The effects of dietary fish oil on exercising skeletal muscle vascular and metabolic control in chronic heart failure rats

Impaired vasomotor control in chronic heart failure (CHF) is due partly to decrements in nitric oxide synthase (NOS) mediated vasodilation. Exercising muscle blood flow (BF) is augmented with polyunsaturated fatty acid (PUFA) supplementation via fish oil (FO) in healthy rats. We hypothesized that FO would augment exercising muscle BF in CHF rats via increased NO-bioavailability. Myocardial infarction (coronary artery ligation) induced CHF in Sprague–Dawley rats which were subsequently randomized to dietary FO (20% docosahexaenoic acid, 30% eicosapentaenoic acid, n = 15) or safflower oil (SO, 5%, n = 10) for 6–8 weeks. Mean arterial pressure (MAP), blood [lactate], and hindlimb muscles BF (radiolabeled microspheres) were determined at rest, during treadmill exercise (20 m·min−1, 5% incline) and exercise + NG-nitro-l-arginine-methyl-ester (l-NAME) (a nonspecific NOS inhibitor). FO did not change left ventricular end-diastolic pressure (SO: 14 ± 2; FO: 11 ± 1 mm Hg, p > 0.05). During exercise, MAP (SO: 128 ± 3; FO: 132 ± 3 mm Hg) and blood [lactate] (SO: 3.8 ± 0.4; FO: 4.6 ± 0.5 mmol·L−1) were not different (p > 0.05). Exercising hindlimb muscle BF was lower in FO than SO (SO: 120 ± 11; FO: 93 ± 4 mL·min−1·100 g−1, p < 0.05) but was not differentially affected by l-NAME. Specifically, 17 of 28 individual muscle BF’s were lower (p < 0.05) in FO demonstrating that PUFA supplementation with FO in CHF rats does not augment muscle BF during exercise but may lower metabolic cost.

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Abstract P237: Is Ischemia/Reperfusion an Efficient Method for Producing Heart Failure in Rats?

Hypertension ◽

10.1161/hyp.68.suppl_1.p237 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Ana Carolina M Omoto ◽

Fábio N Gava ◽

Mauro de Oliveira ◽

Carlos A Silva ◽

Rubens Fazan ◽

...

Keyword(s):

Heart Failure ◽

Diastolic Pressure ◽

Histopathological Examination ◽

Ischemia Reperfusion ◽

Mitral Annulus ◽

Mortality Rates ◽

Tissue Doppler ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Artery Ligation

Myocardium infarction (MI) elicited by coronary artery ligation (CAL) is commonly used to induce chronic heart failure (HF) in rats. However, CAL shows high mortality rates. Given that ischemia-reperfusion (IR) may cause the development of HF, this approach may be useful for obtaining a model of HF with low mortality rates. Therefore, it was compared the model of CAL vs. IR in rats, evaluating the mortality and cardiac morphological and functional aspects. The IR consisted of 30 minutes of cardiac ischemia. Wistar rats were assigned into three groups: CAL: n=18; IR: n=7; SHAM (fictitious IR): n=7. After four weeks of CAL, the subjects were evaluated by echocardiography and ventriculography as well. The statistical analysis consisted of ANOVA combined with Tukey’s posthoc test (p<0.05). There were no deaths in the IR and SHAM groups, whereas in the CAL group the mortality rate was 33.33% (6 out of 18). In the CAL group echocardiography showed increased left ventricular (LV) cavity during systole (8.3 ± 1mm) and diastole (10.5 ± 1mm); decreased LV free wall during systole (1.4 ± 0.5 mm); increased left atrium/aorta (2.3 ± 0.4) ratio. These changes were not significant in IR (4.8 ± 0.5mm, 7.6 ± 0.6mm, 2.6 ± 0.3 mm, 1.6 ± 0.2) and SHAM (4.6 ± 0.6 mm, 7.7 ± 0.8mm, 2.8 ± 0.4mm, 1.5 ± 0.2) groups. There was also the reduction in the ejection fraction in the CAL group (41 ± 12 %) when compared with IR (65 ± 9%) and SHAM (69 ± 7%) groups. The tissue Doppler analysis from the lateral mitral annulus showed reduction in E′ in CAL (-29 ± 8 mm/s) and IR (-31± 9 mm/s) groups when compared with the SHAM (-48 ± 11 mm/s) group. The ventriculography in the CAL group showed smaller maximum dP/dt (6519 ± 1062) and greater end-diastolic pressure (33 ± 8 mmHg) when compared with IR (8716 ± 756 mmHg/s; 9 ± 9 mmHg) and SHAM (7989 ± 1230 mmHg/s; 9 ± 7 mmHg) groups. The CAL group presented transmural infarct size of 40% of the left ventricular wall, measured under histopathological examination. In conclusion, IR for 30 minutes caused only small changes in LV diastolic function, assessed by tissue Doppler; however, the IR was not effective for promoting HF, as observed with CAL. Thus, it is possible that prolonged IR is necessary for promoting significant HF in rats.

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Validation of echocardiographic methods for assessing left ventricular dysfunction in rats with myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00393.2004 ◽

2004 ◽

Vol 287 (5) ◽

pp. H2049-H2053 ◽

Cited By ~ 90

Author(s):

Eric E. Morgan ◽

Michael D. Faulx ◽

Tracy A. McElfresh ◽

Theodore A. Kung ◽

Michael S. Zawaneh ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Index ◽

Diastolic Pressure ◽

Left Ventricular ◽

Lv Function ◽

Coronary Artery Ligation ◽

Sham Operation ◽

Artery Ligation ◽

Peak Rate ◽

Fractional Shortening

The rat infarct model is widely used in heart failure research, but few echocardiographic indexes of left ventricular (LV) function are validated in this model. Accordingly, the objective of this study was to validate a 13-segment LV wall motion score index (WMSI) and the myocardial performance index (MPI) in infarcted rats. Twenty-nine male Wistar rats underwent left coronary artery ligation or sham operation and were evaluated with two-dimensional and Doppler flow echocardiography 8 wk later. After echocardiography, invasive indexes were obtained using a high-fidelity catheter. WMSI and MPI were correlated with the invasive and noninvasive measurements of LV function. WMSI and MPI significantly correlated directly with end-diastolic pressure ( r = 0.72 and 0.42 for WMSI and MPI, respectively) and the time constant of isovolumic relaxation ( r = 0.68 and 0.48) and inversely with peak rate of rise of LV pressure (+dP/d t; r = −0.68 and −0.50), peak rate of decline in LV pressure ( r = −0.57 and −0.44), LV developed pressure ( r = −0.58 and −0.42), area fractional shortening ( r = −0.85 and −0.53), and cardiac index ( r = −0.74 and −0.74). Stepwise linear regression analyses revealed that LV end-diastolic pressure, +dP/d t, area fractional shortening, and cardiac index were independent determinants of WMSI ( r = 0.994) and that cardiac index and +dP/d t were independent determinants of MPI ( r = 0.781). We conclude that the 13-segment WMSI and MPI are reproducible and correlate strongly with established echocardiographic and invasive indexes of systolic and diastolic function. These findings support the use of WMSI and MPI as indexes of global LV function in the rat infarction model of heart failure.

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Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.280.2.h738 ◽

2001 ◽

Vol 280 (2) ◽

pp. H738-H745 ◽

Cited By ~ 61

Author(s):

Keiji Kusumoto ◽

James V. Haist ◽

Morris Karmazyn

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Coronary Artery ◽

Hydrogen Exchange ◽

Diastolic Pressure ◽

Control Diet ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Large Infarct

We investigated the effect of sodium/hydrogen exchange inhibition (NHE-1) on hypertrophy and heart failure after coronary artery ligation (CAL) in the rat. Animals were subjected to occlusion (or sham) of the left main coronary artery and immediately administered a control diet or one consisting of the NHE-1 inhibitor cariporide for 13–15 wk. Hearts were separated by small [≤30% of left ventricle (LV)] and large (>30% of LV) infarcts. CAL depressed change in left ventricular increase in pressure over time (LV +dP/d t) in small and large infarct groups by 18.8% ( P < 0.05) and 34% ( P < 0.01), respectively, whereas comparative values for the cariporide groups were 8.7% (not significant) and 23.1% ( P < 0.01), respectively. LV end-diastolic pressure was increased by 1,225% in the control large infarct group but was significantly reduced to 447% with cariporide. Cariporide also significantly reduced the degree of LV dilation in animals with large infarcts. Hypertrophy, defined by tissue weights and cell size, was reduced by cariporide, and shortening of surviving myocytes was preserved. Infarct sizes were unaffected by cariporide, and the drug had no influence on either blood pressure or the depressed inotropic response of infarcted hearts to dobutamine. These results suggest an important role for NHE-1 in the progression of heart failure after myocardial infarction.

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Effects of nitrite infusion on skeletal muscle vascular control during exercise in rats with chronic heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00421.2015 ◽

2015 ◽

Vol 309 (8) ◽

pp. H1354-H1360 ◽

Cited By ~ 16

Author(s):

Angela A. Glean ◽

Scott K. Ferguson ◽

Clark T. Holdsworth ◽

Trenton D. Colburn ◽

Jennifer L. Wright ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Myocardial Infarct ◽

Muscle Blood Flow ◽

Coronary Artery Ligation ◽

Myocardial Infarct Size ◽

Sprague Dawley ◽

Vascular Control ◽

Artery Ligation

Chronic heart failure (CHF) reduces nitric oxide (NO) bioavailability and impairs skeletal muscle vascular control during exercise. Reduction of NO2− to NO may impact exercise-induced hyperemia, particularly in muscles with pathologically reduced O2 delivery. We tested the hypothesis that NO2− infusion would increase exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats with a preferential effect in muscles composed primarily of type IIb + IId/x fibers. CHF (coronary artery ligation) was induced in adult male Sprague-Dawley rats. After a >21-day recovery, mean arterial pressure (MAP; carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% incline) with and without NO2− infusion. The myocardial infarct size (35 ± 3%) indicated moderate CHF. NO2− infusion increased total hindlimb skeletal muscle VC (CHF: 0.85 ± 0.09 ml·min−1·100 g−1·mmHg−1 and CHF + NO2−: 0.93 ± 0.09 ml·min−1·100 g−1·mmHg−1, P < 0.05) without changing MAP (CHF: 123 ± 4 mmHg and CHF + NO2−: 120 ± 4 mmHg, P = 0.17). Total hindlimb skeletal muscle BF was not significantly different (CHF: 102 ± 7 and CHF + NO2−: 109 ± 7 ml·min−1·100 g−1 ml·min−1·100 g−1, P > 0.05). BF increased in 6 (∼21%) and VC in 8 (∼29%) of the 28 individual muscles and muscle parts. Muscles and muscle portions exhibiting greater BF and VC after NO2− infusion comprised ≥63% type IIb + IId/x muscle fibers. These data demonstrate that NO2− infusion can augment skeletal muscle vascular control during exercise in CHF rats. Given the targeted effects shown herein, a NO2−-based therapy may provide an attractive “needs-based” approach for treatment of the vascular dysfunction in CHF.

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Abstract 48: Differentiation of Moderate and Severe Ischemic Heart Failure by Invasive and Non-invasive Assessments of Diastolic Function in a Rat Model of Chronic Heart Failure

Circulation Research ◽

10.1161/res.119.suppl_1.48 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Saffie Mohran ◽

Jordan Lancaster ◽

Pablo Sanchez ◽

Steven Goldman ◽

Elizabeth Juneman

Keyword(s):

Heart Failure ◽

Coronary Artery ◽

Diastolic Function ◽

Left Coronary Artery ◽

Diastolic Pressure ◽

Left Ventricular ◽

Dead Volume ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Hemodynamic Measurements

Background: This work is designed to determine if specific left ventricle (LV) pressure-volume relations, hemodynamic, and echo derived parameters of diastolic function are able to separate severe from moderate CHF in rats with left coronary artery occlusion. Hypothesis: Echocardiographic indices of diastolic function, end-diastolic pressure (EDP), dead volume, stiffness constants (k), and pressure volume relations predict the severity of CHF in infarcted rats. Methods: Male Sprague Dawley rats (N=14) were randomized to undergo left coronary artery ligation or sham operation. Echocardiography was performed at 3 and 6 weeks post coronary ligation. The rats were categorized into moderate or severe CHF according to their LVEDP at 6 weeks post ligation. Invasive hemodynamic measurements with solid state micro manometer pressure catheters as well as diastolic pressure-volume relation values were obtained at the 6 week end point. Results: Moderate and severe CHF rats had significantly (P<0.05) elevated left ventricular (LV) end-diastolic pressure (LV EDPs), prolonged time constants of LV relaxation (tau), and decreased peak development pressures. When moderate versus severe CHF rats were separated based on LV EDP, early diastolic anterior wall radial relaxation velocity as well as e’, and E/e’ had strong correlations with invasive hemodynamic measurements of diastolic functions. There was a trend towards decreased compliance as measured by stiffness constants in severe heart failure group. Differences (P<0.05) in dead volume, mean arterial pressure (MAP), tau, and ejection fraction (EF) were also displayed. End diastolic pressure-volume analyses illustrated significant differences in plot positioning and curvature. Conclusion: While it is possible to separate rats with moderate and severe CHF in the rat coronary artery ligation model, the separation is not simply based on a specific EF value. This work may be useful in deciding whether there is a differential effect of new treatments for severe versus moderate CHF.

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AIM2-driven inflammasome activation in chronic heart failure

European Heart Journal ◽

10.1093/ehjci/ehaa946.0847 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Ruppert ◽

Z.S Onodi ◽

P Leszek ◽

V.E Toth ◽

G Koncsos ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Animal Models ◽

Left Ventricular ◽

Inflammasome Activation ◽

Coronary Artery Ligation ◽

Funding Source ◽

Human Cardiomyocytes ◽

Pannexin 1 ◽

End Stage

Abstract Background Inflammation and cytokine release have been implicated in the pathogenesis of chronic heart failure (CHF). Of particular interest, Canakinumab, a monoclonal antibody against interleukin-1b (IL-1β), had provided benefit against cardiovascular events, suggesting that blockade of IL-1β secretion and signaling might be a promising new therapeutic target. Although, recent studies have provided evidence that inflammasome activation is the main contributor to IL-1β maturation, the role of inflammasome activation in CHF remains unknown. Objective Therefore, we aimed to assess inflammasome activation in myocardial samples from end-stage failing hearts. Methods Inflammasome activation was assessed by immunoblotting in left ventricular myocardial specimens harvested from patients with end-stage CHF. Furthermore, immunoblot measurements were also performed on translational animal models of CHF (e.g. rat models of permanent coronary artery ligation and transverse aortic constriction). Left ventricular monocyte and macrophage infiltration was detected by immunohistochemistry. To investigate the molecular background of inflammasome activation, a series of cell culture experiments were performed on AC16 human cardiomyocytes and THP-1 human monocytic cell lines. Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human CHF while the NLRP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change. A similar expression pattern in AIM2 and NLRC4 was also noted in CHF animal models. Furthermore, robust infiltration of Iba1+ monocytes/macrophages was observed in human failing hearts as well as in different animal models of CHF. In vitro AIM2 inflammasome activation, as induced by transfection with double-stranded DNA [poly(deoxyadenylic-deoxythymidylic)] was reduced significantly by the pharmacological blockade of pannexin-1 channels. Conclusions AIM2 and NLRC4 inflammasome activation might contribute to chronic inflammation in CHF. Our findings suggest that pannexin-1 channels might be a promising novel target to reduce inflammasome activation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

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Regulation of K+ and Ca2+ channels in experimental cardiac failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.261.6.h1979 ◽

1991 ◽

Vol 261 (6) ◽

pp. H1979-H1987 ◽

Cited By ~ 5

Author(s):

M. Gopalakrishnan ◽

D. J. Triggle ◽

A. Rutledge ◽

Y. W. Kwon ◽

J. A. Bauer ◽

...

Keyword(s):

Heart Failure ◽

Left Ventricle ◽

Right Ventricle ◽

Cardiac Failure ◽

Radioligand Binding ◽

Weight Ratio ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

The Right

To examine the status of ATP-sensitive K+ (K+ATP) channels and 1,4-dihydropyridine-sensitive Ca2+ (Ca2+DHP) channels during experimental cardiac failure, we have measured the radioligand binding properties of [3H]glyburide and [3H]PN 200 110, respectively, in tissue homogenates from the rat cardiac left ventricle, right ventricle, and brain 4 wk after myocardial infarction induced by left coronary artery ligation. The maximal values (Bmax) for [3H]glyburide and [3H]PN 200 110 binding were reduced by 39 and 40%, respectively, in the left ventricle, and these reductions showed a good correlation with the right ventricle-to-body weight ratio in heart-failure rats. The ligand binding affinities were not altered. In the hypertrophied right ventricle, Bmax values for both the ligands were not significantly different when data were normalized to DNA content or right ventricle weights but showed an apparent reduction when normalized to unit protein or tissue weight. Moderate reductions in channel densities were observed also in whole brain homogenates from heart failure rats. Assessment of muscarinic receptors, beta-adrenoceptors and alpha 1-adrenoceptors by [3H]quinuclidinyl benzilate, [3H]dihydroalprenolol, and [3H]prazosin showed reductions in left ventricular muscarinic and beta-adrenoceptor densities but not in alpha 1-adrenoceptor densities, consistent with earlier observations. It is suggested that these changes may in part contribute to the pathology of cardiac failure.

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Progression of heart failure after myocardial infarction in the rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.5.r1734 ◽

2001 ◽

Vol 281 (5) ◽

pp. R1734-R1745 ◽

Cited By ~ 111

Author(s):

J. Francis ◽

R. M. Weiss ◽

S. G. Wei ◽

A. K. Johnson ◽

R. B. Felder

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Ventricular Remodeling ◽

Systolic Function ◽

Left Ventricular Remodeling ◽

Plasma Renin ◽

Left Ventricular Systolic Function ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Artery Ligation

This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple “switching on” of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.

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Integrative System Biology Analyses Identify Seven MicroRNAs to Predict Heart Failure

Non-Coding RNA ◽

10.3390/ncrna5010022 ◽

2019 ◽

Vol 5 (1) ◽

pp. 22 ◽

Cited By ~ 2

Author(s):

Henri Charrier ◽

Marie Cuvelliez ◽

Emilie Dubois-Deruy ◽

Paul Mulder ◽

Vincent Richard ◽

...

Keyword(s):

Heart Failure ◽

Systems Biology ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Mirna Signature ◽

Artery Ligation ◽

Proteomic Data

Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI provide molecular insights into this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches, integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicted that 13 miRNAs and 3 of these miRNAs would be validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicted that 24 miRNAs among 1310 molecules and 6 of these miRNAs would be selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.

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Heart failure switches the RV α1-adrenergic inotropic response from negative to positive

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00259.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. H913-H920 ◽

Cited By ~ 26

Author(s):

Guan-Ying Wang ◽

Che-Chung Yeh ◽

Brian C. Jensen ◽

Michael J. Mann ◽

Paul C. Simpson ◽

...

Keyword(s):

Heart Failure ◽

Clinical Problem ◽

Ventricular Myocardium ◽

Left Ventricular ◽

Left Ventricular Myocardium ◽

Coronary Artery Ligation ◽

Inotropic Response ◽

Artery Ligation ◽

Protein Levels ◽

Inotropic Responses

Right ventricular (RV) failure is a serious common clinical problem that is poorly understood. Therefore, for failing and nonfailing hearts, we examined the distinctive inotropic responses induced in the RV myocardium after the stimulation of α1-adrenergic receptors (ARs). In RV trabeculae from nonfailing mouse hearts, α1-ARs induced a negative inotropic response, consistent with our previous study. In marked contrast, in RV trabeculae from failing hearts, 12 wk after coronary artery ligation, α1-ARs induced a positive inotropic response. Mechanistically, experiments with skinned trabeculae showed that α1-ARs decreased myofilament Ca2+ sensitivity in the nonfailing RV myocardium, whereas α1-ARs increased Ca2+ sensitivity in heart failure. This suggests that a switch in the Ca2+ sensitivity response to α1-AR stimulation explained the switch in the RV α1-AR inotropic response in heart failure. Myosin light chain kinase (MLCK) can increase myofilament Ca2+ sensitivity, and the smooth muscle isoform (smMLCK), which is also present in cardiomyocytes, was more abundant in the RV myocardium from failing versus nonfailing hearts. Moreover, the MLCK inhibitor ML-9 prevented the switch of the RV myocardium to a positive α1-AR inotropic response in heart failure. In the left ventricular myocardium, in contrast, α1-AR inotropic responses were not different in failing versus nonfailing hearts, and smMLCK abundance was not increased in heart failure. In relation to human disease, we found that smMLCK mRNA and protein levels were increased in RVs from failing human hearts. We conclude that the RV inotropic response to α1-ARs is switched from negative to positive in heart failure, through a pathway involving increased myofilament Ca2+ sensitivity. Since α1-AR agonist catecholamines are elevated in heart failure, increased α1-AR inotropic responses in the RV myocardium may be adaptive in heart failure by helping the failing RV respond to increased pulmonary pressures.

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