Reduced Stretch-Induced Force Response in Failing Human Myocardium Caused by Impaired Na
            <sup>+</sup>
            -Contraction Coupling

Lewinski, Dirk von; Kockskämper, Jens; Zhu, Danan; Post, Heiner; Elgner, Andreas; Pieske, Burkert

doi:10.1161/circheartfailure.108.794065

Cited by 20 publications

(19 citation statements)

References 55 publications

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“…On the contrary, Reuter et al have reported no difference in the rate of relaxation or the contractile function of right atrial cardiac muscles from type 2 diabetic patients undergoing CABG [26]. However, the contractile and relaxation measurements reported in that study were much lower in magnitude when compared to values reported in other studies using human right atrial cardiac muscles [27,28] and our study (Table 2). This may be related to tissue degradation in their samples due to prolonged loading with a fluorescence indicator, while our experimental measurements were obtained within 90 minutes after dissection.…”

Section: Discussioncontrasting

confidence: 99%

“…Several studies reported that the Frank-Starling mechanism is maintained in patients with reduced EF [28,30]. More recently, patients with preserved EF showed a preserved static (intrinsic to the heart) Frank-Starling mechanism [31], whereas the beat-to-beat dynamic (including the heart-arterial interaction) Frank-Starling mechanism was impaired in these patients [32].…”

Section: Discussionmentioning

confidence: 99%

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Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Lamberts

Lingam

Wang

et al. 2014

Cardiovasc Diabetol

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BackgroundDiastolic dysfunction is a key factor in the development and pathology of cardiac dysfunction in diabetes, however the exact underlying mechanism remains unknown, especially in humans. We aimed to measure contraction, relaxation, expression of calcium-handling proteins and fibrosis in myocardium of diabetic patients with preserved systolic function.MethodsRight atrial appendages from patients with type 2 diabetes mellitus (DM, n = 20) and non-diabetic patients (non-DM, n = 36), all with preserved ejection fraction and undergoing coronary artery bypass grafting (CABG), were collected. From appendages, small cardiac muscles, trabeculae, were isolated to measure basal and β-adrenergic stimulated myocardial function. Expression levels of calcium-handling proteins, sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and phospholamban (PLB), and of β1-adrenoreceptors were determined in tissue samples by Western blot. Collagen deposition was determined by picro-sirius red staining.ResultsIn trabeculae from diabetic samples, contractile function was preserved, but relaxation was prolonged (Tau: 74 ± 13 ms vs. 93 ± 16 ms, non-DM vs. DM, p = 0.03). The expression of SERCA2a was increased in diabetic myocardial tissue (0.75 ± 0.09 vs. 1.23 ± 0.15, non-DM vs. DM, p = 0.007), whereas its endogenous inhibitor PLB was reduced (2.21 ± 0.45 vs. 0.42 ± 0.11, non-DM vs. DM, p = 0.01). Collagen deposition was increased in diabetic samples. Moreover, trabeculae from diabetic patients were unresponsive to β-adrenergic stimulation, despite no change in β1-adrenoreceptor expression levels.ConclusionsHuman type 2 diabetic atrial myocardium showed increased fibrosis without systolic dysfunction but with impaired relaxation, especially during β-adrenergic challenge. Interestingly, changes in calcium-handling protein expression suggests accelerated active calcium re-uptake, thus improved relaxation, indicating a compensatory calcium-handling mechanism in diabetes in an attempt to maintain diastolic function at rest despite impaired relaxation in the diabetic fibrotic atrial myocardium. Our study addresses important aspects of the underlying mechanisms of diabetes-associated diastolic dysfunction, which is crucial to developing new therapeutic treatments.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Lamberts

Lingam

Wang

et al. 2014

Cardiovasc Diabetol

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“…13, 47 Angiotensin II, endothelin and slow stretch activation are known activators of NHE-1. 47,48 Na + -influx through NHE-1 has been suggested to promote concentric LVH through Ca 2+ -dependent mechanisms. 49, 50 In a small patient study, amiloride was reported to improve exercise hemodynamics and LVEDP in heart failure patients.…”

Section: Discussionmentioning

confidence: 99%

Relaxation and the Role of Calcium in Isolated Contracting Myocardium From Patients With Hypertensive Heart Disease and Heart Failure With Preserved Ejection Fraction

Runte

Bell

Selby

et al. 2017

Circ: Heart Failure

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Background Relaxation characteristics and Ca2+-homeostasis have not been studied in isolated myocardium from patients with hypertensive heart disease (HHD) and heart failure with preserved ejection fraction (HFpEF). Prolonged myocardial relaxation is believed to play an important role in the pathophysiology of these conditions. In this study we evaluated relaxation parameters, myocardial calcium (Ca2+) and sodium (Na+) handling as well as ion transporter expression and tested the effect of Na+-influx inhibitors on relaxation in isolated myocardium from patients with HHD and HFpEF. Methods and Results Relaxation characteristics were studied in myocardial strip preparations under physiological conditions at stimulation rates of 60/min and 180/min. Intracellular Ca2+ and Na+ was simultaneously assessed using Fura-2 and ANG-2, whereas elemental analysis was utilized to measure total myocardial concentrations of Ca, Na and other elements. Quantitative PCR was used to measure expression levels of key ion transport proteins. The lusitropic effect of Na+-influx inhibitors ranolazine, furosemide and amiloride was evaluated. Myocardial LV biopsies were obtained from 36 control patients (CTR), 29 HHD and 19 HHD+HFpEF. When compared to CTR, half maximal relaxation time (RT50) at 60/min was prolonged by 13% in HHD and by 18% in HHD+HFpEF (both p<0.05). Elevated resting Ca2+-levels and a tachycardia-induced increase in diastolic Ca2+ were associated with incomplete relaxation and an increase in diastolic tension in HHD and HHD+HFpEF. Na+-levels were not increased and expression levels of Ca2+- or Na+-handling proteins were not altered. Na+-influx inhibitors did not improve relaxation or prevent incomplete relaxation at high stimulation rates. Conclusions Contraction and relaxation are prolonged in isolated myocardium from patients with HHD and HHD+HFpEF. This leads to incomplete relaxation at higher rates. Elevated calcium levels in HFpEF are neither due to an impaired Na+-gradient nor to expression changes in key ion transporters and regulatory proteins.

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“…After LPS 8 hours, LV muscle strips from seven hearts of NT (n = 23) and five hearts of MH (n = 17) were isolated and equilibrated in Tyrode's solution with 2.5 mM calcium at 38.0°C as described before (24). One heart of MH was missed due to malfunction of the technical setup.…”

Section: Isolated Cardiac Muscle Stripsmentioning

confidence: 99%

Mild Hypothermia Attenuates Circulatory and Pulmonary Dysfunction During Experimental Endotoxemia*

Schwarzl

Seiler

Wallner

et al. 2013

Critical Care Medicine

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Reduced Stretch-Induced Force Response in Failing Human Myocardium Caused by Impaired Na ⁺ -Contraction Coupling

Cited by 20 publications

References 55 publications

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Relaxation and the Role of Calcium in Isolated Contracting Myocardium From Patients With Hypertensive Heart Disease and Heart Failure With Preserved Ejection Fraction

Mild Hypothermia Attenuates Circulatory and Pulmonary Dysfunction During Experimental Endotoxemia*

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Reduced Stretch-Induced Force Response in Failing Human Myocardium Caused by Impaired Na + -Contraction Coupling

Cited by 20 publications

References 55 publications

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Relaxation and the Role of Calcium in Isolated Contracting Myocardium From Patients With Hypertensive Heart Disease and Heart Failure With Preserved Ejection Fraction

Mild Hypothermia Attenuates Circulatory and Pulmonary Dysfunction During Experimental Endotoxemia*

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Reduced Stretch-Induced Force Response in Failing Human Myocardium Caused by Impaired Na ⁺ -Contraction Coupling