Handling In Heart Failure Research Articles

Increased phospholamban phosphorylation limits the force–frequency response in the MLP–/– mouse with heart failure

Reduced Ca(2+) release from the sarcoplasmic reticulum (SR) and a negative force-frequency relation characterize end-stage human heart failure. The MLP(-/-) mouse with dilated cardiomyopathy is used as a model to explore novel therapeutic interventions but the alterations in Ca(2+) handling in MLP(-/-) remain incompletely understood. We studied [Ca(2+)](i) in left ventricular myocytes from MLP(-/-) and WT mice (3-4 months old; whole-cell voltage clamp, 30 degrees C). At 1 Hz stimulation, the amplitude of [Ca(2+)](i) transients was similar. However, in contrast to WT, at higher frequencies the [Ca(2+)](i) transient amplitude declined in MLP(-/-) and there was no increase in SR Ca(2+) content. Unexpectedly, the decline of [Ca(2+)](i) was faster in MLP(-/-) than in WT (at 1 Hz, tau of 80 +/- 9 vs. 174 +/- 29 ms, P < 0.001) and the frequency-dependent acceleration of the decline was abolished suggesting an enhanced basal SERCA activity. Indeed, the Ca(2+) affinity of SR Ca(2+) uptake in homogenates was higher in MLP(-/-), with the maximal uptake rate similar to WT. Phosphorylation of phospholamban in MLP(-/-) was increased (2.3-fold at Ser(16) and 2.9-fold at the Thr(17) site, P < 0.001) with similar SERCA and total phospholamban protein levels. On increasing stimulation frequency to 4 Hz, WT, but not MLP(-/-), myocytes had a net gain of Ca(2+), suggesting inadequate Ca(2+) sequestration in MLP(-/-). In conclusion, increased baseline phosphorylation of phospholamban in MLP(-/-) leads to a reduced reserve for frequency-dependent increase of Ca(2+) release. This represents a novel paradigm for altered Ca(2+) handling in heart failure, underscoring the importance of phosphorylation pathways.

Beta-blocker Ameliorates Intracellular Ca 2+ Handling in Heart Failure via Correction of Defective Inter-domain Interaction within Ryanodine Receptor

Beta-blocker Ameliorates Intracellular Ca 2+ Handling in Heart Failure via Correction of Defective Inter-domain Interaction within Ryanodine Receptor

SERCA upregulation: Breaking the positive feedback in heart failure?

See article by Maier et al. [9] (pages 636–646) in this issue . Much effort has been devoted to devising approaches that may improve survival and the quality of life for the millions of people afflicted by heart failure (HF) all over the world. Because HF develops in association with different etiologies, its treatment represents a challenge for clinicians and investigators. The consistent observation of defective Ca2+ cycling in the failing myocardium has led to the notion that improvement of cardiac Ca2+ handling might be a suitable approach to minimize the systolic and diastolic dysfunction and possibly also the electrophysiological abnormalities that characterize HF. Changes in Ca2+ handling in HF include partial Ca2+ depletion of the sarcoplasmic reticulum (SR), abnormal behavior of SR Ca2+ release channels, increased diastolic SR Ca2+ leak, upregulation of the sarcolemmal Na+–Ca2+ exchanger, and downregulation of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) [1–6]. It is likely that SR dysfunction may arise from the excessive demand on the heart due to prolonged activation of compensatory mechanisms that lead to changes in gene transcription and metabolism, thus representing part of the vicious circle that precipitates HF [7]. Gene therapy aimed at improving SR function has been … *Corresponding author. Centro de Engenharia Biomedica/UNICAMP, Caixa Postal 6040, 13084-971 Campinas, SP, Brazil. Tel.: +55 19 3788 9274; fax: +55 19 3289 3346. Email address: bassani{at}ceb.unicamp.br

Chronic inhibition of Na/H-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure

In patients with heart disease, the transition from compensatory hypertrophy to heart failure (HF) is associated with altered calcium handling. Up-regulated Na(+)/H(+)-exchanger (NHE-1) activity underlies increased [Na(+)](i) and disturbance of cellular calcium handling in HF. We hypothesize that chronic inhibition of NHE-1 activity prevents the hypertrophic response, cellular remodeling, and development of HF. Rabbits received a control or cariporide (inhibitor of NHE-1) diet for 3 months, starting after induction of combined volume and pressure overload. Age-matched animals served as control. Development of HF was examined echocardiographically and electrocardiographically after 3 months. [Na(+)](i), [Ca(2+)](i), pH(i), and action potentials were measured in left ventricular midmural myocytes with SBFI, indo-1, SNARF, and di-4-anepps. Sarcoplasmic reticulum calcium content was calculated from the response of [Ca(2+)](i) to rapid cooling. Calcium after-transients were elicited by cessation of rapid stimulation (3 Hz) in the presence of 100 nmol/l noradrenalin. Chronic treatment of rabbits with the specific Na(+)/H(+)-exchanger activity inhibitor cariporide greatly attenuated development of hypertrophy and entirely abolished development of HF; the heart/body weight ratio increased only little, no change in lung weight occurred, left ventricular dimensions and fractional shortening changed mildly, ascites was not present, QT duration did not increase, and sudden death did not occur. Chronic cariporide treatment also prevented cellular electrical and ionic remodeling. Myocyte dimensions were unaltered, action potentials were not prolonged, cytoplasmic sodium and NHE-1 activity did not increase, cytoplasmic and SR calcium handling remained undisturbed, and no increase of the incidence of calcium after-transient dependent delayed after depolarizations (DADs) occurred. We conclude that enhanced activity of NHE-1 underlies cardiac cellular electrical and ionic remodeling in experimental heart failure, and that chronic dietary treatment with cariporide attenuates hypertrophy, development of HF, and cellular remodeling.

Novel therapeutic approaches for heart failure by normalizing calcium cycling.

Congestive heart failure is the leading cause of death in the Western world. Abnormal intracellular calcium (Ca2+) handling is central to the pathogenesis of heart failure because it contributes to a decrease in ventricular contractile function. Chronic hyperactivity of the sympathetic nervous system causes increased phosphorylation of the ryanodine receptor intracellular Ca2+-release channel, a key Ca2+-handling protein in the heart, by protein kinase A. Alteration of the structure and function of ryanodine receptors contributes to defective intracellular Ca2+ handling and an increased propensity for cardiac arrhythmias in failing hearts. Novel therapeutic strategies are now being evaluated to specifically correct defective Ca2+-handling in heart failure.

Na+]i and the driving force of the Na+/Ca2+-exchanger in heart failure.

Diastolic calcium is increased in myocytes from failing hearts despite up-regulation of the principal calcium extruding mechanism the Na+/Ca2+-exchanger (NCX). We hypothesize that increased diastolic calcium ([Ca2+]i) is secondary to increased cytosolic sodium ([Na+]i) and decreased driving force of NCX (DeltaG(exch)). The stimulation rate dependence of simultaneously measured cytosolic sodium ([Na+]i), calcium transients ([Ca2+]i) and action potentials were determined with SBFI, indo-1 and the perforated patch technique in midmural left ventricular myocytes isolated from rabbits with pressure and volume overload induced heart failure (HF) and in age matched controls. Dynamic changes of DeltaG(exch) were calculated. With increasing stimulation frequency, 0.2-3 Hz (all data HF versus control): [Na+]i increased (6.4 to 10.8 versus 3.8 to 6.4 mmol/l), diastolic [Ca2+]i increased (142 to 219 versus 47 to 98 nmol/l), calcium transient amplitude decreased in HF (300 to 250 nmol/l) but increased in control (201 to 479 nmol/l), action potential duration (APD90) decreased (380 to 260 versus 325 to 205 ms) and time averaged DeltaG(exch) decreased (6.8 to 2.8 versus 8.7 to 6.4 kJ/mol. With increasing stimulation rate the forward mode time integral of DeltaG(exch) decreased in HF by about 30%, the reversed mode time integral increased about ninefold and the duration of reversed mode operation more than sixfold relative to control. [Na+]i is increased in HF and the driving force of NCX is decreased. NCX exerts thermodynamic control over diastolic calcium. Disturbed diastolic calcium handling in HF is due to decreased forward mode DeltaG(exch) secondary to increased [Na+]i and prolongation of the action potential. Enhanced reversed mode DeltaG(exch) may account for increased contribution of NCX to e-c coupling in HF.

The renal dopaminergic system, neurohumoral activation, and sodium handling in heart failure

Background Dopamine of renal origin exerts natriuretic and diuretic actions by activating specific receptors located in the renal proximal tubular epithelial cells. Heart failure (HF) is accompanied by activation of several neurohumoral systems. The interaction of these systems with the renal dopaminergic system and its effect on sodium handling in HF are not clarified. Methods and Results We studied 13 patients with decompensated New York Heart Association class III/IV HF and 17 sex- and age-matched patients with mild to moderate stable class I/II HF. We measured plasma catecholamines, aldosterone, type B natriuretic peptide (BNP), sodium, creatinine (UCr), and 24-hour urinary excretion of sodium, UCr, levo-3,4-dihydroxyphenylalanine (L-DOPA), 3-o -methyldopa, dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovallinic acid, and norepinephrine. All patients had HF of ischemic etiology. No statistically significant differences were found between the groups with respect to urine volume (1.79 ± 0.23 L · d−1 vs 2.20 ± 0.18 L · d−1, P =.18) and urinary sodium (161.3 ± 27.5 mmol · d−1 vs 232.9 ± 28.8 mmol · d−1, P =.12). Urinary L-DOPA was significantly lower in patients with decompensated class III/IV HF than in the other group (79.0 ± 13.8 nmol · g UCr−1 vs 108.4 ± 10.3 nmol · g UCr−1, P =.04). Urinary dopamine showed a nonstatistically significant trend to be slightly higher (1294.3 ± 188.5 nmol · g UCr−1 vs 953.2 ± 107.4 nmol · g UCr−1, P =.14). Consequently, urinary dopamine/L-DOPA ratios were markedly higher in patients with decompensated class III/IV HF than in the other patients (20.6 ± 3.4 vs 9.0 ± 0.9, P <.001). Plasma L-DOPA (38.1 ± 4.4 pmol · mL−1 vs 40.0 ± 3.0 pmol · mL−1, P =.48), dopamine (37.0 ± 6.3 pmol · mL−1 vs 41.1 ± 2.6 pmol · mL−1, P =.53), 3,4-dihydroxyphenylacetic acid (51.7 ± 11.7 pmol · mL−1 vs 56.5 ± 5.4 pmol · mL−1, P =.09), and norepinephrine (9.5 ± 2.4 pmol · mL−1 vs 5.6 ± 1.0 pmol · mL−1, P =.12) did not differ between groups. Plasma aldosterone (180.2 ± 28.0 pg · mL−1 vs 69.9 ± 13.3 pg · mL−1, P <.001) and BNP (677.5 ± 133.9 pg · mL−1 vs 389.4 ± 88.4 pg · mL−1, P <.04) levels were higher in the decompensated class III/IV HF group than in the other group, whereas serum sodium was lower (137.3 ± 1.2 mmol · L−1 vs 143.2 ± 1.0 mmol · L−1, P =.001). Conclusions These results suggest that, in patients with HF, the increased renal utilization of L-DOPA may constitute a compensatory mechanism, activated in response to stimuli leading to sodium reabsorption. (Am Heart J 2002;143:391-7.)

Non-uniform prolongation of intracellular Ca2+ transients recorded from the epicardial surface of isolated hearts from rabbits with heart failure.

To study the time course of Ca2+ transients recorded from the left ventricular epicardial surface of isolated hearts from rabbits with heart failure and to correlate the results with mechanical function. Heart failure was induced in the rabbit 8 weeks after coronary ligation (n = 17) with 13 controls. Echocardiography was used to assess in vivo left ventricular dysfunction. The fluorescent indicator Indo-1 was loaded into isolated Langendorff-perfused hearts and Ca2+ transients were recorded from 15 sites over the left ventricular epicardial surface using a single core light guide. The time course of the Ca2+ transients was analysed and the duration measured and correlated with in vitro mechanical function. Significant mechanical dysfunction was produced in this model of heart failure. The mean duration of the Ca2+ transients obtained from failing hearts was prolonged (156.2 +/- 3.2 ms) when compared to controls (124.9 +/- 2.6 ms, P < 0.001). Delayed relaxation as measured by the maximum rate of intraventricular pressure decay was significantly correlated with the prolonged Ca2+ transients (r = -0.63, P < 0.001). In addition, there was increased variation of the Ca2+ transient duration in the failing hearts. Coronary artery ligation-induced heart failure is associated with changes in the surviving myocardium which result in a non-uniform prolongation of Ca2+ transient duration. This suggests that there is a regional heterogeneity to the abnormal intracellular Ca2+ handling in heart failure.

Atrial Natriuretic Peptide Infusion in Chronic Heart Failure in the Rat

The natriuretic, diuretic, and hypotensive responses to infused atrial natriuretic peptide (ANP) were measured in rats 4 weeks after myocardial infarction induced by coronary artery ligation. Rat [1-28]-ANP was infused intravenously in doses of 0.1, 0.3, and 1.0 microgram/kg/min for 30 min each under pentobarbital anesthesia. There was a marked natriuresis, diuresis, and fall in blood pressure in rats with infarction but each response was significantly attenuated when compared with sham-operated controls (ANOVA: p less than 0.01, p less than 0.05, and p less than 0.01, respectively). Urinary cyclic guanosine monophosphate (cGMP) excretion in rats with infarction was higher than that of controls but rose to the same absolute level in both groups in response to ANP infusion (0.3 microgram/kg/min). Reduced ANP responsiveness may result from impaired postreceptor mechanisms or from physiological antagonism by angiotensin II. Reduced ANP responsiveness may partly explain impaired salt handling in heart failure.

Atrial Natriuretic Peptide Infusion in Chronic Heart Failure in the Rat

The natriuretic, diuretic, and hypotensive responses to infused atrial natriuretic peptide (ANP) were measured in rats 4 weeks after myocardial infarction induced by coronary artery ligation. Rat [1-28]-ANP was infused intravenously in doses of 0.1, 0.3, and 1.0 microgram/kg/min for 30 min each under pentobarbital anesthesia. There was a marked natriuresis, diuresis, and fall in blood pressure in rats with infarction but each response was significantly attenuated when compared with sham-operated controls (ANOVA: p less than 0.01, p less than 0.05, and p less than 0.01, respectively). Urinary cyclic guanosine monophosphate (cGMP) excretion in rats with infarction was higher than that of controls but rose to the same absolute level in both groups in response to ANP infusion (0.3 microgram/kg/min). Reduced ANP responsiveness may result from impaired postreceptor mechanisms or from physiological antagonism by angiotensin II. Reduced ANP responsiveness may partly explain impaired salt handling in heart failure.