Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures

2006 ◽  
Vol 290 (4) ◽  
pp. H1699-H1705 ◽  
Author(s):  
K. A. Connelly ◽  
D. L. Prior ◽  
D. J. Kelly ◽  
M. P. Feneley ◽  
H. Krum ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Systolic Function ◽  
Normal Function ◽  
Left Ventricular ◽  
Doppler Imaging ◽  
Stroke Work ◽  
Sprague Dawley ◽  
Loop Analysis ◽  
Shortening Velocity

Transgenic animal models have provided a vital insight into the pathogenesis of cardiovascular disease, but functional cardiac assessment is often limited by high heart rates and small heart size. We hypothesized that in the presence of concentric left ventricular (LV) hypertrophy (LVH), load-sensitive measures of contractility may be misinterpreted as overestimating global cardiac function, because the normal function of excess sarcomeres may displace a greater volume of blood during contraction. Conductance catheter technology was used to evaluate pressure-volume (P-V) relationships as a load-insensitive method of assessing cardiac function in vivo in 18-wk-old heterozygous (mRen-2)27 transgenic rats (a model of LVH), compared with age-matched Sprague-Dawley (SD) controls. Anesthetized animals underwent echocardiography followed by P-V loop analysis. Blood pressure, body weight, and heart rate were higher in the Ren-2 rats ( P < 0.05). Load-sensitive measures of systolic function, including fractional area change, fractional shortening, ejection fraction, and positive peak rate of LV pressure development, were greater in the Ren-2 than control animals ( P < 0.05). Load-insensitive measures of systolic function, including the preload recruitable stroke work relationship and the end-systolic P-V relationship, were not different between Ren-2 and SD rats. Regional wall motion assessed by circumferential shortening velocity suggested enhanced circumferential fiber contractility in the Ren-2 rats ( P = 0.02), but tissue Doppler imaging, used to assess longitudinal function, was not different between groups. Although conventional measures suggested enhanced systolic function in the Ren-2 rat, load-insensitive measures of contractility were not different between Ren-2 and SD animals. These findings suggest that the normal range of values for load-sensitive indexes of contractility needs to be altered according to the degree of LVH. To accurately identify changes in systolic function, we suggest that a combination of echocardiography with assessment of load-insensitive measures be used routinely.

scholarly journals The Effects of Low-dose Empagliflozin on Cardiac Function in a Rat Model of Streptozotocin-induced Diabetes

2021 ◽  
Author(s):  
Zeynep Eilf Yesilyurt ◽  
Irem Karaomerlioglu ◽  
Betül Rabia Erdogan ◽  
Gaye Ozturk ◽  
Martin C Michel ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Low Dose ◽  
Contractile Response ◽  
Diabetic Rats ◽  
Diabetic Heart ◽  
Stroke Work ◽  
Sprague Dawley ◽  
Loop Analysis

Abstract Purpose: Diabetes mellitus is a metabolic disorder leading to cardiovascular complications. Both in vivo cardiac function and β-adrenoceptor (β-AR) mediated responsiveness have been demonstrated to be blunted in the diabetic heart. Sodium glucose co-transporter-2 (SGLT2) inhibitors, such as empagliflozin (EMPA) have shown cardioprotective effects in patients and in some animal models. In this study, we aimed to investigate the effects of low-dose EMPA (10 mg/kg/day) on in vivo cardiac function and β-AR-mediated contractile response in streptozotocin (STZ)-induced diabetic rats. Methods: 11-12 week old male Sprague Dawley rats were divided into 4 groups; control, EMPA-treated control, diabetic, EMPA-treated diabetic. Diabetes was induced by STZ injection (40 mg/kg, i.p.). After 13-16 weeks, some of the diabetic and control rats were treated with a low dose of EMPA (10 mg/kg/day, oral gavage, once a day) or vehicle for another 8 weeks. At study end, in vivo cardiac function was evaluated by pressure-volume loop analysis. β-AR mediated contractile response was determined using isoprenaline in papillary muscle preparations. Results: EMPA did not change cardiac function in control rats. Diabetic rats had a reduced heart rate, cardiac output, stroke work, +dp/dt and -dp/dt and increased isovolumic relaxation, whereas in vitro responses were reduced to a minor extent. Treatment with EMPA showed a trend for improvement of some but not all parameters. Conclusion: Our results indicate that low dose EMPA treatment had limited effects on cardiac impairment although it reduced blood glucose. Future studies with a higher dose and greater sample sizes could help to clarify the possible benefits of EMPA on the diabetic heart.

Abstract 350: Early Cell-Cell Coupling Contributes to Loss of Transplanted Stem Cell Retention and Efficacy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Santipongse Chatchavalvanich ◽  
David L Geenen
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cardiac Function ◽  
Bystander Effect ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cell Coupling ◽  
Loop Analysis

Bone marrow-derived mesenchymal stem cell (BM-MSC) replacement therapy is beneficial to the heart following ischemia but a significant loss of these cells within hours of administration could diminish their effect. We hypothesized that early coupling between BM-MSC and ischemic cardiomyocytes through gap junctions (GJ) may play a detrimental role in stem cell survival and retention in the acute phase of cell therapy. We seeded HL-1 cardiomyocytes in either normoxic (Nx) or ischemic (Isc) conditions for four hours. Subsequently, BM-MSC were seeded on the HL-1 monolayer and the co-cultures were returned to incubation either in their previous conditions (Nx, Isc) or switched from Isc to Nx condition (ischemia-reperfusion; Isc/Rep) for an additional two hours. Co-cultures were labeled with Annexin V, Sytox Red, and Sca-1 (BM-MSC), and subjected to flow cytometry. Ischemia induced a greater proportion of dead BM-MSC over the two-hour co-culture compared to the Nx group. Isc/Rep resulted in significantly higher early apoptotic but fewer dead BM-MSC. The presence of the GJ inhibitor carbenoxolone (CBX; 100 µM) in the co-culture reduced the number of dead and apoptotic cells in Isc and Isc/Rep groups by 3-5 fold (p<0.05). To determine the effect of GJ inhibition in vivo, we induced ischemia in mice by 90-minute LAD ligation followed by reperfusion for 24 hours. BM-MSC, CBX-treated BM-MSC, or CBX alone were injected at the end of the 90 min Isc period. Twenty-four hours after cell injection, left ventricular diastolic and systolic function was assessed by pressure-volume loop analysis. Isc/Rep caused impaired cardiac function which was attenuated by BM-MSC injection. CBX-treated BM-MSC further enhanced the cardiac function (MSC vs. MSC+CBX: Ees 7.3 ± 1.66 vs. 15.0 ± 5.81; Emax 18.8 ± 6.50 vs. 27.5 ± 9.33; PRSW 49.5 ± 9.89 vs. 99.4 ± 17.4; mean ± SD; p≤0.05; n = 6) while CBX alone did not. While long term integration of stem cells within the myocardium relies on functional GJ, early GJ communication may represent a novel paradigm whereby ischemic cardiomyocytes cause a “bystander effect” in newly transplanted stem cells and thus impair retention and functional benefits.

Depressor effect of diabetes in the spontaneously hypertensive rat: associated changes in heart performance

1986 ◽  
Vol 64 (9) ◽  
pp. 1177-1184 ◽  
Author(s):  
Robert L. Rodgers
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Systolic Arterial Pressure ◽  
Left Ventricular ◽  
Stroke Work ◽  
Sprague Dawley ◽  
Spontaneously Hypertensive ◽  
Rat Hearts ◽  
Heart Size ◽  
Wistar Kyoto

Effects of streptozotocin-induced diabetes (8 weeks) on the performance of perfused hearts from spontaneously hypertensive (SH) rats were compared with effects on normotensive Wistar–Kyoto (WK) and Sprague–Dawley (SD) rat hearts. Diabetes markedly decreased systolic arterial pressure (SAP) of SH rats in vivo but did not affect SAP of either of the normotensive strains. Diabetes also reduced heart size of SH and normotensive rats and reversed absolute left ventricular hypertrophy (wall-to-lumen ratios and left-to-right ventricular weight ratios) of SH rats. Heart perfusion at the end of the 8-week period revealed that diabetes (i) reduced hydraulic work at high pressure loads and efficiency of contraction (work/μ.LO2 consumed) of SH rat hearts but not of WK or SD hearts, and (ii) depressed left ventricular pulse pressure development (LVPP) and contractility (LV + dP/dt) of SH hearts more extensively than it reduced these variables in either of the normotensive control groups. Effects of diabetes which were similar in hypertensive and normotensive hearts were reductions in stroke work at high volume loads and depressions in LV−dP/dt. Attendant hypothyroidism probably contributed to the reductions in SAP, heart size, LVPP, LV+ and −dP/dt, and stroke work but not to the decreased efficiency or reversal of hypertrophy of SH rat hearts. Malnutrition of SH rats, like hypothyroidism, also decreased heart size without reversing hypertrophy but had no effect on SAP and only reduced LV−dP/dt. The results show that diabetes reversed hypertrophy and selectively reduced contraction efficiency, contractility, and LVPP of SH hearts, but otherwise the effects of diabetes in hypertensive and normotensive rat strains were similar to each other. The possible contribution of hypothyroidism to the observed effects of diabetes in SH rats remains to be clarified.

Endurance exercise attenuates cardiotoxicity induced by androgen deprivation and doxorubicin

2014 ◽  
Vol 92 (5) ◽  
pp. 356-362 ◽  
Author(s):  
Traci L. Parry ◽  
David S. Hydock ◽  
Brock T. Jensen ◽  
Chia-Ying Lien ◽  
Carole M. Schneider ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Endurance Exercise ◽  
Cardiac Dysfunction ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Androgen Deprivation ◽  
Maximal Rate ◽  
Sprague Dawley ◽  
Developed Pressure

Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX-induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague–Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg·(kg body mass)–1·d–1 by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (–21% and –27%), maximal rate of pressure development (–29% and –32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective.

P4465Acute Cardio-Selective Functional Modulation via a Small-Molecule Direct Myosin-Attenuator (MYK-581) Preserves Diaphragmatic Function in vivo: Comparison versus Disopyramide

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C L Del Rio ◽  
S Roof ◽  
A R Anto ◽  
R L Anderson
Keyword(s):  
Exercise Capacity ◽  
Small Molecule ◽  
Systolic Function ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Mechanically Ventilated ◽  
Diaphragmatic Function ◽  
Sprague Dawley Rats ◽  
Ventricular Filling

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease characterized by hyper-contractility, hindered relaxation, and impaired exercise capacity. Conventional negative inotropes can alleviate enhanced inotropy in HCM, but do not improve ventricular filling and have the potential to further decrease exercise capacity due to their off/on-target systemic effects. Recently, a novel small molecule cardiac-myosin attenuator, Mavacamten, has been shown to normalize hyper-contractility in the setting of HCM. This study evaluated and compared the in vivo functional selectivity of MYK-581, a mavacamten analog, with those of disopyramide (DISO), a commonly-used negative inotrope. Methods In vivo, the acute cardiac (left ventricular pressures) and neuro-muscular (force of diaphragmatic and skeletal muscle contractions) responses to MYK-581 (up to 0.5 mg/kg IV) and DISO (up to 10 mg/kg IV) were simultaneously evaluated using anesthetized and mechanically-ventilated Sprague-Dawley rats; diaphragmatic (both intrinsic and phrenic nerve stimulated) and skeletal contractions (stimulated quadriceps) were measured via strain gauges. Results MYK-581 decreased indices of systolic function (dP/dtmax: −32±2% and vmax: −14±2%, P<0.05 vs. pre-dose) and increased LV EDV (+9±2%, P<0.05), while preserving EDP (6±1 to 6±1 mmHg), suggesting improved ventricular distensibility. Despite these marked cardiac effects, MYK-581 preserved both diaphragmatic (23.7±2.0 to 23.3±2.2 g) and skeletal in situ function (14.9±1.4 to 13.9±0.8 g). In contrast, DISO at matched levels of negative inotropy (dP/dtmax: −25±2% and vmax: −19±2%, P<0.05 vs. pre-dose) depressed diaphragmatic force (−16±3%, 23.8±1.9 to 19.8±1.2 g, P<0.05). Finally, the cardiac selectivity of MYK-581 was confirmed in kinetic experiments evaluating the Ca2+-activated ATPase activity of both cardiac and diaphragmatic myofibrils. Conclusions Direct myosin modulation with MYK-581, a mavacamten analog, is characterized in vivo by reductions in systolic function with preserved filling pressures and improved LV compliance. Moreover, this cardiovascular profile was devoid in vivo of diaphragmatic/skeletal off-target effects that could further hinder exercise capacity in patients with HCM.

scholarly journals Long-term obesity promotes alterations in diastolic function induced by reduction of phospholamban phosphorylation at serine-16 without affecting calcium handling

2014 ◽  
Vol 117 (6) ◽  
pp. 669-678 ◽  
Author(s):  
Ana Paula Lima-Leopoldo ◽  
André S. Leopoldo ◽  
Danielle C. T. da Silva ◽  
André F. do Nascimento ◽  
Dijon H. S. de Campos ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diastolic Function ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Standard Diet ◽  
Shortening Velocity

Few studies have evaluated the relationship between the duration of obesity, cardiac function, and the proteins involved in myocardial calcium (Ca2+) handling. We hypothesized that long-term obesity promotes cardiac dysfunction due to a reduction of expression and/or phosphorylation of myocardial Ca2+-handling proteins. Thirty-day-old male Wistar rats were distributed into two groups ( n = 10 each): control (C; standard diet) and obese (Ob; high-fat diet) for 30 wk. Morphological and histological analyses were assessed. Left ventricular cardiac function was assessed in vivo by echocardiographic evaluation and in vitro by papillary muscle. Cardiac protein expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a), calsequestrin, L-type Ca2+ channel, and phospholamban (PLB), as well as PLB serine-16 phosphorylation (pPLB Ser16) and PLB threonine-17 phosphorylation (pPLB Thr17) were determined by Western blot. The adiposity index was higher (82%) in Ob rats than in C rats. Obesity promoted cardiac hypertrophy without alterations in interstitial collagen levels. Ob rats had increased endocardial and midwall fractional shortening, posterior wall shortening velocity, and A-wave compared with C rats. Cardiac index, early-to-late diastolic mitral inflow ratio, and isovolumetric relaxation time were lower in Ob than in C. The Ob muscles developed similar baseline data and myocardial responsiveness to increased extracellular Ca2+. Obesity caused a reduction in cardiac pPLB Ser16 and the pPLB Ser16/PLB ratio in Ob rats. Long-term obesity promotes alterations in diastolic function, most likely due to the reduction of pPLB Ser16, but does not impair the myocardial Ca2+ entry and recapture to SR.

Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice

2001 ◽  
Vol 281 (5) ◽  
pp. H1938-H1945 ◽  
Author(s):  
Chari Y. T. Hart ◽  
John C. Burnett ◽  
Margaret M. Redfield
Keyword(s):  
Cardiac Function ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Pressure Rise ◽  
Left Ventricular ◽  
Lv Function ◽  
Ketamine Anesthesia ◽  
The Difference ◽  
And Function ◽  
Derivatives Of

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (τ), and the first derivatives of LV pressure rise and fall (dP/d t max and dP/d t min, respectively). During echocardiography, HR was lower in XK than AV mice (250 ± 14 beats/min in XK vs. 453 ± 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 ± 0.08 mm in XK vs. 3.8 ± 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 ± 1.2% in XK vs. 40 ± 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 ± 24 beats/min) and XK (342 ± 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 ± 5 vs. 6.2 ± 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/d t max: 4,402 ± 798 vs. 8,250 ± 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (τ: 23 ± 2 vs. 14 ± 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.

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 51: Ambulatory Blood Pressure Phenotype And Cardiovascular Risk In Youth: The Ship-ahoy Study

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Joseph T Flynn ◽  
Philip Khoury ◽  
Joshua A Samuels ◽  
Marc B Lande ◽  
Kevin Meyers ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Function ◽  
Linear Models ◽  
Independent Predictor ◽  
Systolic Function ◽  
Left Ventricular ◽  
Cvd Risk ◽  
Oscillometric Device ◽  
Echocardiographic Parameters ◽  
Relationship Of

We investigated whether blood pressure (BP) phenotype based on clinic & 24-hour ambulatory BP (ABP) was associated with intermediate markers of cardiovascular disease (CVD) in 374 adolescents enrolled in a study of the relationship of BP to CV risk. Clinic BP was measured by auscultation and categorized using the 2017 AAP guideline. ABP was measured for 24 hours by an oscillometric device and analyzed using the adult ABP wake SBP cut-point (130 mmHg). This created 4 BP phenotype groups: normal BP (n=224), white coat hypertensive (n=48), ambulatory hypertensive (n=57) & masked hypertensive (n=45). Echocardiographic parameters & carotid-femoral pulse wave velocity (PWVcf) were measured to assess CVD risk. Left ventricular mass (LVM) was lowest in the normal BP group, whereas multiple measures of cardiac function and PWVcf were worse in the masked and ambulatory hypertensive groups: Generalized linear models adjusted for body mass index (BMI) were constructed to examine the associations between BP phenotype and the measured CVD variables. ABP phenotype was an independent predictor of LVM, diastolic and systolic function and PWVcf in the unadjusted model. ABP phenotype remained significantly associated with diastolic function (E/e’, e’/a’), systolic function (ejection fraction) and increased arterial stiffness (PWVcf) after adjustment for BMI percentile (all p<=0.05). We conclude that BP phenotype is an independent predictor of markers of increased CVD risk in adolescents, including impaired cardiac function and increased vascular stiffness. ABP monitoring has an important role in CVD risk assessment in youth.

Abstract 314: BRaf Plays a Major Role in Gene Expression in Cardiomyocytes in Mouse Hearts in vivo

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Michelle A Hardyman ◽  
Stephen J Fuller ◽  
Daniel N Meijles ◽  
Kerry A Rostron ◽  
Sam J Leonard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Braf Mutations ◽  
Gene Markers ◽  
Lv Mass ◽  
Cardiac Volumes

Introduction: Raf kinases lie upstream of ERK1/2 with BRaf being the most highly expressed and having the highest basal activity. V600E BRaf mutations constitutively activate ERK1/2 and are common in cancer. The role of BRaf in the adult heart is yet to be established. ERK1/2 regulate cardiomyocyte gene expression, promoting cardiac hypertrophy and cardioprotection, but effects of ERK1/2 may depend on signal strength. Hypothesis: Our hypotheses are that BRaf is critical in regulating ERK1/2 signaling in cardiomyocytes and, whilst moderate ERK1/2 activity is beneficial, excessive ERK1/2 activity is detrimental to the heart. Methods: We generated heterozygote mice for tamoxifen- (Tam-) inducible cardiomyocyte-specific knockin of V600E in the endogenous BRaf gene. Mice (12 wks) received 2 injections of Tam or vehicle on consecutive days (n=4-10 per group). Kinase activities and mRNA expression were assessed by immunoblotting and qPCR. Echocardiography was performed (Vevo2100). M-mode images (short axis view) were analyzed; data for each mouse were normalized to the mean of 2 baseline controls. Results: V600E knockin did not affect overall BRaf or cRaf levels in mouse hearts, but significantly increased ERK1/2 activities within 48 h (1.51±0.05 fold). Concurrently, mRNAs for hypertrophic gene markers including BNP and immediate early genes (IEGs) increased signficantly. At 72 h, expression of BNP, Fosl1, Myc, Ereg and CTGF increased further, other IEGs (Jun, Fos, Egr1, Atf3) declined, and ANF was upregulated. In contrast, expression of α and β myosin heavy chain mRNAs was substantially downregulated (0.46/0.41±0.05 relative to controls). Within 72 h, left ventricular (LV) mass and diastolic LV wall thickness had increased (1.23±0.05 relative to controls), but cardiac function was severely compromised with significant decreases in ejection fraction and cardiac output (0.53/0.68±0.09 relative to controls) associated with increased LV internal diameters and cardiac volumes. Conclusions: Endogenous cardiomyocyte BRaf is sufficient to activate ERK1/2 in mouse hearts and induce cardiac hypertrophy associated with dynamic temporal changes in gene expression. However, excessive activation of ERK1/2 in isolation is detrimental to cardiac function.

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