients who had ALCAPA received surgical correction. Among them, 49 were infants. The median patient age was 7.8 months. Operative strategies included reimplantation of the coronary artery in 71 patients, the Takeuchi procedure in another 7 patients, and coronary artery ligation in the remaining 2 patients. Results There were 11 hospital deaths and 2 late deaths. Six patients required intraoperative or postoperative mechanical circulatory support. A significant improvement in the ejection fraction (EF) and shortening fraction (SF) was present in all surviving patients at discharge, at a 3-month follow-up and at a 1-year follow-up. MV function improved gradually after surgical repair with no late secondary intervention. Conclusions The repair of ALCAPA can be accomplished by establishment of a dual-coronary system, which offers an acceptable mortality rate and will rarely require a second surgery. Left ventricular (LV) recovery is a progressive process, especially for infants with impaired LV function. Concomitant MV annuloplasty is safe and reliable and can be performed as necessary in patients with moderate or severe mitral valve regurgitation.

Abstract P345: The Neuregulin Glial Growth Factor 2 (GGF2) Produces Sustained Improvement in Left Ventricular Function in Rats with Both Early and Established Heart Failure

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Anindita Ganguly ◽  
Erika Troy ◽  
Maya Srinivas ◽  
Andrea Vecchione ◽  
Patrick Sarmiere ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Cardiac Development ◽  
Left Ventricular ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Sustained Improvement ◽  
Delayed Initiation

Neuregulin-1β is essential for fetal cardiac development and adult cardiac function. Previous reports indicate that neuregulins improve left ventricular function in heart failure models, however the duration of the functional improvements with early or late initiation of neuregulin treatment has not been characterized. The present studies examine the effects of early and delayed initiation of intravenous GGF2 treatment on left ventricular (LV) function in rats with myocardial infarction (MI). Rats underwent surgically-induced MI by left anterior coronary artery ligation. Treatment with vehicle or GGF2 (2.6 mg/kg) was initiated at 2 or 16 w post-MI and continued once or twice weekly or once every two weeks for the in-life duration of the study (approximately 40 weeks). LV function was assessed echocardiographically up to once weekly for the duration of the study. Early and delayed initiation of GGF2 treatment caused sustained and significant improvement (p < 0.05) in both ejection fraction (EF) and fractional shortening (FS) in all regimens tested. The greatest improvements were seen with the once weekly dosing paradigm after early initiation (average EF (%) at 40 weeks post initiation of dosing: vehicle = 44.4 ± 6.0, n = 8 rats, vs. GGF2 = 64.7±6.1. n = 9 rats) and twice weekly dosing paradigm after delayed initiation (average EF (%) at 4 weeks post initiation of dosing: vehicle = 34.18±1.6, n = 7 rats, vs. GGF2 = 50.69±4.68, n = 7 rats). In addition, LV function improved when rats were re-challenged with GGF2 following an extended wash out period. This observation indicates potential efficacy for treatment paradigms that utilize intermittent dosing. These findings suggest that GGF2 produces sustained improvement in LV function after early or delayed initiation of treatment following MI in rats.

Abstract 249: Chronic Neuregulin-1β Treatment Mitigates the Progression of Post-myocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Manisha Gupte ◽  
Hind Lal ◽  
Firdos Ahmad ◽  
Lin Zhong ◽  
Douglas B Sawyer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 1 Diabetes ◽  
Heart Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Aim: Neuregulin-1β (NRG-1β), a growth factor critical for cardiac development as well as maintenance of heart function after injury has been shown to significantly improve heart function in preclinical rodent models. Importantly, number of studies are ongoing to test the efficacy of NRG-1β as a treatment for patients with chronic heart failure. However, the efficacy of recombinant NRG-1β in a typ1 diabetic model of heart failure due to myocardial infarction (MI) has not been investigated. The aim of the present study was to determine the efficacy of exogenous NRG-1β to improve residual cardiac function after MI in type1 diabetic rats. Methods and Results: Sprague Dawley rats were induced type 1 diabetes by a single injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 diabetes, rats underwent left coronary artery ligation to induce MI. STZ-diabetic rats were treated with saline or NRG-1β (100 ug/kg) twice a week for 7 weeks, starting two weeks prior to experimental MI. Residual left ventricular (LV) function was significantly greater in the NRG-1β-treated STZ-diabetic MI group compared to the vehicle-treated STZ-diabetic MI group 5 weeks after MI as assessed by high-resolution echocardiography. Furthermore, NRG-1β treatment in STZ-diabetic MI rats reduced myocardial fibrosis and apoptosis as well as decreased gene expression of key oxidant-producing enzymes. Conclusion: This study demonstrates that augmentation of NRG-1β signaling in STZ-diabetic post-MI rats via therapy with exogenous recombinant NRG-1β will alleviate subsequent HF through improvements in residual LV function via protection against adverse remodeling and apoptosis.

Abstract 176: Saxagliptin and Tadalafil Differentially Alter Global and Cellular Cardiac Function in a Translational Miniature Swine Model of Left Ventricle Hypertrophy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jessica A Hiemstra ◽  
Anne K Gibson ◽  
Jan R Ivey ◽  
Melissa S Cobb ◽  
Christopher P Baines ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Pde5 Inhibitor ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Lv Function ◽  
Swine Model ◽  
Stroke Work ◽  
Wall Stiffness ◽  
Cgmp Signaling ◽  
Whole Heart

Left ventricular (LV) hypertrophy is a common characteristic of heart failure with preserved ejection fraction (HFpEF). Our lab recently characterized a mini-swine model of LV hypertrophy induced by aortic banding (AB) that displays clinical features associated with HFpEF including LV hypertrophy, diastolic dysfunction, and depressed contractile reserve. Disrupted cGMP signaling, a result of impaired production or enhanced catabolism, may play a role in development of HFpEF. We hypothesized preservation of cGMP signaling would attenuate pathological remodeling and improve cardiac function. The purpose of this study was to promote cGMP signaling via two mechanisms: 1) the DPP4 inhibitor saxagliptin; and 2) the PDE5 inhibitor tadalafil. We assessed whole heart and individual cardiomyocyte function 6 months post-AB in: control non-banded (CON; n=6), AB-control (AB; n=7), AB saxagliptin-treated (AB-SAX; n=7), and AB tadalafil-treated (AB-TAD; n=8) swine. Heart weight:body weight ratio increased to a similar extent in all AB groups. However, changes in cardiomyocyte morphology were variable. Cardiomyocyte length was increased only in the AB-TAD group, while cell width increased in both AB and AB-TAD animals. Cardiomyocyte length:width ratio decreased in the AB and AB-TAD groups, commensurate with decreased LV end diastolic (ED) and end systolic (ES) volumes. These changes were prevented in AB-SAX animals, as LV volumes and cell morphology were similar to CON. Pressure-volume analysis showed resting LV wall stiffness (ED pressure volume relationship [EDPVR] slope) was increased similarly in all AB groups. Increased resting LV contractility (ESPVR and preload recruitable stroke work) was observed in AB and AB-TAD animals. Interestingly, cardiomyocyte shortening was reduced in the AB-TAD group contrasting findings observed at the whole heart level. Saxaglitpin attenuated hypercontractile LV function at rest and preserved normal cardiomyocyte shortening. In conclusion, LV and cardiomyocyte function was distinctly altered in response to separate methods of pharmacological cGMP regulation. Our data suggest different pharmacological approaches to augment cGMP signaling promote distinct LV functional adaptations to developing HF.

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