Monocyte migration into the subendothelial space of a coculture of adult human aortic endothelial and smooth muscle cells.

Human aortic endothelial cells (EC) and smooth muscle cells (SMC) were isolated and used to form a multilayer of EC-SMC separated by a layer of collagen. SMC and/or collagen layers exerted minimal effects on Na+ transport but impeded the transport of LDL. The presence of an endothelial monolayer markedly reduced the transport of Na+ and LDL. When monocytes were presented to the complete coculture, in the absence of added chemoattractant, one monocyte entered the subendothelial space for every one to three EC present. In contrast, neither collagen nor SMC plus collagen nor EC plus collagen induced comparable monocyte migration. Despite massive migration of monocytes into the coculture, no significant alteration in Na+ transport was observed. LDL transport into the preparation during massive monocyte migration increased modestly, but this was far less than the amount of LDL transported in the absence of an endothelial monolayer. We conclude that (a) the endothelial monolayer was the principal permeability barrier, (b) a substantial migration of monocytes occurred in the absence of added chemoattractant when both EC and SMC were present in the coculture, (c) endothelial barrier function was largely maintained after monocyte migration; and (d) these experiments indicate the need to study all three cell types (monocytes, EC, and SMC) together to understand the complex interactions that occur between these cells.

Recipient mononuclear cell recognition and adhesion to graft endothelium after human cardiac transplantation. Lymphocyte recognition leads to monocyte adhesion.

Transendothelial migration of mononuclear cells is crucial in the development of allograft rejection and transplant coronary disease. Adhesion of circulating cells to endothelium is the initial step in transendothelial migration. Human aortic endothelial cell cultures were established from aortic tissue harvested at the time of organ donation for cardiac transplantation which allowed specific recipient mononuclear cell-graft endothelial interactions to be studied. Confluent untreated endothelial cells were incubated with recipient mononuclear cells for 15 min to assess adhesion. Adhesion of recipient mononuclear cells to endothelium derived from their graft was threefold higher than adhesion to nonspecific endothelium (93 +/- 20 vs. 30 +/- 11 cells/high power field, P < 0.005). Graft-specific adhesion was inhibited by preincubation of the endothelium with antibodies to class I HLA (34 +/- 16 cells/high power field, P < 0.005). Immunofluorescence performed after adhesion showed that 73 +/- 6% of both specific and nonspecific adherent cells were monocytes. The use of purified lymphocyte and monocyte preparations showed that graft-specific lymphocytes induce unrelated monocytes to become adherent. These results suggest that lymphocytes are primed in vivo to recognize endothelium derived from their graft which leads to a rapid increase in lymphocyte and monocyte adhesion. Such allo-recognition may involve endothelial class I HLA molecules.

Syncope in advanced heart failure: high risk of sudden death regardless of origin of syncope.

OBJECTIVES: The purpose of this study was to assess the importance of syncope as a warning sign for sudden death in advanced heart failure and to determine the relative importance of cardiac syncope and syncope from other causes. BACKGROUND: Despite remarkable advances in the pharmacologic approach to advanced heart failure, 20% to 40% of patients with advanced heart failure will die each year. In such patients, the relation between sudden death and the etiology of syncope has not been evaluated. METHODS: The relation of syncope to sudden death was evaluated in 491 consecutive patients with advanced heart failure (New York Heart Association functional class III or IV), no history of cardiac arrest and a mean left ventricular ejection fraction of 0.20 +/- 0.07. Patients were evaluated for the presence and origin of syncope. The severity of heart failure was assessed from serum sodium levels, ejection fraction, functional class and echocardiographic and hemodynamic variables. RESULTS: Sixty patients (12%) had a history of syncope; the condition had a cardiac origin in 29 (48%) and was due to other causes in 31 (52%). The origin of heart failure was coronary artery disease in 234 patients (48%) and dilated cardiomyopathy in 253 (51%) and its severity was similar in patients with and without syncope. During a mean follow-up interval of 365 +/- 419 days, 69 patients (14%) died suddenly and 66 patients (13%) died of progressive heart failure. The actuarial incidence of sudden death by 1 year was significantly greater in patients with (45%) than in those without (12%, p < 0.00001) syncope. In the Cox proportional hazards model, syncope predicted sudden death independent of atrial fibrillation, serum sodium, cardiac index, angiotensin-converting enzyme inhibition and patient age. The actuarial risk of sudden death by 1 year was similarly high in patients with either cardiac syncope or syncope from other causes (49% vs. 39%, p = NS). CONCLUSIONS: Patients with advanced heart failure are at especially high risk for sudden death regardless of the etiology of syncope.

Timing of sudden death in patients with heart failure.

OBJECTIVES: The purpose of this study was to determine the timing of sudden death in patients with advanced heart failure. BACKGROUND: The frequency of sudden cardiac death and myocardial infarction is greatest in the morning hours, suggesting that physiologic processes associated with morning activities may trigger these events. In patients with advanced heart failure, a variety of mechanisms may cause sudden death, and the frequency of their occurrence may differ from that in other patient groups, perhaps altering the timing of sudden death in heart failure. METHODS: Deaths among 566 consecutive patients followed up after treatment for advanced heart failure were prospectively categorized as sudden death, death due to heart failure or noncardiac death. For 72 sudden deaths the time of death was determined from witnesses to the event and from death certificates. RESULTS: Sudden death occurred 2.5 times more frequently between 6:01 AM and 12 noon than in the three other 6-h intervals, with 46% of deaths occurring during this period (p < 0.005). The morning peak occurred both in patients with coronary artery disease and in those with nonischemic causes of heart failure. CONCLUSIONS: Despite a variety of potential mechanisms of sudden death and underlying causes of heart disease in patients with heart failure, the 24-h distribution of sudden death in these patients is similar to that observed in other patient groups. Morning surges in sympathetic nervous system activity may promote a variety of sudden death mechanisms, including ischemic and nonischemic arrhythmias.

Effect of intensive therapy for heart failure on the vasodilator response to exercise.

OBJECTIVES: The purpose of the study was to evaluate the lower extremity vascular responsiveness to metabolic stimuli in patients with heart failure and to determine whether these responses improve acutely after intensive medical therapy. BACKGROUND: Metabolic regulation of vascular tone is an important determinant of blood flow, and may be abnormal in heart failure. METHODS: The leg blood flow responses were measured in 11 patients with nonedematous class III-IV heart failure before and after inpatient medical therapy and in 10 normal subjects. Venous occlusion plethysmography was used to measure peak blood flow and total hyperemia in the calf after arterial occlusion and also after isotonic ankle exercise. Measurements were repeated following short-term inpatient treatment with vasodilators and diuretics administered to decrease right atrial pressure (18+/-2 to 7+/-1 mm Hg), pulmonary wedge pressure (32+/-3 to 15+/-2 mm Hg), and systemic vascular resistance (1581+/-200 to 938+/-63 dynes.s.cm(-5), all p < 0.02). RESULTS: Leg blood flow at rest, after exercise, and during reactive hyperemia was less in heart failure patients than in control subjects. Resting leg blood flow did not increase significantly after medical therapy, but peak flow after the high level of exercise increased by 59% (p = 0.009). Total hyperemic volume in the recovery period increased by 73% (p = 0.03). Similarly, the peak leg blood flow response to ischemia increased by 88% (p = 0.04), whereas hyperemic volume rose by 98% (p = 0.1). CONCLUSIONS: The calf blood flow responses to metabolic stimuli are blunted in patients with severe heart failure, and improve rapidly with intensive medical therapy.

Altered thyroid hormone metabolism in advanced heart failure.

To determine the prevalence and significance of abnormal thyroid hormone metabolism in congestive heart failure, free thyroxine (T4) index, free triiodothyronine (T3) index, reverse T3 and thyrotropin levels were obtained in 84 hospitalized patients with chronic advanced heart failure. Free T4 index was normal in all patients. Free T3 index was reduced or reverse T3 elevated, or both, leading to a low free T3 index/reverse T3 ratio in 49 (58%) of the 84 patients. A low free T3 index/reverse T3 ratio was associated with higher right atrial, pulmonary artery and pulmonary capillary wedge pressures and lower ejection fraction, cardiac index, serum sodium, albumin and total lymphocyte count. In multivariate analysis, the free T3 index/reverse T3 ratio was the only independent predictor of poor 6 week outcome (p less than 0.001); the actuarial 1 year survival rate was 100% for patients with a normal ratio and only 37% for those with a low ratio (p less than 0.0001). A low free T3 index/reverse T3 ratio is associated with poor ventricular function and nutritional status and is the strongest predictor yet identified for short-term outcome in patients with advanced heart failure.

Prediction of improvement in recent onset cardiomyopathy after referral for heart transplantation.

OBJECTIVES: The purpose of this investigation was to determine how often left ventricular function improves in recent onset dilated cardiomyopathy of sufficient severity to cause referral for heart transplantation and how to predict this improvement at the time of evaluation for transplantation. BACKGROUND: Improvement has been reported to occur frequently in patients with acute dilated cardiomyopathy but has not been described specifically in these patients referred for transplantation. To avoid potentially needless transplantation, it would be useful to know the frequency of improvement and how to predict it in these patients. METHODS: A consecutive series of 297 patients with primary dilated cardiomyopathy evaluated for heart transplantation was reviewed to identify those with onset of heart failure symptoms within the preceding 6 months and to examine their outcome. The clinical, echocardiographic, hemodynamic and laboratory profiles of patients with improvement in left ventricular function (defined as an increase in left ventricular ejection fraction > or = 0.15 to a final ejection fraction of > or = 0.30) were compared with those of patients without improvement to assess which variables might predict improvement. RESULTS: Of 49 patients with recent onset dilated cardiomyopathy, 13 (27%) showed improvement, with an increase in mean left ventricular ejection fraction from 0.22 +/- 0.08 to 0.49 +/- 0.09. All patients with improvement had survived without heart transplantation at 43 +/- 29 months. Survival time was shorter in the remaining 36 patients without improvement with recent onset cardiomyopathy than in the 248 with chronic symptoms (p = 0.03) and in younger compared with older patients with recent onset cardiomyopathy (p = 0.0001). By multivariate analysis, predictors of improvement were shorter duration of symptoms, lower pulmonary wedge and right atrial pressures and higher serum sodium levels. CONCLUSIONS: A minority of patients with dilated cardiomyopathy and symptoms for < or = 6 months will have marked improvement in left ventricular function, after which prognosis is excellent despite previous referral for heart transplantation. Those with symptom duration > 3 months and more severe initial decompensation as reflected by higher filling pressures and lower serum sodium levels are unlikely to show improvement and may require earlier consideration for heart transplantation.

Quantification of absolute myocardial perfusion at rest and during exercise with positron emission tomography after human cardiac transplantation.

The maximal exercise capacity of cardiac transplant recipients is reduced compared with that of normal subjects. To determine if this reduced exercise capacity is related to inadequate myocardial perfusion during exercise, myocardial perfusion was measured noninvasively with use of positron emission tomography and nitrogen (N)-13 ammonia. Twelve transplant recipients with no angiographic evidence of accelerated coronary atherosclerosis were studied. Serial N-13 ammonia imaging was performed at rest and during supine bicycle exercise. The results were compared with those from 10 normal volunteers with a low probability of having cardiac disease. A two-compartment kinetic model for estimating myocardial perfusion was applied to the data. Transplant recipients achieved a significant lower exercise work load than did the volunteers (42 +/- 16 vs. 128 +/- 22 W), but a higher venous lactate concentration (31.3 +/- 14.9 vs. 13.7 +/- 4.1 mg/100 ml). Despite the difference in exercise work load, there was no significant difference in the cardiac work achieved by transplant recipients and normal subjects as evidenced by similar rate-pressure products of 24,000 +/- 3,400 versus 21,300 +/- 2,800 betas/min per mm Hg, respectively. In addition, myocardial blood flow during exercise was not significantly different between the two groups (1.70 +/- 0.60 vs. 1.56 +/- 0.71 ml/min per g, respectively). This study demonstrates that the myocardial flow response to the physiologic stress of exercise is appropriate in transplant recipients and does not appear to explain the decreased exercise capacity in these patients.

The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction.

OBJECTIVES: The present analysis examines the prognostic implications of moderate renal insufficiency in patients with asymptomatic and symptomatic left ventricular systolic dysfunction. BACKGROUND: Chronic elevations in intracardiac filling pressures may lead to progressive ventricular dilation and heart failure progression. The ability to maintain fluid balance and prevent increased intracardiac filling pressures is critically dependent on the adequacy of renal function. METHODS: This is a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) Trials, in which moderate renal insufficiency is defined as a baseline creatinine clearance <60 ml/min, as estimated from the Cockroft-Gault equation. RESULTS: In the SOLVD Prevention Trial, multivariate analyses demonstrated moderate renal insufficiency to be associated with an increased risk for all-cause mortality (Relative Risk [RR] 1.41; p = 0.001), largely explained by an increased risk for pump-failure death (RR 1.68; p = 0.007) and the combined end point death or hospitalization for heart failure (RR 1.33; p = 0.001). Likewise, in the Treatment Trial, multivariate analyses demonstrated moderate renal insufficiency to be associated with an increased risk for all-cause mortality (RR 1.41; p = 0.001), also largely explained by an increased risk for pump-failure death (RR 1.49; p = 0.007) and the combined end point death or hospitalization for heart failure (RR 1.45; p = 0.001). CONCLUSIONS: Even moderate degrees of renal insufficiency are independently associated with an increased risk for all-cause mortality in patients with heart failure, largely explained by an increased risk of heart failure progression. These data suggest that, rather than simply being a marker of the severity of underlying disease, the adequacy of renal function may be a primary determinant of compensation in patients with heart failure, and therapy capable of improving renal function may delay disease progression.

The mechanism of decrease in dynamic mitral regurgitation during heart failure treatment: importance of reduction in the regurgitant orifice size.

OBJECTIVES: The purpose of this study was to quantify and characterize the regurgitant flow pattern and regurgitant orifice area in patients undergoing therapy for severe heart failure using contemporary echocardiographic techniques. BACKGROUND: Mitral regurgitation may be dynamic in patients with heart failure and ultimately correlate with outcome in a group of patients. METHODS: Fourteen patients with severe heart failure felt to require hemodynamic monitoring for the optimization of medical therapy were enrolled. Two-dimensional and Doppler echocardiograms were performed before and following invasively guided therapy. Hemodynamics and standard echocardiographic dimensions were determined as well as regurgitant volume and regurgitant orifice area derived from color M-mode and Doppler measurements. RESULTS: Invasively guided therapy for heart failure was associated with a reduction in weight, filling pressures of the left and right heart, systemic vascular resistance, and echocardiographic left atrial, left ventricular and mitral annular dimensions. The mitral regurgitant volume decreased from 47+/-27 ml before therapy to 14+/-14 ml after therapy; p < 0.001. While therapy for heart failure markedly attenuated the volume of regurgitation, the pattern of regurgitant flow across the mitral valve was not significantly altered. In contrast, there was no difference in the velocity time integral of the continuous-wave Doppler spectra of mitral regurgitation with therapy (128+/-23 cm to 123+/-25 cm, p = 0.23). In all patients, the regurgitant orifice area decreased with therapy from 0.55+/-0.38 cm2 to 0.21+/-0.20 cm2 (p < 0.001). CONCLUSIONS: Pharmacologic reduction in filling pressure and systemic vascular resistance leads to a reduction in the dynamic mitral regurgitation of heart failure through a reduction in the regurgitant orifice area but not through a change in the gradient across the mitral valve. Reduction of the regurgitant orifice area is likely related to decreased left ventricular volumes and decreased annular distention.

Prognostic impact of diabetes mellitus in patients with heart failure according to the etiology of left ventricular systolic dysfunction.

OBJECTIVES: We sought to determine the relative impact of diabetes mellitus on prognosis in ischemic compared with nonischemic cardiomyopathy. BACKGROUND: Ischemic myocardium is characterized by increased reliance on aerobic and anaerobic glycolysis. Because glucose utilization by cardiomyocytes is an insulin-mediated process, we hypothesized that diabetes would have a more adverse impact on mortality and progression of heart failure in ischemic compared with nonischemic cardiomyopathy. METHODS: We performed a retrospective analysis of the Studies Of Left Ventricular Dysfunction (SOLVD) Prevention and Treatment trials. RESULTS: In adjusted analyses, diabetes mellitus was strongly associated with an increased risk for all-cause mortality in patients with ischemic cardiomyopathy, (relative risk [RR] 1.37, 95% confidence interval [CI] 1.21 to 1.55; p < 0.0001), but not in those with nonischemic cardiomyopathy (RR 0.98, 95% CI 0.76 to 1.32; p = 0.98). The increased mortality in patients with ischemic cardiomyopathy compared with nonischemic cardiomyopathy was limited to those with ischemic cardiomyopathy and diabetes mellitus (RR 1.37, 95% CI 1.21 to 1.56; p < 0.0001). When patients with ischemic cardiomyopathy and diabetes mellitus were excluded, there was no significant difference in mortality risk between the ischemic and nonischemic cardiomyopathy groups after adjusted analysis (RR 0.99, 95% CI 0.86 to 1.15; p = 0.99). Previous surgical revascularization identified patients within the cohort with ischemic cardiomyopathy and diabetes mellitus, with improved prognosis. CONCLUSIONS: The differential impact of diabetes on mortality and heart failure progression according to the etiology of heart failure suggests that diabetes and ischemic heart disease interact to accelerate the progression of myocardial dysfunction. Evaluation of the potential for revascularization may be particularly important in patients with ischemic cardiomyopathy and diabetes mellitus.

Is intravenous glucocorticoid therapy better than an oral regimen for asymptomatic cardiac rejection? A randomized trial.

OBJECTIVES: This study assessed whether treatment with oral prednisone (bolus plus tapered doses) is comparable to intravenous methylprednisolone sodium succinate (Solu-Medrol) therapy in patients with asymptomatic moderate cardiac allograft rejection episodes without hemodynamic compromise. BACKGROUND: Intravenous Solu-Medrol therapy is frequently administered for moderate rejection episodes after heart transplantation but has not previously been compared with an oral prednisone therapy for asymptomatic cardiac rejection in a randomized trial. Compared with oral prednisone therapy, the administration of intravenous Solu-Medrol is more costly and resource intensive, and it can require loss of work time for patients and the family members who accompany them to treatment. METHODS: Forty-one heart transplant patients with 43 episodes of asymptomatic moderate cardiac rejection were randomized to receive 3 days of 1,000 mg of intravenous Solu-Medrol (20 episodes) or prednisone as a bolus dose of 100 mg orally for 3 days, tapering to the previous maintenance dosage over 14 days (23 episodes). Follow-up endomyocardial biopsies were performed at 2 and 4 weeks. Infectious complications were monitored and the cost of the two forms of therapy was assessed. RESULTS: Resolution of moderate rejection occurred within 4 weeks in 19 (95%) of 20 patients treated with intravenous steroids and in 21 (91%) of 23 patients treated with oral prednisone. No significant difference in infectious complications occurred between the two groups in the ensuing 3 months after therapy. The cost of the oral prednisone therapy was $6.30 compared with the cost of $180 to $966 for administration of intravenous Solu-Medrol. CONCLUSIONS: Oral prednisone (bolus plus tapered doses) appears to be as effective and to have similar infectious complication rates as intravenous Solu-Medrol for the treatment of asymptomatic cardiac rejection. The convenience and lower cost of oral prednisone therapy may warrant its routine use for this type of cardiac rejection.

Improvement in exercise capacity of candidates awaiting heart transplantation.

OBJECTIVES: This study determined the frequency of improvement in peak oxygen uptake and its role in reevaluation of candidates awaiting heart transplantation. BACKGROUND: Ambulatory candidates for transplantation usually wait > 6 months to undergo the procedure, and during this period symptoms may lessen, and peak oxygen uptake may improve. Whereas initial transplant candidacy is based increasingly on objective criteria, there are no established guidelines for reevaluation to determine who can leave the active waiting list. METHODS: All ambulatory transplant candidates with initial peak oxygen uptake < 14 ml/kg per min were identified. Of 107 such patients listed, 68 survived without early deterioration or transplantation to undergo repeat exercise. A strategy of reevaluation using specific clinical criteria and exercise performance was tested to determine whether patients with improved oxygen uptake could safely be followed without transplantation. RESULTS: In 38 of the 68 patients, peak oxygen uptake increased by > or = 2 ml/kg per min to a level > or = 12 ml/kg per min after 6 +/- 5 months, together with an increase in anaerobic threshold, peak oxygen pulse and exercise heart rate reserve and a decrease in heart rate at rest. Increased peak oxygen uptake was accompanied by stable clinical status without congestion in 31 of 38 patients, and these 31 were taken off the active waiting list. At 2 years, their actuarial survival rate was 100%, and the survival rate without relisting for transplantation was 85%. CONCLUSION: Reevaluation of exercise capacity and clinical status allowed removal of 31 (29%) of 107 ambulatory transplant candidates from the waiting list with excellent early survival despite low peak oxygen uptake on initial testing. The ability to increase peak oxygen uptake, particularly with increased peak oxygen pulse, may indicate improved prognosis as well as functional capacity and, in combination with stable clinical status, may be an indication to defer transplantation in favor of more compromised candidates.

Differentiating cardiomyopathy of coronary artery disease from nonischemic dilated cardiomyopathy utilizing positron emission tomography.

To determine if imaging of blood flow (using N-13 ammonia) and glucose metabolism (using F-18 2-deoxyglucose) with positron emission tomography can distinguish cardiomyopathy of coronary artery disease from nonischemic dilated cardiomyopathy, 21 patients with severe left ventricular dysfunction who were evaluated for cardiac transplantation were studied. The origin of left ventricular dysfunction had been previously determined by coronary angiography to be ischemic (11 patients) or nonischemic (10 patients). Images were visually analyzed by three observers on a graded scale in seven left ventricular segments and revealed fewer defects in dilated cardiomyopathy compared with ischemic cardiomyopathy for N-13 ammonia (2.7 +/- 1.6 versus 5 +/- 0.6; p less than 0.03) and F-18 deoxyglucose (2.8 +/- 2.1 versus 4.6 +/- 1.1; p less than 0.03). An index incorporating extent and severity of defects revealed more homogeneity with fewer and less severe defects in subjects with nonischemic than in those with ischemic cardiomyopathy as assessed by imaging of flow (2.8 +/- 1.8 versus 9.2 +/- 3; p less than 0.001) and metabolism (3.8 +/- 3.3 versus 8.5 +/- 3.6; p less than 0.005). Diagnostic accuracy for distinguishing the two subgroups by visual image analysis was 85%. Using previously published circumferential count profile criteria, patients with dilated cardiomyopathy had fewer ischemic segments (0.4 +/- 0.8 versus 2.5 +/- 2 per patient; p less than 0.01) and infarcted segments (0.1 +/- 0.3 versus 2.4 +/- 1.4 per patient; p less than 0.001) than did patients with cardiomyopathy of coronary artery disease. The sensitivity for differentiating the two clinical subgroups using circumferential profile analysis was 100% and the specificity 80%. An index incorporating both number and severity of defects derived from circumferential profile analysis was significantly lower in subjects with dilated cardiomyopathy than in ischemic cardiomyopathy (0.3 +/- 0.8 versus 2.7 +/- 2.4; p less than 0.005). Thus, noninvasive positron emission tomographic imaging with N-13 ammonia and F-18 deoxyglucose is helpful in distinguishing patients with severe left ventricular dysfunction secondary to coronary artery disease from those with nonischemic cardiomyopathy, and a semiquantitative index such as circumferential profile analysis is superior to that of visual analysis alone.

Decreasing survival benefit from cardiac transplantation for outpatients as the waiting list lengthens.

Many patients are accepted for cardiac transplantation during a period of clinical instability associated with a high risk of death, even though most can be discharged home to await transplantation. As the waiting lists lengthen, priority is awarded solely on the basis of the waiting time of outpatients, who now usually undergo transplantation after they have already survived a major period of jeopardy. To determine the impact of the current waiting times and priority system on the previously expected benefit offered by transplantation, 1-year actuarial survival without transplantation was recalculated after each month without transplantation for 214 potential candidates with an ejection fraction of 0.17 +/- 0.05 discharged on tailored medical therapy after evaluation. These data were compared with the 1-year survival data of 88 outpatients who underwent transplantation. Actuarial survival after 1 year was 67% on tailored therapy compared with 88% after transplantation (p = 0.009). Death without transplantation was sudden in 43 of 51 patients, resulting from hemodynamic decompensation in 8. For outpatients already surviving 6 months without transplantation, actuarial survival over the next 12 months was 83% without transplantation. Thus, the expected improvement in survival after transplantation would be only 5% over the subsequent year for patients waiting 6 months, which is the waiting time for many outpatients. Such patients should be reevaluated to determine whether transplantation remains indicated during the next year.

Effect of direct vasodilation with hydralazine versus angiotensin-converting enzyme inhibition with captopril on mortality in advanced heart failure: the Hy-C trial.

To compare the benefit of angiotensin-converting enzyme inhibition and direct vasodilation on the prognosis of advanced heart failure, 117 patients evaluated for cardiac transplantation who had severe symptoms and abnormal hemodynamic status at rest were randomized to treatment with either captopril or hydralazine plus isosorbide dinitrate (Hy-C Trial). Comparable hemodynamic effects of the two regimens were sought by titrating vasodilator doses to match the hemodynamic status achieved with nitroprusside and diuretic agents, attempting to achieve a pulmonary capillary wedge pressure of 15 mm Hg and a systemic vascular resistance of 1,200 dynes.s.cm-5. Treatment with the alternate vasodilator was started because of poor hemodynamic response or side effects (40% of patients in the captopril group and 22% in the hydralazine group). Adequate hemodynamic response in patients with a serum sodium level less than 135 mg/dl was more likely with hydralazine than with captopril (71% vs. 33%, p = 0.04). Isosorbide dinitrate was prescribed in 88% of the hydralazine-treated patients and 84% of the captopril-treated patients. The hemodynamic improvements from each regimen were equivalent. After 8 +/- 7 months of follow-up, the actuarial 1-year survival rate was 81% in the captopril-treated patients and 51% in the hydralazine-treated patients (p = 0.05). The improved survival with captopril resulted from a lower rate of sudden death, which occurred in only 3 of 44 captopril-treated patients compared with 17 of 60 hydralazine-treated patients (p = 0.01). In the subset of patients who continued treatment with the initial vasodilator, results were similar to those for the entire treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of a comprehensive heart failure management program on hospital readmission and functional status of patients with advanced heart failure.

OBJECTIVES: To assess the impact of a comprehensive heart failure management program, functional status, hospital readmission rate and estimated hospital costs were determined and compared for the 6 months before and the 6 months after referral. BACKGROUND: The course of advanced heart failure is characterized by progressive clinical deterioration reflected in frequent hospital admissions, which comprise the major financial cost. METHODS: Over a 3-year period, 214 patients were accepted for heart transplantation and discharged after evaluation, which included adjustments in medical therapy and intensive patient education. Patients were in New York Heart Association functional class III or IV (94 and 120 patients, respectively), with a mean left ventricular ejection fraction of 0.21, peak oxygen consumption of 11 ml/kg per min and a total of 429 hospital admissions in the previous 6 months (average 2.0 per patient). Changes in the medical regimen included a 98% increase in angiotensin-converting enzyme inhibitor dose and a flexible diuretic regimen after 4.2-liter net diuresis, with counseling also regarding diet and progressive exercise. RESULTS: During the 6 months after referral, there were only 63 hospital readmissions (85% reduction), with 0.29/patient (p < 0.0001). Functional status improved as assessed by functional class (p < 0.0001) and peak oxygen consumption (15.2 vs. 11.0 ml/kg per min, p < 0.001). The same results were seen after excluding the 35 patients without full 6-month follow-up (9 deaths, 14 urgent transplant procedures during hospital readmission, 12 elective transplant procedures from home); 34 hospital admissions occurred after referral, compared with 344 before referral. Even when adding in the initial hospital admission after referral for these 179 patients, there was a 35% decrease in total hospital admissions in the 6-month period. The estimated savings in hospital readmission costs after subtracting the initial hospital costs for management was $9,800 per patient. CONCLUSIONS: Comprehensive heart failure management led to improved functional status and an 85% decrease in the hospital admission rate for transplant candidates discharged after evaluation. The potential to reduce both symptoms and costs suggests that referral to a heart failure program may be appropriate not only for potential heart transplantation, but also for medical management of persistent functional class III and IV heart failure.

Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction.

OBJECTIVE: This study undertook to determine if the presence of atrial fibrillation in patients with asymptomatic and symptomatic left ventricular dysfunction was associated with increased mortality and, if so, whether the increase could be attributed to progressive heart failure or arrhythmic death. BACKGROUND: Atrial fibrillation is a common condition in heart failure with the potential to impact hemodynamics and progression of left ventricular systolic dysfunction as well as the electrophysiologic substrate for arrhythmias. The available data do not conclusively define the effect of atrial fibrillation on prognosis in heart failure. METHODS: A retrospective analysis of the Studies of Left Ventricular Dysfunction Prevention and Treatment Trials was conducted that compared patients with atrial fibrillation to those in sinus rhythm at baseline for the risk of all-cause mortality, progressive pump-failure death and arrhythmic death. RESULTS: The patients with atrial fibrillation at baseline, compared to those in sinus rhythm, had greater all-cause mortality (34% vs. 23%, p < 0.001), death attributed to pump-failure (16.7% vs. 9.4%, p < 0.001) and were more likely to reach the composite end point of death or hospitalization for heart failure (45% vs. 33%, p < 0.001), but there was no significant difference between the groups in arrhythmic deaths. After multivariate analysis, atrial fibrillation remained significantly associated with all-cause mortality (relative risk [RR] 1.34, 95% confidence interval [CI] 1.12 to 1.62, p=0.002), progressive pump-failure death (RR 1.42, 95% CI 1.09 to 1.85, p=0.01), the composite end point of death or hospitalization for heart failure (RR 1.26, 95% CI 1.03 to 1.42, p=0.02), but not arrhythmic death (RR 1.13; 95% CI 0.75 to 1.71; p=0.55). CONCLUSIONS: The presence of atrial fibrillation in patients with asymptomatic and symptomatic left ventricular systolic dysfunction is associated with an increased risk for all-cause mortality, largely explained by an increased risk for pump-failure death. These data suggest that atrial fibrillation is associated with progression of left ventricular systolic dysfunction.

Afterload reduction with vasodilators and diuretics decreases mitral regurgitation during upright exercise in advanced heart failure.

In advanced heart failure, mitral regurgitation increases the burden of the failing ventricle and decreases effective stroke volume. Although tailored afterload reduction decreases mitral regurgitation at rest, it is not known if this benefit is maintained during upright exercise. Simultaneous radionuclide ventriculography and thermodilution stroke volumes were compared to measure the forward ejection fraction in 10 patients during upright bicycle exercise before and after therapy with vasodilators and diuretics tailored to decrease pulmonary capillary wedge pressure and systemic vascular resistance. Ventricular volumes, total ejection fraction and the forward ejection fraction did not change during exercise at baseline. At rest, tailored therapy decreased average pulmonary capillary wedge pressure from 36 to 19 mm Hg (p less than 0.01), systemic vascular resistance from 1,570 to 1,210 dynes.s.cm-5 (p less than 0.05), and left ventricular volume index from 251 to 177 ml/m2 (p less than 0.01), while increasing the forward ejection fraction from 0.53 to 0.85 (p less than 0.01) without change in total ejection fraction (0.18 from 0.17). During steady state exercise at low work load, tailored therapy decreased left ventricular volume index from 279 to 213 (p less than 0.05) and increased forward ejection fraction from 0.52 to 0.79 (p less than 0.01) without change in total ejection fraction (0.20 from 0.19). The total stroke volume during exercise was not increased after therapy; the increase in forward stroke volume after therapy appeared to result instead from the decrease in mitral regurgitant flow. The benefits of tailored afterload reduction are maintained throughout upright exercise.

Improving survival for patients with advanced heart failure: a study of 737 consecutive patients.

OBJECTIVES: This study sought to determine whether survival and risk of sudden death have improved for patients with advanced heart failure referred for consideration for heart transplantation as advances in medical therapy were systematically implemented over an 8-year period. BACKGROUND: Recent survival trials in patients with mild to moderate heart failure and patients after a myocardial infarction have shown that angiotensin-converting enzyme inhibitors are beneficial, type I antiarrhythmic drugs can be detrimental, and amiodarone may be beneficial in some groups. The impact of advances in therapy may be enhanced or blunted when applied to severe heart failure. METHODS: One-year mortality and sudden death were determined in relation to time, baseline variables and therapeutics for 737 consecutive patients referred for heart transplantation and discharged home on medical therapy from 1986 to 1988, 1989 to 1990 and 1991 to 1993. Medical care was directed by a single team of physicians with policies established by consensus. From 1986 to 1990, the hydralazine/isosorbide dinitrate combination or angiotensin-converting enzyme inhibitors were the initial vasodilators, and class I antiarrhythmic drugs were allowed. After 1990, captopril was the initial vasodilator, given to 86% of patients compared with 46% of patients before 1989. After mid-1989, class I agents were routinely withdrawn, and amiodarone was used for frequent ventricular ectopic beats or atrial fibrillation (53% of patients after 1990 vs. 10% before 1989). RESULTS: The total 1-year mortality rate decreased from 33% before 1989 to 16% after 1990 (p = 0.0001), and sudden death decreased from 20% to 8% (p = 0.0006). Adjusted for clinical and hemodynamic variables in multivariate proportional hazards models, total mortality and sudden death were lower after 1990. CONCLUSIONS: The large reduction in mortality, particularly in sudden death, from advanced heart failure since 1990 may reflect an enhanced impact of therapeutic advances shown in large randomized trials when they are incorporated into a comprehensive approach in this population. This improved survival supports the growing practice of maintaining potential heart transplant candidates on optimal medical therapy until clinical decompensation mandates transplantation.