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Activation of cardiorenal and pulmonary tissue endothelin-1 in experimental heart failure. Am J Physiol Regulatory Integrative Comp Physiol 279: R974-R979, 2000.--Endothelin-1 (ET-l) is a peptide that has been implicated in congestive heart failure (CHF). Although increased concentrations of circulating ET-1 have been repeatedly demonstrated, the activation of local ET-1 in target tissues of CHF remains poorly defined. Our objective was to characterize ET-1 tissue concentrations and gene expression of prepro ET-1 in myocardial, renal, and pulmonary tissue in rapid ventricular pacing-induced canine CHF. Progressive rapid ventricular pacing (38 days) resulted in impaired cardiovascular hemodynamics, increased atrial and left ventricular mass, decreased renal sodium excretion, and increased ET-1 plasma concentrations (all P [is less than] 0.05). Tissue analysis revealed significant increases in local ET-1 during CHF in left ventricular, renal, and pulmonary tissue, whereas a moderate increase in left atrial ET-1 did not reach statistical significance. In contrast, prepro-ET-1 gene expression was increased more than threefold in pulmonary tissue and more than twofold in left atrial myocardium with no increase in left ventricular or renal gene expression. The present studies demonstrate a differential pattern of ET-1 activation in cardiorenal and pulmonary tissue with a strong accumulation of ET-1 in kidney and lung during CHF. Although the observed increase in left ventricular and renal ET-1 in association with unaltered gene expression is consistent with increased uptake, pulmonary and atrial tissue may contribute to increased circulating and local ET-1 in CHF. dog; pacing; gene

We have recently described a modified model of progressive rapid ventricular pacing-induced heart failure which evolves over a period of 38 days. To further characterize left ventricular remodeling during the progression of heart failure, we assessed left ventricular geometry, wall stress, and atrial natriuretic peptide (ANP) gene expression and protein content during control conditions, asymptomatic left ventricular dysfunction, and overt congestive heart failure (CHF). Although asymptomatic left ventricular dysfunction was characterized by a significant increase in systolic and diastolic left ventricular dimension (+30% and +6%, respectively, P<0.05 each) and a marked increase in left ventricular systolic wall stress (+68%, P<0.01), left ventricular ANP gene expression was unchanged as compared to control. In contrast, strong left ventricular ANP gene expression (+449%, P<0.05) was observed during overt CHF in the absence of further significant increases in left ventricular systolic wall stress. The onset of strong left ventricular ANP gene expression was associated with increased ANP content (+88%, P<0.05) and left ventricular mass index (+13%, P<0.05). In contrast, left atrial ANP gene expression and left ventricular diastolic wall stress increased progressively during asymptomatic left ventricular dysfunction (+39%, P=n.s. and +131%, P<0.01) and overt CHF (+76% and +336% vs. control, P<0.01 each). Progressive rapid ventricular pacing is associated with the induction of left ventricular ANP gene expression and protein synthesis exclusively during overt CHF. The current studies provide new insight into the temporal pattern of ANP-activation and the disparity between left ventricular systolic wall stress and ANP-activation in a large animal model of progressive CHF. [ABSTRACT FROM AUTHOR]

Background Congestion is a primary driver of symptoms in patients with acute heart failure (AHF), and relief of congestion is a critical goal of therapy. Monitoring of response to therapy through the assessment of daily weights and net fluid loss is the current standard of care, yet the relationship between commonly used markers of decongestion and both patient reported symptom relief and clinical outcomes are unknown. Methods and Results We performed a retrospective analysis of the randomized clinical trial -Diuretic Optimization Strategy Evaluation in Acute Heart Failure (DOSE-AHF), enrolling patients hospitalized with a diagnosis of acute decompensated heart failure (ADHF). We assessed the relationship between 3 markers of decongestion at 72 hours—weight loss, net fluid loss and % reduction in serum NT-proBNP level—and relief of symptoms as defined by the dyspnea visual analog scale area under the curve (VAS AUC). We also determined the relationship between each marker of decongestion and 60-day clinical outcomes defined as time to death, first re-hospitalization or ER visit. Mean age was 66 years, mean EF was 35% and 27% had EF ≥50%. Of the 3 measures of decongestion assessed, only % reduction in NT-proBNP was significantly associated with symptom relief (r=0.13, P = 0.04). There was no correlation between either weight loss or net fluid loss and symptom relief, (r=0.04, P=0.54 and r=0.07, P=0.27, respectively). Favorable changes in each of the 3 markers of decongestion were associated with improvement in time to death, re-hospitalization or ED visit at 60 days [weight: HR 0.91 (95% confidence interval 0.85, 0.97) per 4 lbs. weight lost; fluid HR 0.94 (0.90, 0.99) per 1000mL fluid loss; NT-proBNP HR 0.95 (0.91, 0.99) per 10% reduction]. These associations were unchanged after multivariable adjustment with the exception that % reduction in NT-proBNP was no longer a significant predictor (HR 0.97; 0.93, 1.02). Patients with 2 or 3 markers of decongestion (above the median value for each marker) had improved clinical outcomes versus those with 0 or 1 marker above the median value (39.0% versus 53.8%; P=0.03). Conclusions Weight loss, fluid loss and NT-proBNP reduction at 72 hours are poorly correlated with dyspnea relief. However, favorable improvements in each of the 3 markers were associated with improved clinical outcomes at 60 days. These data suggest the need for ongoing research to understand the relationships between symptom relief, congestion, and outcomes in patients with ADHF.

Deals with the echocardiographic and pathologic features of patients with valvular disease associated with long-term ingestion of ergot alkaloids. Patients; Disease management; Diagnosis; Conclusion.

The article presents a study that examines the usefulness of mild, moderate, or severe diastolic dysfunction in predicting all causes of mortality. It describes the method of the study that observes 2042 patients who participated in the Rochester Epidemiology Project in Olmsted County, Minnesota. It notes the result of the study which indicates that mild, moderate, or severe can increase all causes of mortality.

BACKGROUND The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [Cl], 0.75 to 1.01; P=0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% Cl, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% Cl, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% Cl, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% Cl, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% Cl, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. [ABSTRACT FROM AUTHOR]

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (tau), and the first derivatives of LV pressure rise and fall (dP/dt(max) and dP/dt(min), respectively). During echocardiography, HR was lower in XK than AV mice (250 +/- 14 beats/min in XK vs. 453 +/- 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 +/- 0.08 mm in XK vs. 3.8 +/- 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 +/- 1.2% in XK vs. 40 +/- 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 +/- 24 beats/min) and XK (342 +/- 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 +/- 5 vs. 6.2 +/- 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/dt(max): 4,402 +/- 798 vs. 8,250 +/- 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (tau: 23 +/- 2 vs. 14 +/- 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.

Objectives: To determine levels of natriuretic peptides (NPs) in patients with end-stage renal disease (ESRD) and to examine the relationship of these cardiovascular peptides to left ventricular hypertrophy (LVH) and to cardiac mortality., Patients and Methods: One hundred twelve dialysis patients without clinical evidence of congestive heart failure underwent plasma measurement of NP concentrations and echocardiographic investigation for left ventricular mass index (LVMI)., Results: Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations correlated positively with LVMI and inversely with left ventricular ejection fraction, whereas C-type NP and Dendroaspis NP levels did not correlate with LVMI. In dialysis patients with LVH (LVMI >125 g/m2), plasma ANP and BNP concentrations were increased compared with those in dialysis patients without LVH (both P<001). In a subset of 15 dialysis patients without LVH or other concomitant diseases, plasma BNP concentrations were not significantly increased compared with those in 35 controls (mean +/- SD, 20.1+/-13.4 vs 13.5+/-9.6 pg/mL; P=.06), demonstrating that the BNP concentration was not increased by renal dysfunction alone. Furthermore, the BNP level was significantly higher in the 16 patients who died from cardiovascular causes compared with survivors (mean +/- SD, 129+/-13 vs 57+/-7 pg/mL; P<.003) and was significantly associated with greater risk of cardiovascular death in Cox regression analysis (P<.001), as was the ANP level (P=.002)., Conclusions: Elevation of the plasma BNP concentration is more specifically related to LVH compared with the other NP levels in patients with ESRD independent of congestive heart failure. Thus, BNP serves as an important plasma biomarker for ventricular hypertrophy in dialysis patients with ESRD.

Three well-controlled epidemiology studies in the U.S. have reported that 40% of incident congestive heart failure (CHF) cases and 50% to 60% of prevalent CHF cases occur in the setting of preserved systolic function. This condition has been termed "diastolic heart failure" (DHF). Despite minor differences in the types of populations examined, these community-based studies have established DHF as a major health problem in the U.S., particularly among the elderly. Although extensive data are available concerning the natural history of CHF associated with reduced systolic dysfunction (systolic heart failure; SHF), the natural history of DHF is not well-characterized. Indeed, it remains unclear whether patients with DHF share the grim prognosis described for patients with SHF. In this review we examine the available studies comparing survival observed in patients with DHF to that observed in patients with SHF. Although there are insufficient data at present to make definitive conclusions, careful examination of the available studies raises the possibility that the natural history of patients with DHF may not be different from that observed in patients with CHF and reduced systolic function.

Approximately 50% of patients with a firm clinical diagnosis of heart failure (HF) have a normal ejection fraction. Some patients have valvular disease, but most have underlying diastolic dysfunction that leads to pulmonary and systemic congestion and signs and symptoms of HF. Although diastolic HF is clinically and radiographically indistinguishable from HF with depressed left systolic ventricular function, knowledge of which patients are at risk of diastolic HF, the common clinical profiles, and the common echocardiographic findings enhances the clinician's ability to diagnose diastolic HF with confidence. The prognostic implications of a diagnosis of diastolic HF and the therapeutic approach to such patients are reviewed.

beta-Adrenergic hyporesponsiveness in congestive heart failure (CHF) is mediated, in part, by nitric oxide (NO). NO and brain natriuretic peptide (BNP) share cGMP as a second messenger. Left ventricular (LV) function and inotropic response to intravenous dobutamine (Dob) were assessed during sequential intracoronary infusion of saline, HS-142-1 (a BNP receptor antagonist), and HS-142-1 + N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs with CHF due to rapid pacing and in normal dogs during intracoronary infusion of saline, exogenous BNP, and sodium nitroprusside (SNP). In CHF dogs, intracoronary HS-142-1 did not alter the inotropic response to Dob [percent change in first derivative of LV pressure (% Delta dP/dt) 47 +/- 4% saline vs. 54 +/- 7% HS-142-1, P = not significant]. Addition of intracoronary L-NMMA to HS-142-1 enhanced the response to Dob (% Delta dP/dt 73 +/- 8% L-NMMA + HS-142-1, P < 0.05 vs. H142-1). In normal dogs, intracoronary SNP blunted the inotropic response to Dob (% Delta dP/dt 93 +/- 6% saline vs. 71 +/- 5% SNP, P < 0.05), whereas intracoronary BNP had no effect. In CHF dogs, the time constant of LV pressure decay during isovolumic relaxation increased with intracoronary HS-142-1 (48 +/- 4 ms saline vs. 58 +/- 5 ms HS-142-1, P < 0.05) and further increased with intracoronary L-NMMA (56 +/- 6 ms HS-142-1 vs. 66 +/- 7 ms L-NMMA + HS-142-1, P < 0.05). Endogenous BNP and NO preserve diastolic function in CHF, whereas NO but not BNP inhibits beta-adrenergic responsiveness.

This review focuses on diastolic dysfunction with special emphasis on isolated diastolic dysfunction where impairment in diastolic function occurs in the absence of concomitant reduction in systolic function. The phenomena which influence diastolic function, the clinical spectrum of diastolic dysfunction, the physiological perturbations which may serve as therapeutic targets for pharmacological therapy and recent therapeutic trials are reviewed. Recommendations regarding the therapeutic approach to the patient with diastolic dysfunction are summarised.

Background: Cardiac dilatation is a predictor of poor outcome in patients with dilated cardiomyopathy. Whereas cardiac chamber dimensions or volumes can be assessed by various noninvasive and invasive techniques, simple chest radiography also may provide a valuable assessment of cardiac size., Methods and Results: To determine the relative power of radiographic heart measurements for predicting outcome in dilated cardiomyopathy, we retrospectively studied 88 adult patients with chest radiographs obtained within 35 days of echocardiography. Standard radiographic variables were measured for each patient, and the cardiothoracic (CT) ratio, frontal cardiac area, and volume were calculated. During a mean 4.1-year follow-up, 62 of the 88 (71%) patients died. CT ratio was the best predictor of mortality among the radiographic cardiac measurements. By multivariate analysis, a model including echocardiographic ejection fraction, New York Heart Association (NYHA) functional class, and history of heart failure was highly predictive of survival. When added to this model, CT ratio also was independently associated with mortality, but not radiographic cardiac area or volume. When radiographic variables were each added to CT ratio, they did not add incremental predictive value to the model that included CT ratio alone. Echocardiographic measurement of left ventricular (LV) size, especially when indexed for body size, was independently predictive of outcome, but it did not supersede the predictive power of CT ratio., Conclusion: The simply derived radiographic CT ratio is a useful predictor of outcome in patients with dilated cardiomyopathy and compares favorably with other clinical and selected echocardiographic variables.

Objectives: The objective of this investigation was to define for the first time the cardiorenal and humoral actions of repeated short-term administration of subcutaneous (SQ) brain natriuretic peptide (BNP) administration during the evolution of experimental heart failure., Background: The rationale of this study was based on BNP as a vasodilating, natriuretic, renin-inhibiting and lusitropic peptide of cardiac origin., Methods: First, we defined the cardiorenal and humoral responses to acute low and high dose (5 microg/kg or 25 microg/kg) of SQBNP in experimental heart failure to establish the acute efficacy of an SQ delivery. Second, we characterized the response to 10 days of repeated short-term administration of BNP during the evolution of experimental heart failure produced by rapid ventricular pacing., Results: Plasma BNP and 3',5'-cyclic guanosine monophosphate rapidly increased and peaked at 30 min after acute SQBNP administration with increases in urinary sodium excretion, urine flow and renal blood flow in association with reductions in cardiac filling pressures. After 10 days of repeated short-term administration of SQBNP, cardiac output was increased and systemic vascular resistance and pulmonary capillary wedge pressure were decreased, as compared with untreated dogs with heart failure., Conclusions: This study demonstrated for the first time that repeated short-term administration of SQ BNP administration for 10 days during the evolution of left ventricular dysfunction in a canine model results in an improvement in cardiovascular hemodynamics. This investigation supports a potential novel strategy for the chronic administration of BNP in the therapeutics of heart failure.

Background: Coenzyme Q10 (CoQ10) is essential for ATP generation and has antioxidant properties. Decreased CoQ10 levels have been reported in human heart failure (CHF), but it remains unclear if this is a conserved feature of CHF. The objective of the study was to determine if tachycardia-induced CHF in the dog is associated with reduced CoQ10 levels. Furthermore, it was hypothesized that CoQ10 supplementation may improve CHF severity by preventing CoQ10 deficiency (if present) or via antioxidant effects., Methods and Results: Serum and myocardial levels of CoQ10 were examined in normal dogs (n = 6), dogs with CHF (control, n = 5), and dogs with CHF treated with CoQ10 (CoQ10; 10 mg/kg/day, n = 5). Serum CoQ10 levels did not change with CHF in control dogs, and myocardial levels were similar to those of normal dogs. CoQ10 therapy increased serum but not myocardial levels of CoQ10. In early CHF, CoQ10-treated dogs had lower filling pressures, and, in severe CHF, CoQ10-treated dogs had less hypertrophy as compared with untreated dogs. Other indices of CHF severity were similar in control and CoQ10-treated dogs., Conclusion: These data indicate that CoQ10 deficiency is not present in this model of CHF. Although dramatic effects on hemodynamics were not observed, CoQ10 supplementation did appear to attenuate the hypertrophic response associated with CHF. Key words: enzymes, cardiomyopathy, hormones, antioxidant.

Although it is now widely recognized that isolated diastolic dysfunction can lead to the classic signs and symptoms of congestive heart failure (CHF), this disease process is poorly understood and remains of great interest and concern to cardiovascular disease specialists, as well as to primary care physicians. Recent epidemiologic data have suggested that diastolic heart failure is predominantly a disease of the elderly, the fastest growing segment of our population. Diagnosis is often difficult in this subgroup of patients due to the presence of confounding comorbidities. However, early identification in community-based practices and timely intervention is important due to the significant disability and death that results from this progressive disease process. The poor prognosis of CHF patients with systolic dysfunction is shared by those with isolated diastolic heart failure and preserved systolic function. Further studies of the prevalence, clinical characteristics, and natural history of patients with diastolic dysfunction are needed. This review focuses on the emerging data regarding the prevalence and natural history of diastolic heart failure in the community.

Myocardial actions of the vasodilator peptide adrenomedullin (ADM) in the intact animal are unknown. Negative and positive inotropic actions have been reported in ex vivo experiments. Myocardial and load-altering actions of ADM in dogs before and after development of heart failure were studied. With controlled heart rate (atrial pacing) and after beta-blockade, ADM was administered to five normal dogs in doses of 20 ng. kg(-1). min(-1) iv, 100 ng. kg(-1). min(-1) iv, and 200 ng. kg(-1). min(-1) into the left ventricle (LV). LV peak systolic pressure and end-systolic volume decreased with each dose of ADM. End-systolic pressure decreased with the two higher doses. At the highest dose, arterial elastance and the time constant of LV isovolumic relaxation (tau) decreased, and LV end-systolic elastance (E(es)) increased. LV end-diastolic pressure and volume were unchanged. In five additional normal dogs receiving only the highest dose of ADM (200 ng. kg(-1). min(-1) intra-LV), to control for increased heart rate and sympathetic activation observed with the cumulative infusion, ADM produced arterial vasodilation but no change in E(es) or tau. In four dogs with pacing-induced heart failure, ADM (200 ng. kg(-1). min(-1) intra-LV) was without effect on tau, E(es), and systolic or diastolic pressure and volume. In vivo, ADM appears to be a selective arterial dilator without inotropic or lusitropic effects. The vasodilatory actions are attenuated in heart failure.

Background: This study was designed to assess the use of clinical criteria and biochemical testing to detect systolic dysfunction. Our goal is to develop strategies that may enhance the detection and treatment of patients with early ventricular dysfunction while reducing the use of echocardiography., Methods and Results: We compared the predictive characteristics of the plasma brain natriuretic peptide (BNP) concentration with that of a 5-point clinical score derived from elements of the history, electrocardiogram, and chest radiograph in outpatients (n = 466) referred for echocardiography because of symptoms of heart failure or risk factors for systolic dysfunction. Systolic dysfunction was defined as an ejection fraction (EF) less than 45% and was present in 10.9% of patients. By receiver operating characteristic analysis, BNP was sensitive and specific for the detection of systolic dysfunction, with an area under the receiver operating characteristic curve for the detection of EF less than 45% of 0.79. The BNP assay was abnormal in 41% of patients and identified a group with a high prevalence of systolic dysfunction (21% with an EF less than 45%), whereas a normal BNP value identified a group with a low prevalence of systolic dysfunction (4% with an EF less than 45%). The clinical score was positive in 43% of the population and identified a group with a high prevalence of systolic dysfunction (24% with an EF less than 45%). A normal score identified a group with a low prevalence of systolic dysfunction (1% with an EF less than 45%)., Conclusion: This study supports previous studies, which showed that BNP assay predicts systolic dysfunction with acceptable sensitivity and specificity, and it underscores the effectiveness of additional readily available clinical criteria. Both of these strategies should be considered in screening for left ventricular dysfunction in populations at risk while limiting expensive cardiac imaging modalities.

Objective: To determine the frequency of tachycardia-related cardiomyopathy in patients with atrial fibrillation and systolic dysfunction referred for atrioventricular node ablation., Patients and Methods: This prospective multicenter cohort study was conducted at 16 tertiary care centers. The ejection fraction was measured before and 3 and 12 months after atrioventricular node ablation. Patients with reduced systolic function (ejection fraction < or = 45%) before atrioventricular ablation were included in this study. Patients whose ejection fraction increased by at least 15 percentage points and to higher than 45% were considered to have tachycardia-related cardiomyopathy., Results: Of 63 patients with systolic dysfunction, 48 had at least 1 adequate follow-up echocardiographic study. Sixteen (25%) of the 63 had marked improvement in the ejection fraction (mean +/- SD change, 27 +/- 8 percentage points) to a value higher than 45% after ablation., Conclusions: Tachycardia-related cardiomyopathy is common in patients with atrial fibrillation and systolic dysfunction referred for atrioventricular node ablation. This diagnosis should be considered in all patients in whom systolic dysfunction occurs subsequent to or concomitant with onset of atrial fibrillation.

The perpetual and vigorous nature of heart muscle work requires efficient myocardial energetics. This depends not only on adequate ATP production, but also on efficient delivery of ATP to muscle ATPases and rapid removal of ADP and other by-products of ATP hydrolysis. Indeed, recent evidence indicates that defects in communication between ATP-producing and ATP-consuming cellular sites are a major factor contributing to energetic deficiency in heart failure. In particular, the failing myocardium is characterized by reduced catalytic activity of creatine kinase, adenylate kinase, carbonic anhydrase, and glycolytic enzymes, which collectively facilitate ATP delivery and promote removal of ADP, Pi, and H+ from cellular ATPases. Although energy transfer through adenylate kinase and glycolytic enzymes has been recognized as an adaptive mechanism supporting compromised muscle energetics, in the failing myocardium the total compensatory potential of these systems is diminished. A gradual accumulation of defects at various steps in myocardial energetic signaling, along with compromised compensatory mechanisms, precipitates failure of the whole cardiac energetic system, ultimately contributing to myocardial dysfunction. These advances in our understanding of the molecular bioenergetics in heart failure provide a new perspective toward improving the energetic balance of the failing myocardium.