Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium

Burkert Pieske, Lars S. Maier, Donald M Bers, Gerd Hasenfuss

Research output: Contribution to journalArticle

314 Citations (Scopus)

Abstract

Disturbed sarcoplasmic reticulum (SR) Ca2+ content may underlie the altered force-frequency and postrest contractile behavior in failing human myocardium. We used rapid cooling contractures (RCCs) to assess SR Ca2+ 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 Ca2+ uptake and Na+/Ca2+ exchange to cytosolic Ca2+ removal during relaxation. SR Ca2+ uptake (relative to the Na+/Ca2+ 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 Ca2+ content to increase sufficiently at high frequencies and thus cannot overcome the frequency- dependent refractoriness of SR Ca2+ release. The rest-dependent decay in twitch force in failing myocardium is due to rest-dependent decline in SR Ca2+ content. These alterations could be secondary to depressed SR Ca2+- ATPase combined with enhanced cytosolic Ca2+ extrusion via Na+/Ca2+ exchange.

Original languageEnglish (US)
Pages (from-to)38-46
Number of pages9
JournalCirculation Research
Volume85
Issue number1
StatePublished - Jul 9 1999
Externally publishedYes

Fingerprint

Sarcoplasmic Reticulum
Myocardium
Contracture
Calcium-Transporting ATPases
Handling (Psychology)
Muscles

Keywords

  • Ca
  • Heart failure
  • Myocardial contraction
  • Na/Ca exchange
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium. / Pieske, Burkert; Maier, Lars S.; Bers, Donald M; Hasenfuss, Gerd.

In: Circulation Research, Vol. 85, No. 1, 09.07.1999, p. 38-46.

Research output: Contribution to journalArticle

Pieske, Burkert ; Maier, Lars S. ; Bers, Donald M ; Hasenfuss, Gerd. / Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium. In: Circulation Research. 1999 ; Vol. 85, No. 1. pp. 38-46.
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abstract = "Disturbed sarcoplasmic reticulum (SR) Ca2+ content may underlie the altered force-frequency and postrest contractile behavior in failing human myocardium. We used rapid cooling contractures (RCCs) to assess SR Ca2+ 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 Ca2+ uptake and Na+/Ca2+ exchange to cytosolic Ca2+ removal during relaxation. SR Ca2+ uptake (relative to the Na+/Ca2+ 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 Ca2+ content to increase sufficiently at high frequencies and thus cannot overcome the frequency- dependent refractoriness of SR Ca2+ release. The rest-dependent decay in twitch force in failing myocardium is due to rest-dependent decline in SR Ca2+ content. These alterations could be secondary to depressed SR Ca2+- ATPase combined with enhanced cytosolic Ca2+ extrusion via Na+/Ca2+ exchange.",
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