Aortic Stenosis: From Pressure Overload to Heart Failure

The load dependence (LD) of relaxation was studied in the diaphragm of rabbits with congestive heart failure (CHF). CHF ( n = 15) was induced by combined chronic volume and pressure overload. Aortic insufficiency was induced by forcing a catheter through the aortic sigmoid valves, followed 3 wk later by abdominal aortic stenosis. Six weeks after the first intervention, animals developed CHF. Sham-operated animals served as controls (C; n = 12). Diaphragm mechanics were studied in vitro on isolated strips, at 22°C, in isotonic and isometric loading conditions. Contractility was lower in the CHF group, as reflected by lower total tension: 1.11 ± 0.10 in CHF vs. 2.38 ± 0.15 N/cm2 in C in twitch ( P < 0.001) and 2.46 ± 0.22 in CHF vs. 4.90 ± 0.25 N ⋅ cm−2 in C in tetanus ( P < 0.001). The index LD was used to quantify the load dependence of relaxation: LD is <1 in load-dependent muscles and tends toward 1 in load-independent muscles. LD was significantly higher in CHF than in C rabbits, in both twitch (0.99 ± 0.01 vs. 0.75 ± 0.03; P < 0.001) and tetanus (0.95 ± 0.02 vs. 0.84 ± 0.02; P < 0.001). In the CHF rabbits’ diaphragm, the fall in total tension was linearly related to the fall in load dependence of relaxation. The decrease in load dependence of relaxation in CHF animals suggests sarcoplasmic reticulum abnormalities. Impairment of the sarcoplasmic reticulum may also partly account for the decrease in contractile performance of diaphragm in CHF animals.

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Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure

Physiological Genomics ◽

10.1152/physiolgenomics.00016.2011 ◽

2012 ◽

Vol 44 (2) ◽

pp. 162-172 ◽

Cited By ~ 89

Author(s):

Ida G. Lunde ◽

Jan Magnus Aronsen ◽

Heidi Kvaløy ◽

Eirik Qvigstad ◽

Ivar Sjaastad ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Aortic Stenosis ◽

Cardiac Hypertrophy ◽

Intracellular Signaling ◽

Cardiac Contractility ◽

Pressure Overload ◽

Left Ventricular ◽

Mrna Levels ◽

Novel Concept

Reversible protein O-GlcNAc modification has emerged as an essential intracellular signaling system in several tissues, including cardiovascular pathophysiology related to diabetes and acute ischemic stress. We tested the hypothesis that cardiac O-GlcNAc signaling is altered in chronic cardiac hypertrophy and failure of different etiologies. Global protein O-GlcNAcylation and the main enzymes regulating O-GlcNAc, O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and glutamine-fructose-6-phosphate amidotransferase (GFAT) were measured by immunoblot and/or real-time RT-PCR analyses of left ventricular tissue from aortic stenosis (AS) patients and rat models of hypertension, myocardial infarction (MI), and aortic banding (AB), with and without failure. We show here that global O-GlcNAcylation was increased by 65% in AS patients, by 47% in hypertensive rats, by 81 and 58% post-AB, and 37 and 60% post-MI in hypertrophic and failing hearts, respectively ( P < 0.05). Noticeably, protein O-GlcNAcylation patterns varied in hypertrophic vs. failing hearts, and the most extensive O-GlcNAcylation was observed on proteins of 20–100 kDa in size. OGT, OGA, and GFAT2 protein and/or mRNA levels were increased by pressure overload, while neither was regulated by myocardial infarction. Pharmacological inhibition of OGA decreased cardiac contractility in post-MI failing hearts, demonstrating a possible role of O-GlcNAcylation in development of chronic cardiac dysfunction. Our data support the novel concept that O-GlcNAc signaling is altered in various etiologies of cardiac hypertrophy and failure, including human aortic stenosis. This not only provides an exciting basis for discovery of new mechanisms underlying pathological cardiac remodeling but also implies protein O-GlcNAcylation as a possible new therapeutic target in heart failure.

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Left atrial function in heart failure with preserved ejection fraction vs. aortic stenosis: evidence for atrial myopathy?

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeaa356.049 ◽

2021 ◽

Vol 22 (Supplement_1) ◽

Author(s):

X Jin ◽

JV Melle ◽

AA Voors ◽

DKL Sim ◽

FR Jaufeerally ◽

...

Keyword(s):

Heart Failure ◽

Aortic Stenosis ◽

Ejection Fraction ◽

Left Atrial ◽

Pressure Overload ◽

Filling Pressure ◽

Community Dwelling ◽

Volume Index ◽

Aortic Valve Area ◽

Preserved Ejection Fraction

Abstract Funding Acknowledgements Type of funding sources: None. Background and Aim Left atrial (LA) enlargement and impaired LA function are frequently found in patients with heart failure with preserved ejection fraction (HFpEF). Whether these structural and functional LA abnormalities are a consequence of increased LA pressure or whether HFpEF patients have an intrinsic LA myopathy is unknown. We compared LA pressure, size and function between patients with HFpEF and aortic stenosis, as a comparator with LA pressure overload, as well as community-dwelling control subjects. Methods Extensive echocardiographic assessments were performed in 219 patients with HFpEF (age 68 ± 11, 48% female), 173 patients with moderate to severe AS (age 69 ± 11, 55% female, aortic valve area index 0.55 ± 0.15 cm2/m2), and 219 controls (age 65 ± 9, 48% female, 42.2% hypertensive) Results Compared to controls, both patients with HFpEF and AS had larger LV and LA size and worse LV systolic, diastolic and LA function. Compared with AS patients, HFpEF patients had smaller LA volume index (40.2 ± 19.4 vs. 44.5 ± 11.9 ml/m2 p = 0.01) but similar LV filling pressure estimated by E/e’ (13.4 ± 4.8 13.4 ± 4.8 , p = 0.12). Despite smaller LA volume index and similar LV filling pressure, HFpEF patients had remarkably poorer LA function compared to AS [reservoir GLS, 22.6 ± 10% vs 31.4 ± 10.1 (p < 0.001); contractile GLS, 15.8 ± 6.1% vs 17.5 ± 6.9 (p < 0.05); LASrs, 0.92 ± 0.35% vs 1.27 ± 0.41 (p < 0.001); LASre, -1.49 ± 0.65 vs -1.86 ± 0.67 (p < 0.001)]. The differences in LA reservoir GLS and LASrs remained significant after adjustment for atrial fibrillation, diabetes, coronary artery disease, LV ejection fraction and LV mass index. Conclusion Patients with HFpEF had significantly worse LA function than patients with AS, despite similar LA pressure overload. These findings support the concept of an intrinsic LA myopathy in patients with HFpEF, beyond LA pressure overload. Abstract Figure.

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