Chronic congestive heart failure. Where have we been? Where are we heading?

Chronic congestive heart failure is a frequently occurring disease associated with an impaired quality of life and significant mortality rate. Progress has been made in dissecting the pathophysiologic changes of congestive failure and in using vasodilators, newer positive inotropic agents, and other treatment modalities. Despite these advances, the overall mortality rate from congestive heart failure has not decreased. Further, many unanswered questions remain: How and why does a myocardial cell die? How should quality of life be measured? When should vasodilators and positive inotropic agents be given? What role do receptors play in pathogenesis and therapy? Can sudden death in heart failure be prevented? These and other questions will provide the stimulus for further studies in congestive heart failure.

Digitalis and other positive catecholamine-like inotropic agents in the management of congestive heart failure.

Positive inotropic agents are used to improve the impaired cardiac contractility that characterizes chronic heart failure. Digitalis is the traditional drug given for this purpose. However, there is controversy about the effectiveness of digitalis in chronic heart failure. Analysis of the available data indicates the efficacy of digoxin in mild heart failure (i.e., New York Heart Association functional classes I and II) and the relative lack of efficacy in advanced heart failure (i.e., NYHA functional class IV). Further, digoxin can be stopped in a substantial number of patients without recurrence of congestive heart failure. In selected patients whose condition no longer responds to digoxin, the long-term administration of dobutamine may be an effective alternative approach.

Cardiac disease after radiation therapy for Hodgkin's disease: analysis of 48 patients.

Occult or overt but delayed cardiac disease after thoracic radiotherapy for Hodgkin's disease may be common. Detailed cardiac evaluations were performed in 48 patients with Hodgkin's disease at risk a mean of 97 months after radiotherapy. The study protocol included echocardiography, gated radionuclide ventriculography, and cardiac catheterization. Cardiac disease was found in 46 patients (96%) and included constrictive or occult constrictive pericarditis (24 patients), an abnormal hemodynamic response to a fluid challenge (14 patients), coronary artery disease (6 patients), and left ventricular dysfunction (2 patients). Most patients (53%) had normal echocardiograms. Gated blood pool radionuclide angiocardiography was performed in 42 patients. Excluding patients with occlusive coronary artery disease, the left ventricular ejection fraction at rest (mean 59%) and during exercise (mean 69%) was within normal limits. Congestive heart failure occurred in 2 patients. Six patients had pericardiectomy for constrictive pericarditis and 3 patients had coronary artery bypass surgery for coronary artery disease. Thus (1) delayed cardiac disease after radiotherapy is common, (2) chronic pericardial disorders are the most frequent manifestations of this disease, and (3) the prognosis for patients who have radiation-induced cardiac disease is generally favorable.

Intermittent, continuous outpatient dobutamine infusion in the management of congestive heart failure.

The use of outpatient dobutamine infusions by a small, portable infusion pump in 3 patients with intractable congestive heart failure (CHF) is described. With this therapy left ventricular function improved and CHF resolved in each. Tolerance to dobutamine was obviated by giving infusions twice weekly. Except for 3 mild infections around the catheter exit site, there have been no complications of this therapy is 58 cumulative patient weeks.

Delayed pericardial disease after radiotherapy.

Delayed chronic constrictive pericarditis developed in seven patients 51 to 268 (mean 116) months after radiotherapy. Six of the seven complained of exertional dyspnea that was initially believed to be caused by mediastinal fibrosis. All patients had raised jugular venous pressure, although in two patients this finding was not appreciated by the primary physician. There were no consistent noninvasively identifiable features to allow prediction of constrictive pericarditis other than consideration of its existence and careful examination of the cardiovascular system. All patients had constrictive pericarditis proved at cardiac catheterization. Of the five patients who underwent pericardiectomy, two had an excellent functional result, one has residual pericardial constriction and two died of unrelated causes. Recommendations for the treatment of radiation-induced pericardial disease are given.

Aspergillus vegetative endocarditis and complete heart block in a patient with acute leukemia.

Aspergillus flavus vegetative endocarditis together with myocardial abscesses and pneumonitis developed in a patient with acute lymphocytic leukemia. The initial diagnosis was not suspected until 67gallium imaging revealed a radiographically undetectable thoracic abnormality. Despite apparently "early" diagnosis, antifungal therapy was inadequate to prevent disruption of the bundle of His, complete heart block and death.

Digoxin pharmacokinetics in congestive heart failure.

The steady-state pharmacokinetics of oral digoxin in eight hospitalized patients was compared upon their admission with marked right-sided congestive heart failure and later when they were compensated. Large intersubject variations in the serum digoxin concentration profiles were observed. However, over a 24-hour dosing interval, digoxin concentrations in each patient studied during heart failure were either similar or higher than those observed when the patient became compensated. There were no significant differences in digoxin half-life of elimination between the two states. In contrast, the mean ratio of the fraction of digoxin dose absorbed to its apparent volume of distribution was increased by 37 per cent (P less than 0.05) in heart failure. Contrary to the prevailing notion, we found that the oral administration of supplemental doses of digoxin only on the basis of its reduced serum concentration in patients with congestive heart failure is unwarranted.

Oral torsemide in patients with chronic congestive heart failure: effects on body weight, edema, and electrolyte excretion. Torsemide Investigators Group.

STUDY OBJECTIVE: To assess the effects of torsemide on the primary end point of change in body weight from baseline, and the following secondary end points: urinary sodium, potassium, and chloride excretion, and urine volume after the first dose of drug. DESIGN: Randomized, parallel, double-blind, multicenter study in patients treated with torsemide 5 mg (n = 19), 10 mg (n = 18), or 20 mg (n = 14), or placebo (n = 15) for 7 days. PATIENTS: Sixty-six patients with New York Heart Association class II or III congestive heart failure and edema. RESULTS: At the end of the study, patients treated with torsemide 10 and 20 mg demonstrated a significant reduction in body weight compared with those receiving placebo (-1.62 and -1.30 kg, respectively), and those treated with torsemide 5 mg did not (-0.60 kg). The severity of edema decreased with increasing torsemide dose. Torsemide caused no greater frequency of adverse effects with increasing dose. CONCLUSION: Orally administered torsemide 5, 10, and 20 mg once/day for 7 days were well tolerated. Doses of 10 and 20 mg were effective in producing weight loss.

The value of mixed venous oxygen saturation as a therapeutic indicator in the treatment of advanced congestive heart failure.

This retrospective study attempted to determine if the mixed venous oxygen saturation (SVO2) is an appropriate therapeutic monitoring parameter in assessing the effectiveness of dobutamine administration in patients with advanced congestive heart failure (CHF). Twelve patients (mean age 56.7 +/- 3.2 years, SEM) with New York Heart Association functional class III or IV (11 patients) received increasing doses of dobutamine with hemodynamic and SVO2 determinations. Dose-dependent hemodynamic improvements occurred with dobutamine administration. The correlation between cardiac output (CO) and SVO2 was poor (r2 = 0.37). One subset of patients (seven patients) had a good correlation (r2 greater than or equal to 0.7), whereas a second subset (five patients) had a weak correlation (r2 less than 0.7) between CO and SVO2. The baseline hemodynamic profile of the latter group demonstrates a trend toward a more seriously ill subset of patients compared to the former group. A parallel relationship between CO and SVO2 may not occur in seriously ill CHF patients. One possible explanation may be a changing oxygen consumption rate in the seriously ill patient, resulting in changes in CO without concomitant changes in SVO2.

Congestive heart failure and endocardial fibroelastosis caused by chronic lymphocytic leukemia.

Endocardial fibroelastosis developed in the heart of a patient who had chronic lymphocytic leukemia. Leukemic infiltrates were found in the endocardial scar tissue, myocardium, coronary arteries, and other viscera. In view of the absence of any other known cause of endocardial fibroelastosis, it is postulated that endocardial fibroelastosis was caused by myocardial leukemic infiltration. This is the first reported case of endocardial fibroelastosis in a patient with chronic lymphocytic leukemia.

Traumatic left anterior descending coronary artery to right ventricle fistula: report of two cases.

Two cases of traumatic fistulas between the left anterior descending coronary artery and right ventricular outflow tract are presented. One was due to a stab wound and the other to blunt chest trauma. Both patients had small left-to-right shunts. The first patient had surgical closure of the fistula, but it recurred postoperatively. His murmur subsequently disappeared spontaneously four months later. The second patient is being treated medically. Based upon review of the available data, we believe that surgical therapy should be individualized, that asymptomatic individuals with small shunts may be treated conservatively, and that this entity may be more common than previously thought.

Acute anthracycline cardiotoxicity. Comparative morphologic study of three analogues.

Chemotherapeutic use of anthracycline antibiotics is limited by their cardiotoxic effects. A potential solution to this problem is the development of anthracycline analogues retaining antitumor efficacy but without cardiac toxicity. An isolated perfused rabbit heart model was used to compare the nature and extent of early ultrastructural effects on the myocyte of three anthracycline analogues purported to have lesser cardiotoxicity than Adriamycin (doxorubicin). Seventeen rabbit hearts were perfused with oxygenated Krebs-Ringer bicarbonate buffer at 39 degrees C containing either Adriamycin (4 mg/L), daunomycin (10.6 mg/L), aclacinomycin (8 mg/L), or rubidazone (17.6 mg/L). For comparison, three hearts each were exposed to phosphoramide mustard (14.7 mg or 25 mg/L) or 4-hydroperoxy cyclophosphamide (24 mg or 17 mg/L), two active congeners of cyclophosphamide, an agent interacting with DNA differently than the anthracyclines and which is known to be cardiotoxic in high dose. Two hearts were exposed to dactinomycin (0.1 mg or 0.2 mg/L) which intercalates with DNA in a manner similar to the anthracyclines but which is not cardiotoxic. Ten control hearts were perfused with oxygenated buffer solution only. Light microscopic study disclosed no differences between treated and control hearts. Electron microscopic examination showed a striking and distinctive clumping of nuclear chromatin with clearing of chromatin from the nuclear membrane in all anthracycline treated hearts but in no hearts treated with 4-hydroperoxy cyclophosphamide, phosphoramide Mustard, dactinomycin, or control hearts. The nuclear effects of the four anthracycline analogues were indistinguishable. Thus, all anthracycline analogues studied produced acute nuclear alterations which were distinctive from the changes produced by other DNA interactive chemotherapeutic agents. The relationship of the distinctive anthracycline nuclear changes to the late cardiomyopathy requires further definition.

Long-term cardiovascular evaluation of patients with Hodgkin's disease treated by thoracic mantle radiation therapy.

The long-term cardiac effects of anterior-weighted thoracic mantle field radiotherapy were assessed in 25 patients treated for Hodgkin's disease. These patients underwent an evaluation that included a careful history and physical examination, ECG, M-mode echocardiogram, exercise ECG-gated radionuclide ventriculography, and cardiac catheterization. In these 25 patients evaluated 37-144 months (median, 96) after completion of thoracic mantle radiotherapy, eight had constrictive pericarditis; eight had occult constrictive pericarditis; three had an abnormal response to fluid challenge; three had suspected or proven occlusive coronary artery disease; and one each had a cardiomyopathy and diminished functional capacity on exercise testing. Only one patient appears to be normal after evaluation. The clinical spectrum of delayed-appearing radiation-induced cardiac disease in patients treated by anterior-weighted thoracic mantle fields and our suggestions for its treatment are discussed.

Phase I trial of aclacinomycin A.

Aclacinomycin A (ACM-A), an anthracycline analog, was given to 17 patients with solid tumors and to one patient with multiple myeloma, in a phase I clinical trial. A single dose of 60-120 mg/m2 was given every 3 weeks. Dose-limiting toxicity was myelosuppression, especially thrombocytopenia. Granulocytopenia was variable and did not always recover by Day 21 in time for the next ACM-A treatment. Other toxic effects were nausea, vomiting, urticaria, and elevation of hepatic enzymes. Alopecia was not a side effect, even in patients receiving multiple courses of ACM-A. Nine patients were monitored with 24-hour continuous ECG recordings (Holter) on 19 ACM-A treatment days. The incidence of premature atrial and ventricular beats was significantly increased following ACM-A administration. In addition, one patient developed episodes of high-degree atrioventricular block and complete heart block after each of four ACM-A doses, necessitating the insertion of a pacemaker. No antitumor responses were seen in the ten patients who had measurable disease and who had received two or more courses of ACM-A. The recommended doses for solid tumor phase II studies are 100 mg/m2 as a single dose every 4 weeks for patients with high performance status and minimal prior chemotherapy and 60 mg/m2 every 4 weeks for all other patients. Until the acute cardiac effects of ACM-A are further understood, we recommend that all patients receiving ACM-A be monitored by ECG recordings.

Outpatient dobutamine and dopamine infusions in the management of chronic heart failure: clinical experience in 21 patients.

Dobutamine (and dopamine) are potent positive inotropic drugs which are frequently given to treat decompensated congestive heart failure. This study reports on the use of ambulatory dobutamine (and dopamine) infusions in 21 outpatients with advanced congestive heart failure. Each patient was initially hospitalized, and hemodynamic and clinical efficacy to dobutamine (and dopamine) was assessed. These 21 patients were carefully selected from a larger population of approximately 40 patients referred for this therapy. Chronic venous access was established and a drug infusion pump was supplied. Patients and family members were trained in the use of these devices. Eleven patients were treated with intermittent dobutamine infusions for 48 consecutive hours weekly, six patients with continuous (i.e., 24 hours daily) dobutamine infusions, and four patients with continuous, daily dobutamine and dopamine infusions. Significant (p less than 0.001) increases in cardiac index (1.8 +/- 0.6 to 2.7 +/- 0.7 L/min/m2) occurred during the initial dobutamine titrations. Functional classification (3.8 +/- 0.4 to 2.8 +/- 0.7) also improved significantly (p less than 0.01) during the 1.8 to 24 (mean 7.8) months of outpatient infusion therapy with dobutamine (and dopamine). Complications during outpatient therapy included drug tolerance (two instances), infection (two with bacteremias, eight with exit site infections), drug extravasation (three instances), and pump malfunction (two instances). Twenty patients have died: eleven from heart failure, four suddenly (one of them 9 months after dobutamine was stopped), and five from noncardiac causes. Our data suggest that outpatient dobutamine (and dopamine) infusions may be an effective form of therapy for selected patients with severe congestive failure who are refractory to more conventional treatment or who are awaiting cardiac transplantation.

The late appearance of chronic pericardial disease in patients treated by radiotherapy for Hodgkin's disease.

Radiation-induced chronic pericardial disease was recognized in nine patients 53 to 124 months (mean, 88 months) after radiotherapy for Hodgkin's disease. Depending on whether abnormal cardiac hemodynamics occurred before or after a fluid challenge, patients were considered to have either constrictive pericarditis (Group I) or occult constrictive pericarditis (Group II). There were no differences between these groups in various radiotherapy data, the use of chemotherapy, or the interval after treatment when the diagnosis of chronic pericardial disease was made. There were no consistent noninvasive variables to support the diagnosis of radiation-induced chronic pericardial disease before cardiac catheterization. Four patients underwent pericardiectomy. Two of the four operated patients had an excellent surgical result; a third patient died 4 months postoperatively of drug-induced granulocytopenia; the fourth patient has persistent visceral constrictive pericarditis 18 months after surgery. Speculation over the causes of radiation-induced chronic pericardial disease is made and our recommendations for its treatment given.

Intermittent dobutamine hydrochloride infusions in outpatients with chronic congestive heart failure.

Patients with severe chronic congestive heart failure were treated with intermittent dobutamine hydrochloride infusions administered on an outpatient basis with a portable infusion device. Eleven patients (eight women and three men), ages 28-71 years, were given initial dobutamine hydrochloride infusions at a rate of 1-2 micrograms/kg/min, and the dose was gradually increased to a maximum dose of 15 micrograms/kg/min. Patients were considered dobutamine responders if their cardiac output increased by at least 30% and pulmonary-capillary wedge pressure did not rise. After a sustained hemodynamic response was demonstrated, the infusion was discontinued to assess the patients' symptoms during drug-free intervals. The patients were instructed and trained in proper catheter care after a venous-access catheter was surgically implanted. Patients were also shown how to use the ambulatory infusion pump. The patients were treated with long-term intermittent dobutamine hydrochloride infusions for 3-24 months. All patients adjusted easily to the routine of catheter and pump care and drug administration. The mean dose of dobutamine hydrochloride resulting in the maximum improvement in cardiac index was 9.4 micrograms/kg/min. All patients observed an improvement in their symptoms of congestive heart failure during the drug infusions and the intervals between the infusions. There was a mean reduction of 1.2 in New York Heart Association functional class. There were 18 congestive heart failure-related hospital readmissions among the 11 patients during 108 cumulative months of long-term dobutamine therapy. The intermittent administration of dobutamine hydrochloride via a portable infusion system appears to have improved the functional capacity of the 11 patients studied. This may be a viable treatment alternative for selected ambulatory patients with severe heart failure who demonstrate hemodynamic improvement with dobutamine.