Frequency-dependent Changes in Contribution of SR Ca2+to Ca2+Transients in Failing Human Myocardium Assessed with Ryanodine

Schlotthauer, Klaus; Schattmann, J.; Bers, Donald M.; Maier, Lars S.; Schütt, U.; Minami, Kiyokazu; Just, Hanjörg; Hasenfuß, Gerd; Pieske, Burkert

doi:10.1006/jmcc.1998.0690

Cited by 40 publications

(19 citation statements)

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“…Despite the fact that numerous studies from both human (3,24) and animal (2, 22, 36) models of HF have attributed the mechanical dysfunction to changes in the calcium regulation observed in isolated myocytes (see Refs. 37 and 40 for reviews), few reports have made comparisons from intact tissue (16,21,23,25,34). We found in canine tachycardia-induced HF that calcium transient amplitude is reduced and the duration is prolonged compared with normal.…”

Section: Discussionmentioning

confidence: 73%

Spontaneous calcium release in tissue from the failing canine heart

Hoeker

Katra

Wilson

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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malities in calcium handling have been implicated as a significant source of electrical instability in heart failure (HF). While these abnormalities have been investigated extensively in isolated myocytes, how they manifest at the tissue level and trigger arrhythmias is not clear. We hypothesize that in HF, triggered activity (TA) is due to spontaneous calcium release from the sarcoplasmic reticulum that occurs in an aggregate of myocardial cells (an SRC) and that peak SCR amplitude is what determines whether TA will occur. Calcium and voltage optical mapping was performed in ventricular wedge preparations from canines with and without tachycardia-induced HF. In HF, steady-state calcium transients have reduced amplitude [135 vs. 170 ratiometric units (RU), P Ͻ 0.05] and increased duration (252 vs. 229 s, P Ͻ 0.05) compared with those of normal. Under control conditions and during ␤-adrenergic stimulation, TA was more frequent in HF (53% and 93%, respectively) compared with normal (0% and 55%, respectively, P Ͻ 0.025). The mechanism of arrhythmias was SCRs, leading to delayed afterdepolarization-mediated triggered beats. Interestingly, the rate of SCR rise was greater for events that triggered a beat (0.41 RU/ms) compared with those that did not (0.18 RU/ms, P Ͻ 0.001). In contrast, there was no difference in SCR amplitude between the two groups. In conclusion, TA in HF tissue is associated with abnormal calcium regulation and mediated by the spontaneous release of calcium from the sarcoplasmic reticulum in aggregates of myocardial cells (i.e., an SCR), but importantly, it is the rate of SCR rise rather than amplitude that was associated with TA. heart failure; arrhythmia; delayed afterdepolarization; triggered activity HEART FAILURE (HF) is a serious public health problem that afflicts millions of people in the United States alone (32). HF is associated with impaired cardiac contractility and relaxation, as well as a high incidence of ventricular arrhythmias and sudden death. Abnormal calcium handling has been implicated as a source of both mechanical and electrical dysfunction observed in HF, making it a key target for investigation and clinical therapy.At the myocyte level, impaired ventricular contractility and relaxation in HF have been attributed to decreased calcium transient amplitude due to diastolic sarcoplasmic reticulum (SR) calcium leak (12,13,35) and reduced SR calcium uptake (3,8,22,24). Calcium dysregulation in human HF has been associated with a significant incidence of nonreentrant arrhythmias (28,30,33) that can occur as the result of early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). At the subcellular level, a DAD is caused by spontaneous calcium release from the SR that activates a transient inward current with a magnitude that depends on the amount of calcium flux (33). While studies in isolated myocytes have provided valuable insight into cellular pathophysiology, the translation of these results to arrhythmogenesis at the tissue level is not straightforward.The fact...

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Section: Discussionmentioning

confidence: 73%

Spontaneous calcium release in tissue from the failing canine heart

Hoeker

Katra

Wilson

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Upregulation of NCX in heart failure has been proposed as a compensatory reaction for reduced SERCA levels (23,48). Maladaptive changes in NCX protein elicit frequency-dependent functional abnormalities in muscle strips (22) and cellular preparations (42). ␤-Blockers reverse rising NCX levels in failing human hearts (28), suggesting that normalizing this protein may improve myocardial function.…”

Section: Discussionmentioning

confidence: 99%

“…Immunoblot and patchclamp analyses of samples from failing human hearts possess increased NCX (37), reduced SERCA (22), and possibly reduced L-type Ca 2ϩ channel density (35,45). Recorded Ca 2ϩ transients of cardiomyocytes from failing hearts show prolonged Ca 2ϩ reuptake and frequencydependent elevation in diastolic Ca 2ϩ levels (29,42,43). Normalizing these regulatory proteins restores intracellular Ca 2ϩ dynamics and reestablishes improved function to the failing myocardium (10,28,41).…”

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confidence: 99%

Calcium dynamics in the failing heart: restoration by β-adrenergic receptor blockade

Plank

Yatani²,

Honda³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Changes in calcium (Ca2+) regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using β-adrenergic receptor antagonists (β-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of β-blocker treatment on Ca2+ dynamics in the failing heart are unknown. To address this issue, tropomodulin-overexpressing transgenic (TOT) mice, which suffer from dilated cardiomyopathy, were treated with a nonselective β-receptor blocker (5 mg · kg-1 · day-1 propranolol) for 2 wk. Ca2+ dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared with untreated TOT mice. Frequency-dependent diastolic and Ca2+ transient amplitudes were returned to normal in propranolol-treated TOT mice and but not in untreated TOT mice. Ca2+ kinetic measurements of time to peak and time decay of the caffeine-induced Ca2+ transient to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), whereas Na+/Ca2+ exchanger (NCX) concentrations were increased 2.6-fold relative to nontransgenic samples. Propranolol treatment of TOT mice reversed the alterations in SERCA and NCX protein levels but not potassium channels. Although restoration of Ca2+ dynamics occurred within 2 wk of β-blockade treatment, evidence of functional improvement in cardiac contractility assessed by echocardiography took 10 wk to materialize. These results demonstrate that β-adrenergic blockade restores Ca2+ dynamics and normalizes expression of Ca2+-handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts.

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“…In contrast to these results in mice, there is strong, albeit circumstantial evidence in human myocardium that increased Ca 2+ delivery to the myofilaments plays a major role in the positive FFR. 33,44,45 Another limitation is that the phosphomimetic substitutions targeted only the PKA sites on MyBP-C. As discussed in the articles, 10,11 MyBP-C has multiple non-PKA phosphorylation sites that can potentially modulate myofilament function in a complex fashion both independently and in conjunction with PKA.…”

Section: Limitationsmentioning

confidence: 99%