Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase.

To determine how signals emanating from Trk transmit neurotrophin actions in primary neurons, we tested the ability of TrkB mutated at defined effector binding sites to promote sympathetic neuron survival or local axon growth. TrkB stimulated signaling proteins and induced survival and growth in a manner similar to TrkA. TrkB mutated at the Shc binding site supported survival and growth poorly relative to wild-type TrkB, whereas TrkB mutated at the PLC-gamma1 binding site supported growth and survival well. TrkB-mediated neuronal survival was dependent on P13-kinase and to a lesser extent MEK activity, while growth depended upon both MEK and P13-kinase activities. These results indicate that the TrkB-Shc site mediates both neuronal survival and axonal outgrowth by activating the P13-kinase and MEK signaling pathways.

Energetics of acute pressure overload of the porcine right ventricle. In vivo 31P nuclear magnetic resonance.

In vivo 31P nuclear magnetic resonance (NMR) spectroscopy of the right ventricular (RV) free wall was employed to determine (a) whether phosphorus energy metabolites vary reciprocally with workload in the RV and (b) the mechanisms that limit RV contractile function in acute pressure overload. In 20 open-chest pigs, phosphocreatine (PCr)/ATP ratio (an index of energy metabolism inversely related to free ADP concentration), myocardial blood flow (microspheres), and segment shortening (sonomicrometry, n = 14) were measured at control (RV systolic pressure 31 +/- 1 mm Hg), and with pulmonary artery constriction to produce moderate pressure overload (RV systolic pressure 45 +/- 1 mm Hg), and maximal pressure overload before overt RV failure and systemic hypotension (RV systolic pressure 60 +/- 1 mm Hg). With moderate pressure overload, PCr/ATP declined to 89% of control (P = 0.01), while contractile function increased. Adenosine (n = 10, mean dose 0.16 mg/kg-min) increased RV blood flow by an additional 41% without increasing PCr/ATP, indicating that coronary reserve was not depleted and that the decrease in PCr/ATP from control was not due to ischemia. With maximal pressure overload and incipient RV failure, PCr/ATP fell further to 81% of control and RV blood flow did not increase further, even with adenosine. Thus: (a) The decline in PCr/ATP with moderate RV pressure overload, without evident ischemia or contractile dysfunction, supports the positive regulation of oxidative phosphorylation by ATP hydrolysis products. (b) Depletion of RV coronary flow reserve accompanies the onset of RV failure at maximal pressure overload.

Cardiac contractile dysfunction during mild coronary flow reductions is due to an altered calcium-pressure relationship in rat hearts.

Coronary artery stenosis or occlusion results in reduced coronary flow and myocardial contractile depression. At severe flow reductions, increased inorganic phosphate (Pi) and intracellular acidosis clearly play a role in contractile depression. However, during milder flow reductions the mechanism(s) underlying contractile depression are less clear. Previous perfused heart studies demonstrated no change of Pi or pH during mild flow reductions, suggesting that changes of intravascular pressure (garden hose effect) may be the mediator of this contractile depression. Others have reported conflicting results regarding another possible mediator of contractility, the cytosolic free calcium (Cai). To examine the respective roles of Cai, Pi, pH, and vascular pressure in regulating contractility during mild flow reductions, Indo-1 calcium fluorescence and 31P magnetic resonance spectroscopy measurements were performed on Langendorff-perfused rat hearts. Cai and diastolic calcium levels did not change during flow reductions to 50% of control. Pi demonstrated a close relationship with developed pressure and significantly increased from 2.5 +/- 0.3 to 4.2 +/- 0.4 mumol/g dry weight during a 25% flow reduction. pH was unchanged until a 50% flow reduction. Increasing vascular pressure to superphysiological levels resulted in further increases of developed pressure, with no change in Cai. These findings are consistent with the hypothesis that during mild coronary flow reductions, contractile depression is mediated by an altered relationship between Cai and pressure, rather than by decreased Cai. Furthermore, increased Pi and decreased intravascular pressure may be responsible for this altered calcium-pressure relationship during mild coronary flow reductions.

Relationship between myocardial metabolites and contractile abnormalities during graded regional ischemia. Phosphorus-31 nuclear magnetic resonance studies of porcine myocardium in vivo.

The mechanisms responsible for changes in myocardial contractility during regional ischemia are unknown. Since changes in high-energy phosphates during ischemia are sensitive to reductions in myocardial blood flow, it was hypothesized that myocardial function under steady-state conditions of graded regional ischemia is closely related to changes in myocardial high-energy phosphates. Therefore, phosphorus-31 nuclear magnetic resonance spectroscopy was employed in an in vivo porcine model of graded coronary stenosis. Simultaneous measurements of regional subendocardial blood flow, high-energy phosphates, pH, and myocardial segment shortening were made during various degrees of regional ischemia in which subendocardial blood flow was reduced by 16-94%. During mild reductions in myocardial blood flow (subendocardial blood flow = 83% of nonischemic myocardium), only the ratio of phosphocreatine to inorganic phosphate (PCr/Pi), Pi, and [H+] were significantly changed from control. PCr, ATP, and PCr/ATP were not significantly reduced from control with mild reductions in blood flow. Changes in myocardial segment shortening were most closely associated with changes in PCr/Pi (r = 0.94). Pi and [H+] were negatively correlated with segment shortening (r = -0.64 and -0.58, respectively) and increased over twofold when blood flow was reduced by 62%. Thus, these data demonstrate that PCr/Pi is sensitive to reductions in myocardial blood flow and closely correlates with changes in myocardial function. These data are also consistent with a role for Pi or H+ as inhibitors of myocardial contractility during ischemia.

Impaired skeletal muscle function in patients with congestive heart failure. Relationship to systemic exercise performance.

In patients with congestive heart failure (CHF), the poor relationship between systemic exercise performance and cardiac function, together with morphologic and metabolic abnormalities in skeletal muscle, raises the possibility that skeletal muscle function may be impaired and limit systemic exercise performance. We assessed strength and endurance of the knee extensors during static and dynamic exercise in 16 patients with Class I-IV CHF and eight age-matched sedentary controls and related these measurements to systemic exercise performance. To assess skeletal muscle function independent of peripheral blood flow, endurance was repeated under ischemic conditions. Strength was not significantly different in the two groups. Dynamic endurance, quantified as the decline in peak torque during 15 successive isokinetic knee extensions, was significantly reduced in the patients compared to controls during aerobic (peak torque 65 vs. 86% of initial for exercise at 90 deg/s and 60 vs. 85% for exercise at 180 deg/s; P less than 0.002 for both), and during ischemic exercise (56 vs. 76% of initial torque; P less than 0.01). Static endurance, defined as the time required for force during a sustained maximal voluntary contraction to decline to 60% of maximal, was reduced in the patients compared to controls (40 +/- 14 vs. 77 +/- 29 s; P less than 0.02). There were highly significant relationships between systemic exercise performance and skeletal muscle endurance at 90 and 180 deg/s in the patients with CHF (r = 0.90 and 0.66, respectively). These findings indicate that skeletal muscle endurance is impaired in patients with CHF, that this abnormality is in part independent of limb blood flow, and that these changes may be important determinants of systemic exercise performance.

Skeletal muscle response to exercise training in congestive heart failure.

To examine the ability of the skeletal muscle of congestive heart failure (CHF) patients to adapt to chronic exercise, five patients performed localized nondominant wrist flexor training for 28 d. Inorganic phosphate (Pi) and phosphocreatine (PCr) were monitored by magnetic resonance spectroscopy in both forearms at rest and during submaximal wrist flexion exercise at 6, 12, 24, and 36 J.min-1 before and after exercise training. Simultaneous measurements of limb blood flow were made by plethysmography at 12, 24, and 36 J.min-1. Forearm muscle mass and endurance were measured by magnetic resonance imaging and wrist flexion exercise before and after training. The Pi/PCr ratio and pH were calculated from the measured Pi and PCr. Exercise cardiac output, heart rate, plasma norepinephrine, and lactate measured during training were not elevated above resting values, confirming that training was localized to the forearm flexor muscles. After training, muscle bioenergetics, as assessed by the slope of the regression line relating Pi/PCr to submaximal workloads, were improved in the trained forearm of each patient, although muscle mass, limb blood flow, and pH were unchanged. Forearm endurance increased by greater than 260% after training. In the dominant untrained forearm, none of the measured indices were affected. We conclude that localized forearm exercise training in CHF patients improves muscle energetics at submaximal workloads in the trained muscle, an effect which is independent of muscle mass, limb blood flow, or a central cardiovascular response during training. These findings indicate that peripheral muscle metabolic and functional abnormalities in CHF can be improved without altering cardiac performance.

Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy.

A promising approach for cancer gene therapy is the combination of adenovirus vectors (AdV) with the suicide gene cytosine deaminase and uracil phosphoribosyl transferase (CDColon, two colonsUPRT). While such vectors have been tested in tumor cell lines and xenograft models, it is not clear how these therapeutic vectors would perform in primary human tumors. We, thus, examined the effect of the combination of a recombinant adenovirus expressing the CDColon, two colonsUPRT (AdCU) with 5-fluorocytosine (5-FC) on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers. In such models, we have found a direct correlation between the patients' response to 5-FU and the response shown by the cancer cells in vitro, confirming the clinical relevance of this methodology. Our findings demonstrated that this combination was able to kill primary tumor cells, including those that had developed resistance to 5-FU. Furthermore, while proliferating cells were more susceptible to 5-FU, the combination was effective in both rapid and slow proliferating samples. Our study demonstrated that this gene therapy approach could provide an effective therapeutic option for cancers and is not affected by acquired 5-FU resistance. Also of importance is the effectiveness of this gene therapy approach on slower proliferating cells that is typical of the majority of cancers in vivo. This suggests a greater likelihood that it will be effective in a clinical setting.

Construction of a helper-free recombinant adenovirus that expresses polyomavirus large T antigen.

Adenovirus-polyomavirus recombinant viruses were constructed in vitro by inserting a hybrid transcription unit composed of the adenovirus type 2 major late promoter and the early coding region of polyomavirus into the adenovirus type 5 vector Ad5 delta E1/dl309. The vector lacks the E1a and E1b transcription units and contains a unique restriction endonuclease cleavage site in their place. The polyomavirus genomic insert contained a small deletion which precluded the synthesis of functional small and middle T antigen but allowed for the synthesis of large T antigen. One recombinant virus, Ad5PyR39, which contained the hybrid transcription unit in the opposite transcriptional orientation from the overall direction of late-gene transcription, was studied in detail. Ad5PyR39 replicated efficiently without a helper virus in human 293 cells and expressed hybrid mRNAs of the expected size and composition that were translated to yield large T antigen. The large T antigen synthesized in 293 cells was the same size as that produced in mouse 3T6 cells lytically infected with polyomavirus, and this protein bound efficiently and specifically to the large-T-antigen-binding sites in polyomavirus DNA. Moreover, the large T antigen encoded by the recombinant virus proved capable of catalyzing the replication in mouse 3T6 cells of a plasmid containing the polyomavirus origin for DNA replication. Comparison of the amount of large T antigen produced in 3T6 cells infected with polyomavirus with that in 293 cells infected with Ad5PyR39, under optimal conditions for each system, revealed at least a fivefold greater yield of the protein on a per cell basis in the latter system compared with the former. Ad5PyR39 should prove to be useful to isolate large quantities of functional polyomavirus large T antigen for structural and biochemical studies.

The DNA-binding activity of the human heat shock transcription factor is regulated in vivo by hsp70.

The human heat shock transcription factor (HSF) is maintained in an inactive non-DNA-binding form under nonstress conditions and acquires the ability to bind specifically to the heat shock promoter element in response to elevated temperatures or other conditions that disrupt protein structure. Here we show that constitutive overexpression of the major inducible heat shock protein, hsp70, in transfected human cells reduces the extent of HSF activation after a heat stress. HSF activation was inhibited more strongly in clones that express higher levels of hsp70. These results demonstrate that HSF activity is negatively regulated in vivo by hsp70 and suggest that the cell might sense elevated temperature as a decreased availability of hsp70. HSF activation in response to treatment with sodium arsenite or the proline analog azetidine was also depressed in hsp70-expressing cells relative to that in the nontransfected control cells. As well, the level of activated HSF decreased more rapidly in the hsp70-expressing clones when the cells were heat shocked and returned to 37 degrees C. These results suggest that hsp70 could play an active role in the conversion of HSF back to a conformation that does not bind the heat shock promoter element during the attenuation of the heat shock response.

Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis.

Resistance to stress-induced apoptosis was examined in cells in which the expression of hsp70 was either constitutively elevated or inducible by a tetracycline-regulated transactivator. Heat-induced apoptosis was blocked in hsp70-expressing cells, and this was associated with reduced cleavage of the common death substrate protein poly(ADP-ribose) polymerase (PARP). Heat-induced cell death was correlated with the activation of the stress-activated protein kinase SAPK/JNK (c-Jun N-terminal kinase). Activation of SAPK/JNK was strongly inhibited in cells in which hsp70 was induced to a high level, indicating that hsp70 is able to block apoptosis by inhibiting signaling events upstream of SAPK/JNK activation. In contrast, SAPK/JNK activation was not inhibited by heat shock in cells with constitutively elevated levels of hsp70. Cells that constitutively overexpress hsp70 resist apoptosis induced by ceramide, a lipid signaling molecule that is generated by apoptosis-inducing treatments and is linked to SAPK/JNK activation. Similar to heat stress, resistance to ceramide-induced apoptosis occurs in spite of strong SAPK/JNK activation. Therefore, hsp70 is also able to inhibit apoptosis at some point downstream of SAPK/JNK activation. Since PARP cleavage is prevented in both cell lines, these results suggest that hsp70 is able to prevent the effector steps of apoptotic cell death. Processing of the CED-3-related protease caspase-3 (CPP32/Yama/apopain) is inhibited in hsp70-expressing cells; however, the activity of the mature enzyme is not affected by hsp70 in vitro. Caspase processing may represent a critical heat-sensitive target leading to cell death that is inhibited by the chaperoning function of hsp70. The inhibition of SAPK/JNK signaling and apoptotic protease effector steps by hsp70 likely contributes to the resistance to stress-induced apoptosis seen in transiently induced thermotolerance.

The chaperone function of hsp70 is required for protection against stress-induced apoptosis.

Cellular stress can trigger a process of self-destruction known as apoptosis. Cells can also respond to stress by adaptive changes that increase their ability to tolerate normally lethal conditions. Expression of the major heat-inducible protein hsp70 protects cells from heat-induced apoptosis. hsp70 has been reported to act in some situations upstream or downstream of caspase activation, and its protective effects have been said to be either dependent on or independent of its ability to inhibit JNK activation. Purified hsp70 has been shown to block procaspase processing in vitro but is unable to inhibit the activity of active caspase 3. Since some aspects of hsp70 function can occur in the absence of its chaperone activity, we examined whether hsp70 lacking its ATPase domain or the C-terminal EEVD sequence that is essential for peptide binding was required for the prevention of apoptosis. We generated stable cell lines with tetracycline-regulated expression of hsp70, hsc70, and chaperone-defective hsp70 mutants lacking the ATPase domain or the C-terminal EEVD sequence or containing AAAA in place of EEVD. Overexpression of hsp70 or hsc70 protected cells from heat shock-induced cell death by preventing the processing of procaspases 9 and 3. This required the chaperone function of hsp70 since hsp70 mutant proteins did not prevent procaspase processing or provide protection from apoptosis. JNK activation was inhibited by both hsp70 and hsc70 and by each of the hsp70 domain mutant proteins. The chaperoning activity of hsp70 is therefore not required for inhibition of JNK activation, and JNK inhibition was not sufficient for the prevention of apoptosis. Release of cytochrome c from mitochondria was inhibited in cells expressing full-length hsp70 but not in cells expressing the protein with ATPase deleted. Together with the recently identified ability of hsp70 to inhibit cytochrome c-mediated procaspase 9 processing in vitro, these data demonstrate that hsp70 can affect the apoptotic pathway at the levels of both cytochrome c release and initiator caspase activation and that the chaperone function of hsp70 is required for these effects.

Hsp72-mediated suppression of c-Jun N-terminal kinase is implicated in development of tolerance to caspase-independent cell death.

Pretreatment with mild heat shock is known to protect cells from severe stress (acquired thermotolerance). Here we addressed the mechanism of this phenomenon by using primary human fibroblasts. Severe heat shock (45 degrees C, 75 min) of the fibroblasts caused cell death displaying morphological characteristics of apoptosis; however, it was caspase independent. This cell death process was accompanied by strong activation of Akt, extracellular signal-regulated kinase 1 (ERK1) and ERK2, p38, and c-Jun N-terminal (JNK) kinases. Suppression of Akt or ERK1 and -2 kinases increased cell thermosensitivity. In contrast, suppression of stress kinase JNK rendered cells thermoresistant. Development of thermotolerance was not associated with Akt or ERK1 and -2 regulation, and inhibition of these kinases did not reduce acquired thermotolerance. On the other hand, acquired tolerance to severe heat shock was associated with downregulation of JNK. Using an antisense-RNA approach, we found that accumulation of the heat shock protein Hsp72 is necessary for JNK downregulation and is critical for thermotolerance. The capability of naive cells to withstand moderate heat treatment also appears to be dependent on the accumulation of Hsp72 induced by this stress. Indeed, exposure to 45 degrees C for 45 min caused only transient JNK activation and was nonlethal, while prevention of Hsp72 accumulation prolonged JNK activation and led to massive cell death. We also found that JNK activation by UV irradiation, interleukin-1, or tumor necrosis factor was suppressed in thermotolerant cells and that Hsp72 accumulation was responsible for this effect. Hsp72-mediated suppression of JNK is therefore critical for acquired thermotolerance and may play a role in tolerance to other stresses.

Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial.

BACKGROUND: Sudden unexpected death frequently occurs in chronic heart failure. The importance of acute coronary events in triggering sudden death (SD) is unclear. METHODS AND RESULTS: We evaluated at autopsy the prevalence of acute coronary findings (coronary thrombus, ruptured plaque, or myocardial infarction [MI]) and their relation to SD. Autopsy results in 171 patients in the randomized ATLAS trial were reviewed. The prevalence of acute coronary findings was 33%: in 54% of patients with significant coronary artery disease (CAD) who died suddenly, 32% who died of myocardial failure, but in non-CAD patients, they were present in only 5% and 10% respectively. The percentage of patients classified as dying of MI was 28% in the autopsy group versus 4% in the nonautopsied group (P<0.0001). Of the autopsied group with acute MI, 97% (31 of 32 patients) with SD and 40% (6 of 15 patients) with myocardial failure did not have the MI diagnosed during life. When undiagnosed MI was classified as "sudden unexpected" or "myocardial failure" from clinical information only, the distribution of death causes was similar in the autopsy and nonautopsied groups. CONCLUSIONS: Acute coronary findings are frequent and usually not clinically diagnosed in heart failure patients with CAD, particularly in those dying suddenly, suggesting the importance of acute coronary events as a trigger for SD in this setting.

Exercise intolerance in chronic heart failure is not associated with impaired recovery of muscle function or submaximal exercise performance.

OBJECTIVES: This study investigated whether recovery of skeletal muscle function is impaired in patients with heart failure and whether impaired recovery is associated with abnormal submaximal systemic exercise tolerance during repeated testing. BACKGROUND: Patients with heart failure experience fatigue during daily activities. Because abnormalities of skeletal muscle play a role in their exercise intolerance, these symptoms may reflect a delay in muscle recovery and a resulting limitation in submaximal exercise tolerance. METHODS: Two protocols were used. In protocol 1, knee extensor strength and endurance, and their recovery after fatiguing exercise, were evaluated in 11 patients (mean [+/- SEM] age 62 +/- 5 years, New York Heart Association functional class 2.3 +/- 0.2, ejection fraction 24 +/- 5%) and in 10 age-matched sedentary control subjects. Protocol 2 examined the recovery of knee extensor endurance and submaximal exercise tolerance, as quantified on a self-powered treadmill, over 24 h in 18 patients (mean age 65 +/- 3 years, functional class 2.4 +/- 0.2, ejection fraction 23 +/- 3%) and in 10 control subjects. RESULTS: Peak oxygen consumption was reduced in both heart failure groups (15.4 +/- 1.4 and 15.6 +/- 1.0 ml/kg per min) compared with that in the respective control groups (23.1 +/- 2.9 and 25.6 +/- 1.0 ml/kg per min, both p < 0.05), as was muscle endurance but not muscle strength. In protocol 1, knee extensor endurance recovered more slowly in the patients than in control subjects (to 62 +/- 4% and 87 +/- 7% of the baseline value after 5 min, respectively, p < 0.05). In protocol 2, submaximal exercise tolerance was lower in the patients with heart failure than in control subjects (1,075 +/- 116 vs. 1,390 +/- 110 m), but knee extensor endurance and walking distance recovered fully by 10 and 30 min, respectively. CONCLUSIONS: Although these findings confirm earlier studies that demonstrated impaired muscle endurance in patients with heart failure, the results provide no evidence that recovery of either muscle function or submaximal exercise tolerance is delayed beyond the initial 5 to 10 min after exercise.

Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials.

OBJECTIVES: We sought to evaluate the current evidence for an effect of beta-blockade treatment on mortality in patients with congestive heart failure (CHF). BACKGROUND: Although numerous small studies have suggested a benefit with beta-blocker therapy in patients with heart failure, a clear survival benefit has not been demonstrated. A recent combined analysis of several studies with the alpha- and beta-adrenergic blocking agent carvedilol demonstrated a significant survival advantage; however, the total number of events was small. Furthermore, it is unclear if previous studies with other beta-blockers are consistent with this finding. METHODS: Randomized clinical trials of beta-blockade treatment in patients with CHF from January 1975 through February 1997 were identified using a MEDLINE search and a review of reports from scientific meetings. Studies were included if mortality was reported during 3 or more months of follow-up. RESULTS: We identified 35 reports, 17 of which met the inclusion criteria. These studies included 3,039 patients with follow-up ranging from 3 months to 2 years. Beta-blockade was associated with a trend toward mortality reduction in 13 studies. When all 17 reports were combined, beta-blockade significantly reduced all-cause mortality (random effect odds ratio [OR] 0.69, 95% confidence interval [CI] 0.54 to 0.88). A trend toward greater treatment effect was noted for nonsudden cardiac death (OR 0.58, 95% CI 0.40 to 0.83) compared with sudden cardiac death (OR 0.84, 95% CI 0.59 to 1.2). Similar reductions in mortality were observed for patients with ischemic (OR 0.69, 95% CI 0.49 to 0.98) and nonischemic cardiomyopathy (OR 0.69, 95% CI 0.47 to 0.99). The survival benefit was greater for trials of the drug carvedilol (OR 0.54, 95% CI 0.36 to 0.81) than for noncarvedilol drugs (OR 0.82, 95% CI 0.60 to 1.12); however, the difference did not reach statistical significance (p = 0.10). CONCLUSIONS: Pooled evidence suggests that beta-blockade reduces all-cause mortality in patients with CHF. Additional trials are required to determine whether carvedilol differs in its effect from other agents.

Differences between primary care physicians and cardiologists in management of congestive heart failure: relation to practice guidelines.

OBJECTIVES: This study was designed to characterize physician practices in the management of congestive heart failure (CHF) and to determine whether these practices vary by specialty and how they relate to guideline recommendations. BACKGROUND: Congestive heart failure is responsible for considerable mortality, morbidity and health care resource utilization. Although there have been important advances in the diagnostic evaluation and treatment of CHF, little information is available on physician practices in this area. METHODS: We surveyed physicians concerning their management of patients with CHF. The results were analyzed in multivariate models to determine the relation of diagnostic and treatment approaches to physician specialty, time since training, board certification and volume of patients with CHF. Surveys were sent to a sample of 2,250 family and general practitioners (FP/GPs), internists and cardiologists. Responses were examined in relation to guidelines issued by the Agency for Health Care Policy and Research that had been released 9 months previously. RESULTS: Significant differences were found between physician groups with regard to each of the major guideline recommendations. For example, routine evaluation of left ventricular function, a point of emphasis in the guideline, is performed by 87% of cardiologists, but by only 77% of internists and 63% of FP/GPs (p < 0.001 between groups). Angiotensin-converting enzyme inhibitors were used by cardiologists, internists and FP/GPs in 80%, 71% and 60% of patients with mild to moderate CHF, respectively (p < 0.001 between groups). Larger differences were reported in the prescribed dosages of these drugs and their use in patients with renal dysfunction. CONCLUSIONS: Cardiologists report practices more in conformity with published guidelines for CHF than do internists and FP/GPs. Because of the large numbers of patients with CHF and their substantial mortality, morbidity and cost of care, these differences may have a major impact on outcomes and health care costs.

Hemodynamic responses to combined therapy with captopril and hydralazine in patients with severe heart failure.

The hemodynamic benefits and safety of combined therapy with captopril and hydralazine were studied during invasive hemodynamic monitoring in 14 patients with severe heart failure. In eight patients, the individual effects of both drugs were evaluated before the administration of combined therapy, whereas hydralazine was added to maintenance captopril therapy in the other six patients. In the first group, captopril alone produced a marked decrease in pulmonary wedge pressure (28 +/- 4 to 18 +/- 5 mm Hg) and mean arterial pressure (85 +/- 20 to 69 +/- 13 mm Hg) (both p less than 0.001) without a significant increase in cardiac index. Hydralazine alone produced a marked increase in cardiac index (1.6 +/- 0.4 to 2.7 +/- 0.5 liters/min per m2) (p less than 0.001), but with a minimal decrease in pulmonary wedge pressure (28 +/- 4 to 23 +/- 4 mm Hg) (p less than 0.05) and without a significant change in mean arterial pressure. The combination of captopril and hydralazine produced an increase in cardiac index similar to that of hydralazine alone and decreases in pulmonary wedge pressure and mean arterial pressure similar to those with captopril alone. Most important, when hydralazine was added to captopril in the entire group of 14 patients, cardiac index increased markedly with little additional decrease in mean arterial pressure and no significant increase in heart rate. The one patient who experienced symptomatic hypotension with combination therapy also had dizziness with captopril alone. Seven of the nine patients maintained on long-term treatment experienced symptomatic improvement. Thus, in patients with severe chronic heart failure, the combined use of captopril and hydralazine is feasible and produces acute hemodynamic improvement superior to that from either drug alone.

Improved regional ventricular function after successful surgical revascularization.

Left ventricular segments with reversible asynergy at rest demonstrate reversible myocardial perfusion defects on exercise thallium-201 scintigrams. To determine if improved perfusion eliminates asynergy at rest, 23 patients with angina (stable in 21, unstable in 2) were studied before and after coronary artery bypass surgery. All patients underwent exercise myocardial perfusion scintigraphy, contrast ventriculography and coronary arteriography before and after surgery. Selective graft angiography was performed during the postoperative catheterization to determine graft patency. Segmental ventricular function was quantitated by a regional fraction method. The scintigrams were divided into five regions and compared with the corresponding regions of the ventriculogram. Seventy-one of a possible 142 ventricular segments exhibited exercise-induced perfusion deficits. Preoperative regional ejection fraction was normal in 42 of these segments and abnormal in 29. Postoperatively, in 19 of the abnormal segments, function improved or normalized. All these segments had improved perfusion during exercise after surgery and were supplied by a patent bypass graft. Nine of the 10 segments in which abnormal wall motion persisted postoperatively continued to have exercise-induced perfusion deficits, and 9 of the 10 segments were supplied by an occluded or stenotic graft or one with poor run off. Of the 42 segments with normal wall motion preoperatively, 30 had improved perfusion after surgery and 35 maintained normal function. This study indicates that asynergy at rest is permanently reversed after coronary bypass surgery if improved myocardial perfusion can be documented. These findings are consistent with but do not prove the concept that reversible rest asynergy may reflect chronic ischemia or a prolonged effect from previous ischemic episodes.

Relation of systemic and local muscle exercise capacity to skeletal muscle characteristics in men with congestive heart failure.

OBJECTIVES: The present study was undertaken to further characterize changes in skeletal muscle morphology and histochemistry in congestive heart failure and to determine the relation of these changes to abnormalities of systemic and local muscle exercise capacity. BACKGROUND: Abnormalities of skeletal muscle appear to play a role in the limitation of exercise capacity in congestive heart failure, but information on the changes in muscle morphology and biochemistry and their relation to alterations in muscle function is limited. METHODS: Eighteen men with predominantly mild to moderate congestive heart failure (mean +/- SEM New York Heart Association functional class 2.6 +/- 0.2, ejection fraction 24 +/- 2%) and eight age- and gender-matched sedentary control subjects underwent measurements of peak systemic oxygen consumption (VO2) during cycle ergometry, resistance to fatigue of the quadriceps femoris muscle group and biopsy of the vastus lateralis muscle. RESULTS: Peak VO2 and resistance to fatigue were lower in the patients with heart failure than in control subjects (15.7 +/- 1.2 vs. 25.1 +/- 1.5 ml/min-kg and 63 +/- 2% vs. 85 +/- 3%, respectively, both p < 0.001). Patients had a lower proportion of slow twitch, type I fibers than did control subjects (36 +/- 3% vs. 46 +/- 5%, p = 0.048) and a higher proportion of fast twitch, type IIab fibers (18 +/- 3% vs. 7 +/- 2%, p = 0.004). Fiber cross-sectional area was smaller, and single-fiber succinate dehydrogenase activity, a mitochondrial oxidative marker, was lower in patients (both p < or = 0.034). Likewise, the ratio of average fast twitch to slow twitch fiber cross-sectional area was lower in patients (0.780 +/- 0.06 vs. 1.05 +/- 0.08, p = 0.019). Peak VO2 was strongly related to integrated succinate dehydrogenase activity in patients (r = 0.896, p = 0.001). Peak VO2, resistance to fatigue and strength also correlated significantly with several measures of fiber size, especially of fast twitch fibers, in patients. None of the skeletal muscle characteristics examined correlated with exercise capacity in control subjects. CONCLUSIONS: These results indicate that congestive heart failure is associated with changes in the characteristics of skeletal muscle and local as well as systemic exercise performance. There are fewer slow twitch fibers, smaller fast twitch fibers and lower succinate dehydrogenase activity. The latter finding suggests that mitochondrial content of muscle is reduced in heart failure and that impaired aerobic-oxidative capacity may play a role in the limitation of systemic exercise capacity.