Ca2+Handling and Sarcoplasmic Reticulum Ca2+Content in Isolated Failing and Nonfailing Human Myocardium
Abstract
Abstract—Disturbed sarcoplasmic reticulum (SR) Ca 2+content may underlie the altered force-frequency and postrest contractile behavior in failing human myocardium. We used rapid cooling contractures (RCCs) to assess SR Ca 2+content in ventricular muscle strips isolated from nonfailing and end-stage failing human hearts. With an increase in rest intervals (1 to 240 s; 37°C), nonfailing human myocardium (n=7) exhibited a parallel increase in postrest twitch force (at 240 s by 121±44%;P<0.05) and RCC amplitude (by 69±53%;P<0.05). In contrast, in failing myocardium (n=30), postrest twitch force decreased at long rest intervals and RCC amplitude declined monotonically with rest (by 25±9% and 53±9%, respectively;P<0.05). With an increase in stimulation frequencies (0.25 to 3 Hz), twitch force increased continuously in nonfailing human myocardium (n=7) by 71±17% (at 3 Hz;P<0.05) and RCC amplitude increased in parallel by 247±55% (P<0.05). In contrast, in failing myocardium (n=26), twitch force declined by 29±7% (P<0.05) and RCC amplitude increased only slightly by 36±14% (P<0.05). Paired RCCs were evoked to investigate the relative contribution of SR Ca 2+uptake and Na+/Ca 2+exchange to cytosolic Ca 2+removal during relaxation. SR Ca 2+uptake (relative to the Na+/Ca 2+exchange) increased significantly in nonfailing but not in failing human myocardium as stimulation rates increased. We conclude that the negative force-frequency relation in failing human myocardium is due to an inability of SR Ca 2+content to increase sufficiently at high frequencies and thus cannot overcome the frequency-dependent refractoriness of SR Ca 2+release. The rest-dependent decay in twitch force in failing myocardium is due to rest-dependent decline in SR Ca 2+content. These alterations could be secondary to depressed SR Ca 2+-ATPase combined with enhanced cytosolic Ca 2+extrusion via Na+/Ca 2+exchange.
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The post-rest behavior differences are largely attributed to changes in sarcoplasmic reticulum calcium content during rest, which decreases in rabbits and increases in humans.
“This has largely been attributed to changes in sarcoplasmic reticulum calcium content during rest periods where rabbits’ and humans’ are decreased and increased, respectively (Maier, Bers, et al., 2000; Pieske, et al., 1999).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Pieske, et al., 1999
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References 45 · Cited by 369
Research works printed but not linked: 2
- Pieske B, Su ¨tterlin M, Schmidt-Schweda S, Minami K, Meyer M, Olschewski M, Holubarsch C, Just H, Hasenfuss G. Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy. J Clin Invest. 1996;98:764 -776.
- Schiefer A, Meissner G, Isenberg G. Ca 2ϩ activation and Ca 2ϩ inacti- vation of cardiac sarcoplasmic reticulum Ca 2ϩ -release channels. J Physiol (Lond). 1995;489:337-348.
- Authors
- Pieske, B., Maier, L. S., Bers, D. M., & Hasenfuss, G.
- Affiliations
- Loyola University Chicago (US)
- Venue
- Circulation Research
- Published
- 1999-07-09
- Volume
- 85
- Issue
- 1
- Pages
- 38-46
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2138783312
- Cited by
- 369
- References
- 45
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 8 · 2019: 6 · 2018: 13 · 2017: 3 · 2016: 7 · 2015: 12 · 2014: 9 · 2013: 12 · 2012: 17
- FWCI
- 13.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Funders
- Boehringer Ingelheim Fonds
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (5r01hl052478-05)
- National Heart, Lung, and Blood Institute (HL52478)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- sarcoplasmic reticulum calcium stores, calcium handling, rapid cooling contracture, force-frequency relationship, SR calcium uptake, sodium-calcium exchange, end-stage heart failure
- MeSH terms
- Adult, Calcium, Cardiac Output, Low, Child, Preschool, Cold Temperature, Electric Stimulation, Female, Humans, Male, Middle Aged, Myocardial Contraction, Myocardium, Reference Values, Refractory Period, Electrophysiological, Sarcoplasmic Reticulum, Ventricular Function, In Vitro Techniques
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