Handling In Heart Failure Research Articles

Evaluation of renal sodium handling in heart failure with preserved ejection fraction: A pilot study.

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.

Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.

Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca2+) handling, mitochondrial Ca2+ overload, and oxidative stress. In cardiomyocytes, Ca2+ not only regulates excitation-contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca2+ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca2+ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca2+ handling in heart failure and the potential therapeutic strategies.

Role of Sodium and Sodium Restriction in Heart Failure.

Sodium plays an essential role in the regulation of extracellular volume. The current review discusses the physiologic handling of sodium in the body, underscores pathophysiologic alterations in sodium handling in heart failure and assesses the evidence and rational for sodium restriction in heart failure. Recent trials such as the SODIUM-HF trial have failed to demonstrate a benefit of sodium restriction in heart failure. The current review re-evaluates physiologic elements in sodium handling and discusses how the intrinsic renal sodium avidity, which drives the renal propensity towards retaining sodium, differs amongst patients. The sodium intake in heart failure patients is often above the threshold set by guidelines. This review gives an overview of the pathophysiology of sodium retention in heart failure and the rational for sodium restriction and potential of individualizing sodium restriction recommendations based on renal sodium avidity profiles.

β-Adrenergic Receptor Desensitization/Down-Regulation in Heart Failure: A Friend or Foe?

Cardiac sympathetic activation, mediated by β-adrenergic receptors (β-ARs), normally increases cardiac contraction and relaxation. Accomplishing this task requires a physiological, concerted Ca2+ signaling, being able to increase Ca2+ release from sarcoplasmic reticulum (SR) in systole and speed up Ca2+ re-uptake in diastole. In heart failure (HF) myocardial β-ARs undergo desensitization/down-regulation due to sustained sympathetic adrenergic activation. β-AR desensitization/down-regulation diminishes adrenergic signaling and cardiac contractile reserve, and is conventionally considered to be detrimental in HF progression. Abnormal Ca2+ handling, manifested as cardiac ryanodine receptor (RyR2) dysfunction and diastolic Ca2+ leak (due to sustained adrenergic activation) also occur in HF. RyR2 dysfunction and Ca2+ leak deplete SR Ca2+ store, diminish Ca2+ release in systole and elevate Ca2+ levels in diastole, impairing both systolic and diastolic ventricular function. Moreover, elevated Ca2+ levels in diastole promote triggered activity and arrhythmogenesis. In the presence of RyR2 dysfunction and Ca2+ leak, further activation of the β-AR signaling in HF would worsen the existing abnormal Ca2+ handling, exacerbating not only cardiac dysfunction, but also ventricular arrhythmogenesis and sudden cardiac death. Thus, we conclude that β-AR desensitization/down-regulation may be a self-preserving, adaptive process (acting like an intrinsic β-AR blocker) protecting the failing heart from developing lethal ventricular arrhythmias under conditions of elevated sympathetic drive and catecholamine levels in HF, rather than a conventionally considered detrimental process. This also implies that medications simply enhancing β-AR signaling (like β-AR agonists) may not be so beneficial unless they can also correct dysfunctional Ca2+ handling in HF.

Arrhythmogenic Remodeling in the Failing Heart.

Chronic heart failure is a clinical syndrome with multiple etiologies, associated with significant morbidity and mortality. Cardiac arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, are common in heart failure. A number of cardiac diseases including heart failure alter the expression and regulation of ion channels and transporters leading to arrhythmogenic electrical remodeling. Myocardial hypertrophy, fibrosis and scar formation are key elements of arrhythmogenic structural remodeling in heart failure. In this article, the mechanisms responsible for increased arrhythmia susceptibility as well as the underlying changes in ion channel, transporter expression and function as well as alterations in calcium handling in heart failure are discussed. Understanding the mechanisms of arrhythmogenic remodeling is key to improving arrhythmia management and the prevention of sudden cardiac death in patients with heart failure.

Disturbed cardiac mitochondrial and cytosolic calcium handling in a metabolic risk-related rat model of heart failure with preserved ejection fraction.

AimCalcium ions play a pivotal role in matching energy supply and demand in cardiac muscle. Mitochondrial calcium concentration is lower in animal models of heart failure with reduced ejection fraction (HFrEF), but limited information is available about mitochondrial calcium handling in heart failure with preserved ejection fraction (HFpEF).MethodsWe assessed mitochondrial Ca2+ handling in intact cardiomyocytes from Zucker/fatty Spontaneously hypertensive F1 hybrid (ZSF1)‐lean (control) and ZSF1‐obese rats, a metabolic risk‐related model of HFpEF. A mitochondrially targeted Ca2+ indicator (MitoCam) was expressed in cultured adult rat cardiomyocytes. Cytosolic and mitochondrial Ca2+ transients were measured at different stimulation frequencies. Mitochondrial respiration and swelling, and expression of key proteins were determined ex vivo.ResultsAt rest, mitochondrial Ca2+ concentration in ZSF1‐obese was larger than in ZSF1‐lean. The diastolic and systolic mitochondrial Ca2+ concentrations increased with stimulation frequency, but the steady‐state levels were larger in ZSF1‐obese. The half‐widths of the contractile responses, the resting cytosolic Ca2+ concentration and the decay half‐times of the cytosolic Ca2+ transients were higher in ZSF1‐obese, likely because of a lower SERCA2a/phospholamban ratio. Mitochondrial respiration was lower, particularly with nicotinamide adenine dinucleotide (NADH) (complex I) substrates, and mitochondrial swelling was larger in ZSF1‐obese.ConclusionThe free mitochondrial calcium concentration is higher in HFpEF owing to alterations in mitochondrial and cytosolic Ca2+ handling. This coupling between cytosolic and mitochondrial Ca2+ levels may compensate for myocardial ATP supply in vivo under conditions of mild mitochondrial dysfunction. However, if mitochondrial Ca2+ concentration is sustainedly increased, it might trigger mitochondrial permeability transition pore opening.

174 - Modulation of Cardiac Function by Oxidized Type I Protein Kinase A

L-type Ca2+ channels (LTCC) are known to be involved in the dysregulation of intracellular Ca2+ handling in heart failure (HF) contributing to contractile dysfunction and arrhythmias. Beside alteration in subcellular localization, reduced LTCC function may be a consequence of altered posttranslational modification. It is known that cAMP-dependent protein kinase A (PKA) can phosphorylate LTCC resulting in increased Ca2+ current (ICa). PKA-dependent LTCC phosphorylation has been shown to occur upon acute pressure overload partly compensating for reduced Ca2+ release from sarcoplasmic reticulum (SR). However, the mechanisms of PKA-dependent LTCC activation upon pressure overload are inadequately understood. Recent data suggest that PKA can be activated upon direct oxidation of its regulatory subunit (RI) without binding to its physiologic agonist, cAMP. In this thesis, I have investigated the pathophysiological relevance of this oxidative PKA activation for intracellular Ca2+ homeostasis, contractile function, and arrhythmogenesis upon pressure overload. Here, a novel PKA redox-dead knock-in mouse line was used harboring a RI point mutation that results in the exchange of cysteine 17 with serine (KI). Oxidation of cysteine 17 with consequent intersubunit disulfide bridge, RI-RI dimer, formation is inhibited. The later is a prerequisite for catalytic subunit release and phosphorylation of target proteins, i.e. oxidative activation of the kinase. At baseline, no alterations in Ca2+ handling (FURA-2-loaded isolated cardiomyocytes) or contractile function (echocardiography) are observed in these mice. However, NAPDH oxidase 2 (NOX2)-dependent oxidants stimulated by angiotensin II (AngII, 1µmol/L) could not result in RI dimer (Western blotting) formation in KI. In accordance, ICa and Ca2+ transient amplitude were significantly smaller in KI mice in the presence of AngII. Similarly, pressure overload by transverse aortic constriction did not result in RI dimer formation in KI. Moreover, compared to WT mice KI mice displayed significantly reduced ICa and Ca2+ transient amplitude with a significantly impaired ejection fraction (echocardiography) upon pressure overload. Western blot analyses revealed that AngII and pressure overload-dependent LTCC phosphorylation at the PKA site were inhibited. Beside disturbed contractile function, KI mice displayed severe QTc prolongation and increased the propensity for ventricular arrhythmias (ECG and programmed ventricular stimulation), which results in significantly reduced survival rates upon pressure overload. In summary, oxidative activation of PKA appears to be important for adaptation of the heart during increased afterload. Thus, stimulation of oxidative PKA activation could be a potential therapeutic option for patients with cardiac diseases, like heart failure.

Intrarenal Flow Alterations During Transition From Euvolemia to Intravascular Volume Expansion in Heart Failure Patients

ObjectivesThe goal of this study was to assess: 1) the intrarenal flow in heart failure (HF) patients during the transition from euvolemia to intravascular volume overload; and 2) the relationship between intrarenal flow and diuretic efficiency. BackgroundIntrarenal blood flow alterations may help to better understand impaired volume handling in HF. MethodsResistance index (RI) and venous impedance index (VII) were assessed in 6 healthy subjects, 40 euvolemic HF patients with reduced ejection fraction (HFrEF), and 10 HF patients with preserved ejection fraction (HFpEF). Assessments were performed by using Doppler ultrasonography at baseline, during 3 h of intravascular volume expansion with 1 l of hydroxyethyl starch 6%, and 1 h after the administration of a loop diuretic. Clinical parameters, echocardiography, and biochemistry were assessed. Urine output was collected after 3 and 24 h. ResultsIn response to volume expansion, VII increased significantly in HFrEF patients (0.4 ± 0.3 to 0.7 ± 0.2; p < 0.001) and in HFpEF patients (0.4 ± 0.3 to 0.7 ± 0.2; p = 0.002) but not in healthy subjects (0.2 ± 0.2 to 0.3 ± 0.1; p = 0.622). This outcome was reversed after loop diuretic administration. In contrast, RI did not change significantly after volume expansion. Echocardiographic-estimated filling pressures did not change significantly. VII during volume expansion was significantly correlated with diuretic response in HF patients independent of baseline renal function (R2 = 0.35; p < 0.001). ConclusionsIn HF patients, intravascular volume expansion resulted in significant blunting of venous flow before a significant increase in cardiac filling pressures could be demonstrated. The observed impaired renal venous flow is correlated with less diuretic efficiency. Intrarenal venous flow patterns may be of interest for evaluating renal congestion.

Cardioprotective effects of Qishen Granule () on sarcoplasmic reticulum Ca2+ handling in heart failure rats.

To assess the effects of Qishen Granule (, QSG) on sarcoplasmic reticulum (SR) Ca2+ handling in heart failure (HF) model of rats and to explore the underlying molecular mechanisms. HF rat models were induced by left anterior descending coronary artery ligation surgery and high-fat diet feeding. Rats were randomly divided into sham (n=10), model (n=10), QSG (n=12, 2.2 g/kg daily) and metoprolol groups (n=12, 10.5 mg/kg daily). The therapeutic effects of QSG were evaluated by echocardiography and blood lipid testing. Intracellular Ca2+ concentration and sarco-endoplasmic reticulum ATPase 2a (SERCA2a) activity were detected by specifific assay kits. Expressions of the critical regulators in SR Ca2+ handling were evaluated by Western blot and real-time quantitative polymerase chain reaction. HF model of rats developed ventricular remodeling accompanied with calcium overload and defective Ca2+ release-uptake cycling in cardiomyocytes. Treatment with QSG improved contractive function, attenuated ventricular remodeling and reduced the basal intracellular Ca2+ level. QSG prevented defective Ca2+ leak by attenuating hyperphosphorylation of ryanodine receptor 2, inhibiting expression of protein kinase A and up-regulating transcriptional expression of protein phosphatase 1. QSG also restored Ca2+ uptake by up-regulating expression and activity of SERCA2a and promoting phosphorylation of phospholamban. QSG restored SR Ca2+ cycling in HF rats and served as an ideal alternative drug for treating HF.

Abstract 11235: Improvement of Defective Channel Function on RyR2 Mediated by CaMKII Activation Suppresses Arrhythmogenesis in TnT-related Hypertrophic Cardiomyopathy

Backgrounds: In Familial Hypertrophic Cardiomyopathy (FHC) caused by cardiac troponin T (cTnT) mutations, Ca 2+ sensitivity in myofilaments is increased, results in leading to sudden cardiac death. The activation of calcium/calmodulin-dependent protein kinase II (CaMKII) is known to be one of the key elements for the alteration of calcium handling in heart failure, presumably mediated through defective channel function of cardiac ryanodine receptor (RyR2). However, how cTnT mutations lead to lethal arrhythmias and abnormal calcium handling through defective RyR2 remains elusive. Here, we investigated the pathogenic role of CaMKII on aberrant Ca 2+ release through RyR2 for arrhythmogenesis in FHC hearts and therapeutic effects of dantrolene, which was found to correct inter-domain interactions between N-terminal and central domain of RyR2 in FHC-related cTnT-mutated transgenic mouse (TG; cTnT-delta160E). TG have been reported myocardial disarray in histology and increased Ca 2+ sensitivity in myofilaments. Methods and results: On confocal Ca 2+ imaging by fluo4-AM exposed to isoproterenol (ISO; 10 nmol/L), the Ca 2+ spark frequency (SpF:s-1·100μm-1) was much higher in TG cardiomyocytes (ISO-TG: n=11: 7.8±0.6; p&lt;0.05) than in non-TG (n=8: 3.4±0.4). It was largely reversed by CaMKII inhibitor {KN-93(1μM), n=7: 5.2±0.5; p&lt;0.05}, but not by PKA inhibitor (PKI){H-89(1μM), n=7: 7.3±0.4}. The significant increase of spontaneous Ca 2+ transient (sCaT), which was measured after sequential pacing at 5 Hz was appeared in ISO-TG (42.1%; p&lt;0.05 vs ISO-treated non-TG 14.0%), whereas it was again attenuated by CaMKII inhibitor (15.8%), but not by PKI (33.0%). These abnormal events in ISO-TG were reproduced by adding EGTA-AM into ISO-treated non-TG, suggesting that increased Ca 2+ buffering capacity, causing an increase in diastolic [Ca 2+ ], predisposes to aberrant Ca 2+ release events. Moreover, after the treatment of dantrolene (1μM), ISO-induced SpF (n=6: 5.2±0.3; p&lt;0.05 vs ISO-TG) and sCaT (25.9%) were decreased in TG. Conclusions: CaMKII activation may play a role in the development of abnormal calcium handling in FHC-linked cTnT mutated hearts, possibly through defective inter-domain interaction between N-terminal and central domain of RyR2.

Post-extrasystolic Potentiation: Link between Ca(2+) Homeostasis and Heart Failure?

Post-extrasystolic potentiation (PESP) describes the phenomenon of increased contractility of the beat following an extrasystole and has been attributed to changes in Ca(2+) homeostasis. While this effect has long been regarded to be a normal physiological phenomenon, a number of reports describe an enhanced potentiation of the post-extrasystolic beat in heart failure patients. The exact mechanism of this increased PESP is unknown, but disruption of normal Ca(2+) handling in heart failure may be the underlying cause. The use of PESP as a prognostic marker or therapeutic intervention have recently regained new attention, however, the value of the application of PESP in the clinic is still under debate. In this review, the mechanism of PESP with regard to Ca(2+) in the normal and failing heart will be discussed and the possible diagnostic and therapeutic role of this phenomenon will be explored.

The kidney in congestive heart failure: ‘are natriuresis, sodium, and diuretics really the good, the bad and the ugly?’

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron's function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy-refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter-regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction-although not by conventional GFR measurements-is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function.

Calcium is omnipresent in the physiology and pathophysiology of heart disease

Calcium is omnipresent in the physiology and pathophysiology of heart disease 277 1 3 In western industrialized nations, the burden of cardiovascular disease is increasing steadily. Despite numerous pharmacological, interventional, and surgical therapeutic options and promising novel additions to the field, cardiovascular disease remains the leading cause of death. The physiology of the healthy human heart has been characterized well in vivo and in vitro. However, to develop novel therapeutic and diagnostic tools, it is necessary to transfer our physiological perceptions into the field of pathophysiology. In human physiology, the role of calcium ions is ubiquitous. In particular, skeletal and cardiac muscles depend on calcium as their main effectors of contraction, but calcium is also essential in vascular function, neural transduction, endocrinological processes, and several other physiological functions of the human body. Similarly, the role of calcium is ubiquitous in the human heart. Not only it is an essential effector of the most obvious of all cardiac functions—contractility—but it also plays important roles in regulating and generating heart rhythm and metabolism. Thus, the contemplation of calcium handling in the development and maintenance of cardiac disease can of course not be limited to a single cardiac disease entity. Instead, one has to discuss the role of calcium in several cardiac disease categories such as arrhythmia, heart failure, and cardiac ischemia. One also has to be aware that these disease entities mutually depend on one another reciprocating their development and maintenance. In any of these three pathological entities—arrhythmia, heart failure, and ischemia—aberrations of calcium handling may not always be cause but can also be consequence of the disease mechanism in the sense of adaptive or maladaptive mechanisms. This thematic issue of the Wiener Medizinische Wochenschrift aims at adding to the translational research process by presenting a collection of papers that review specific cardiac disease entities in light of their associated aberrations of cardiac calcium handling. To begin with, Bogeholz et al. will give a brief overview on physiologi cal calcium handling, i.e. as it occurs in the healthy human heart. Next, Frommeyer et al. and Heijman et al. are going to review the growing field of research on calcium handling in life threatening ventricular arrhythmias and atrial fibrillation, respectively. Closely related to this field, Kochhauser et al. give an overview on mutations of calcium handling proteins and the associated disease categories. Reuter and Schwinger will review the topic of calcium handling in heart failure while Kleinbongard et al. give an overview on the role of calcium antagonists in ischemic heart disease. Finally, Vogler et al. will add a digest on established and novel pharmacological agents that can influence specific targets of cardiac calcium handling.

Exercise training corrects control of spontaneous calcium waves in hearts from myocardial infarction heart failure rats

Impaired cardiac control of intracellular diastolic Ca(2+) gives rise to arrhythmias. Whereas exercise training corrects abnormal cyclic Ca(2+) handling in heart failure, the effect on diastolic Ca(2+) remains unstudied. Here, we studied the effect of exercise training on the generation and propagation of spontaneous diastolic Ca(2+) waves in failing cardiomyocytes. Post-myocardial infarction heart failure was induced in Sprague-Dawley rats by coronary artery ligation. Echocardiography confirmed left ventricular infarctions of 40 ± 5%, whereas heart failure was indicated by increased left ventricular end-diastolic pressures, decreased contraction-relaxation rates, and pathological hypertrophy. Spontaneous Ca(2+) waves were imaged by laser linescanning confocal microscopy (488 nm excitation/505-530 nm emission) in 2 µM Fluo-3-loaded cardiomyocytes at 37°C and extracellular Ca(2+) of 1.2 and 5.0 mM. These studies showed that spontaneous Ca(2+) wave frequency was higher at 5.0 mM than 1.2 mM extracellular Ca(2+) in all rats, but failing cardiomyocytes generated 50% (P < 0.01) more waves compared to sham-operated controls at Ca(2+) 1.2 and 5.0 mM. Exercise training reduced the frequency of spontaneous waves at both 1.2 and 5.0 mM Ca(2+) (P < 0.05), although complete normalization was not achieved. Exercise training also increased the aborted/completed ratio of waves at 1.2 mM Ca(2+) (P < 0.01), but not 5.0 mM. Finally, we repeated these studies after inhibiting the nitric oxide synthase with L-NAME. No differential effects were found; thus, mediation did not involve the nitric oxide synthase. In conclusion, exercise training improved the cardiomyocyte control of diastolic Ca(2+) by reducing the Ca(2+) wave frequency and by improving the ability to abort spontaneous Ca(2+) waves after their generation, but before cell-wide propagation.

Changes in the Organization of Excitation-Contraction Coupling Structures in Failing Human Heart

BackgroundThe cardiac myocyte t-tubular system ensures rapid, uniform cell activation and several experimental lines of evidence suggest changes in the t-tubular system and associated excitation-contraction coupling proteins may occur in heart failure.Methods and ResultsThe organization of t-tubules, L-type calcium channels (DHPRs), ryanodine receptors (RyRs) and contractile machinery were examined in fixed ventricular tissue samples from both normal and failing hearts (idiopathic (non-ischemic) dilated cardiomyopathy) using high resolution fluorescent imaging. Wheat germ agglutinin (WGA), Na-Ca exchanger, DHPR and caveolin-3 labels revealed a shift from a predominantly transverse orientation to oblique and axial directions in failing myocytes. In failure, dilation of peripheral t-tubules occurred and a change in the extent of protein glycosylation was evident. There was no change in the fractional area occupied by myofilaments (labeled with phalloidin) but there was a small reduction in the number of RyR clusters per unit area. The general relationship between DHPRs and RyR was not changed and RyR labeling overlapped with 51±3% of DHPR labeling in normal hearts. In longitudinal (but not transverse) sections there was an ∼30% reduction in the degree of colocalization between DHPRs and RyRs as measured by Pearson's correlation coefficient in failing hearts.ConclusionsThe results show that extensive remodelling of the t-tubular network and associated excitation-contraction coupling proteins occurs in failing human heart. These changes may contribute to abnormal calcium handling in heart failure. The general organization of the t-system and changes observed in failure samples have subtle differences to some animal models although the general direction of changes are generally similar.

Does Deregulation Of Calcium Handling Precede Or Follow Alterations Of Cardiac Function During Progression To Heart Failure?

In heart failure (HF), abnormalities of in vivo cardiac function are closely correlated with reduced sarcoplasmic reticulum (SR) Ca release and myocyte contractility, supporting the concept that HF is a result of deranged Ca cycling. However, most studies addressing the role and mechanisms of altered Ca handling in HF have been performed at advanced stages of HF providing little information as to whether these deficiencies are causes or consequences of HF.In the present study we compared the time course of development of alterations in myocytes Ca handling, using a canine tachypacing model of chronic HF. In vivo function of left ventricle was assessed at several time points (1, 4, and >8 mo) with parallel studies in single ventricular myocytes of Ca handling utilizing Ca imaging in intact, permeabilized, and patch-clamped cells.LV fractional shortening progressively decreased by 50, 65, and 75 % of control values at 1, 4, and >8 month of tachypacing, respectively. The frequency of Ca sparks and the rate of SR Ca leak increased progressively with the duration of tachypacing, while diastolic [Ca]SR decreased with the duration of tachypacing. Na/Ca exchange activity was significantly augmented at 1 mo, and did not change thereafter. The SERCA-mediated Ca uptake and the density of peak Ca current were not changed up to >8 mo of tachypacing. Progressive decreases in the amplitude of depolarization-induced Ca transients and single-cell contractions were observed only starting at the 4th month of tachypacing.These results suggest that diminished SR Ca release follows rather than precedes deterioration of in vivo cardiac function, thus is not likely to be a cause of HF.

Getting energy to where it is required is a problem in the failing heart

Getting energy to where it is required is a problem in the failing heart

Modulation of late sodium current by Ca2+, calmodulin, and CaMKII in normal and failing dog cardiomyocytes: similarities and differences.

Augmented and slowed late Na(+) current (I(NaL)) is implicated in action potential duration variability, early afterdepolarizations, and abnormal Ca(2+) handling in human and canine failing myocardium. Our objective was to study I(NaL) modulation by cytosolic Ca(2+) concentration ([Ca(2+)](i)) in normal and failing ventricular myocytes. Chronic heart failure was produced in 10 dogs by multiple sequential coronary artery microembolizations; 6 normal dogs served as a control. I(NaL) fine structure was measured by whole cell patch clamp in ventricular myocytes and approximated by a sum of fast and slow exponentials produced by burst and late scattered modes of Na(+) channel gating, respectively. I(NaL) greatly enhanced as [Ca(2+)](i) increased from "Ca(2+) free" to 1 microM: its maximum density increased, decay of both exponentials slowed, and the steady-state inactivation (SSI) curve shifted toward more positive potentials. Testing the inhibition of CaMKII and CaM revealed similarities and differences of I(NaL) modulation in failing vs. normal myocytes. Similarities include the following: 1) CaMKII slows I(NaL) decay and decreases the amplitude of fast exponentials, and 2) Ca(2+) shifts SSI rightward. Differences include the following: 1) slowing of I(NaL) by CaMKII is greater, 2) CaM shifts SSI leftward, and 3) Ca(2+) increases the amplitude of slow exponentials. We conclude that Ca(2+)/CaM/CaMKII signaling increases I(NaL) and Na(+) influx in both normal and failing myocytes by slowing inactivation kinetics and shifting SSI. This Na(+) influx provides a novel Ca(2+) positive feedback mechanism (via Na(+)/Ca(2+) exchanger), enhancing contractions at higher beating rates but worsening cardiomyocyte contractile and electrical performance in conditions of poor Ca(2+) handling in heart failure.

Targeting Myocardial β-Adrenergic Receptor Signaling and Calcium Cycling for Heart Failure Gene Therapy

Heart failure (HF) is a leading cause of morbidity and mortality in Western countries and projections reveal that HF incidence in the coming years will rise significantly because of an aging population. Pharmacologic therapy has considerably improved HF treatment during the last 2 decades, but fails to rescue failing myocardium and to increase global cardiac function. Therefore, novel therapeutic approaches to target the underlying molecular defects of ventricular dysfunction and to increase the outcome of patients in HF are needed. Failing myocardium generally exhibits distinct changes in beta-adrenergic receptor (betaAR) signaling and intracellular Ca2+-handling providing opportunities for research. Recent advances in transgenic and gene therapy techniques have presented novel therapeutic strategies to alter myocardial function and to target both betaAR signaling and Ca2+-cycling. In this review, we will discuss functional alterations of the betaAR system and Ca2+-handling in HF as well as corresponding therapeutic strategies. We will then focus on recent in vivo gene therapy strategies using the targeted inhibition of the betaAR kinase (betaARK1 or GRK2) and the restoration of S100A1 protein expression to support the injured heart and to reverse or prevent HF.

Cellular and molecular determinants of altered Ca2+handling in the failing rabbit heart: primary defects in SR Ca2+uptake and release mechanisms

Myocytes from the failing myocardium exhibit depressed and prolonged intracellular Ca(2+) concentration ([Ca(2+)](i)) transients that are, in part, responsible for contractile dysfunction and unstable repolarization. To better understand the molecular basis of the aberrant Ca(2+) handling in heart failure (HF), we studied the rabbit pacing tachycardia HF model. Induction of HF was associated with action potential (AP) duration prolongation that was especially pronounced at low stimulation frequencies. L-type calcium channel current (I(Ca,L)) density (-0.964 +/- 0.172 vs. -0.745 +/- 0.128 pA/pF at +10 mV) and Na(+)/Ca(2+) exchanger (NCX) currents (2.1 +/- 0.8 vs. 2.3 +/- 0.8 pA/pF at +30 mV) were not different in myocytes from control and failing hearts. The amplitude of peak [Ca(2+)](i) was depressed (at +10 mV, 0.72 +/- 0.07 and 0.56 +/- 0.04 microM in normal and failing hearts, respectively; P < 0.05), with slowed rates of decay and reduced Ca(2+) spark amplitudes (P < 0.0001) in myocytes isolated from failing vs. control hearts. Inhibition of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a revealed a greater reliance on NCX to remove cytosolic Ca(2+) in myocytes isolated from failing vs. control hearts (P < 0.05). mRNA levels of the alpha(1C)-subunit, ryanodine receptor (RyR), and NCX were unchanged from controls, while SERCA2a and phospholamban (PLB) were significantly downregulated in failing vs. control hearts (P < 0.05). alpha(1C) protein levels were unchanged, RyR, SERCA2a, and PLB were significantly downregulated (P < 0.05), while NCX protein was significantly upregulated (P < 0.05). These results support a prominent role for the sarcoplasmic reticulum (SR) in the pathogenesis of HF, in which abnormal SR Ca(2+) uptake and release synergistically contribute to the depressed [Ca(2+)](i) and the altered AP profile phenotype.