Search

Publishe d decades after several randomized controlled trials (RCT) demonstrating decreased hospitalizations and no effect on all-cause mortality with digoxin use, a series of meta-analyses linking digoxin treatment and mortality have contributed to a narrower application of this medication for the management of heart failure (HF) and atrial fibrillation (AF). Given the conflicting data from the earlier RCTs and more recent meta-analyses, there is a growing polarization among providers for and against the use of digoxin in managing these conditions.To help close this divide, we provide a perspective on the literature with special attention to the quality of both older and more recent studies on this subject.The data from the highest quality studies we have, RCTs, suggest that digoxin use in patients with HF and/or AF is associated with improvement in several areas of outcomes including functional capacity, symptom management, reduced hospitalizations, fewer deaths due to HF, and treatment of refractory chronic heart failure with rEF, and may even have overall mortality benefit when serum digoxin concentrations are within therapeutic range. These effects are more pronounced in patients with EF 25% and NYHA Class II-IV and at highest risk for hospitalization.As the risk of confounding factors was minimized by the study design, the likelihood that positive outcomes were identified with digoxin use increased. Clinicians and researchers need further adequately designed and powered RCTs exploring the connection between digoxin therapy and mortality, hospitalizations, and symptom management.

Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival.We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV).Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event.As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.

Aims To determine the sequence of critical cardiovascular events in the progression of heart failure, and whether aetiology or high-dose vs low-dose lisinopril affected these pathways. Methods and Results This was a post-hoc investigation of the ATLAS database, which comprised 3164 patients with chronic heart failure, randomized to low- (2·5–5·0mg.day−1) or high-dose (32·5–35·0mg.day−1) lisinopril, followed up for a median of 46 months. Two-thirds (64·3%) of patients had heart failure attributed to ischaemic heart disease. During the study, most patients (61·1%) had at least one cardiovascular hospitalization and 42·5% of all patients died: most deaths (88·2%) were cardiovascular. Nearly half (49·7%) of the cardiovascular deaths were considered sudden and 45·2% of cardiovascular deaths occurred as the first cardiovascular event. A third (30·2%) of deaths resulted from heart failure and were generally preceded by hospitalization, either for heart failure (85·5%), myocardial ischaemic events (21·7%) or arrhythmias (18·0%). Compared with low-dose, high-dose lisinopril was associated with a lower risk of death or hospitalization for any reason ( P =0·002) and death or hospitalization with worsening heart failure ( P

Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits.We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fractionor = 30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n=1596) or high doses (32.5 to 35 mg daily, n=1568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death (P=0.128) but a significant 12% lower risk of death or hospitalization for any reason (P=0.002) and 24% fewer hospitalizations for heart failure (P=0.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication. Conclusions-These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small.

We sought to study the efficacy of "triple" therapy with digoxin, diuretic and angiotensin-converting enzyme inhibitor (ACEI) compared to other combinations of these drugs in patients with symptomatic left ventricular systolic dysfunction.Controversy continues concerning the role of combining digoxin with diuretic and ACEI in the initial management of patients with heart failure.The study utilized data from two studies of digoxin efficacy: Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Worsening heart failure defined as augmentation of heart failure therapy or an emergency room visit or hospitalization for increased heart failure was the main outcome measure.A total of 266 patients comprising the four treatment groups of the combined PROVED (diuretic alone or digoxin and diuretic) and RADIANCE (ACEI and diuretic, or digoxin, diuretic and ACEI) trials were analyzed. Worsening heart failure occurred in only 4 of the 85 patients who continued digoxin, diuretic and ACEI therapy (4.7%) compared to 18 of the 42 patients (19%) on digoxin and diuretic therapy (p=0.009), to 23 of the 93 patients (25%) on ACEI and diuretic therapy (p=0.001) and to 18 of the 46 patients (39%) on diuretic alone (p0.001). Life table and multivariate analysis also demonstrated that worsening heart failure was least likely in patients treated with triple therapy (p0.01 vs. all other groups).Pending definitive, prospective clinical trials, our results argue for triple therapy as the initial management of patients with symptomatic heart failure due to systolic dysfunction.

Right heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationship of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy.The 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n = 41) or conventional therapy alone (n = 40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricular dilatation and dysfunction, abnormal septal curvature, and significant tricuspid regurgitation with a high regurgitant velocity. Pericardial effusions were common. More pronounced abnormalities in right heart structure and function were associated with higher pulmonary arterial and mean right atrial pressures, lower cardiac index, and impaired exercise capacity but had no predictable relationship to quality-of-life indicators. The 12-week infusion of prostacyclin had beneficial effects on right ventricular size, curvature of the interventricular septum, and maximal tricuspid regurgitant jet velocity.The echocardiographic manifestations of severe primary pulmonary hypertension reflect abnormalities in hemodynamics and exercise capacity. Prostacyclin has beneficial effects on right heart structure and function that may contribute to the clinical improvement and prolonged survival observed with this drug.

We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction.Patients (n = 366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF)or = 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n = 232) or placebo (n = 134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P = .008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated.Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

Patients with advanced heart failure often remain severely symptomatic and have a high mortality rate despite currently available therapy. We studied the safety and efficacy of a new approach to the patient with refractory heart failure: continuous intravenous treatment via a portable infusion pump with epoprostenol (prostacyclin), a potent pulmonary and systemic vasodilator. A group of 33 patients with severe heart failure (64% New York Heart Association class IV and 36% class III) and profound ventricular dysfunction (median left ventricular ejection fraction, 0.15)--despite prior treatment with diuretics (100%), digitalis (91%), angiotensin-converting enzyme inhibitors (85%), and dobutamine (30%)--underwent a baseline 6-minute walk test prior to dose titration with epoprostenol during invasive hemodynamic monitoring. Subjects responding during the dose titration were randomized, on an open basis, to receive either continuous epoprostenol infusion via an indwelling central venous catheter plus conventional therapy or conventional therapy alone for 12 weeks. The initial dose-ranging study with epoprostenol produced a significant decline in systemic and pulmonary vascular resistance and a substantial increase in cardiac index despite a fall in pulmonary capillary wedge pressure. Symptoms related to vasodilation were noted within the first week after randomization to epoprostenol in 9 of 16 patients but resolved with adjustment of the infusion and concomitant medications in all but one subject. Dose adjustments during the chronic epoprostenol infusion were infrequent after the first week and complications related to the drug delivery system were rare. The change in distance walked from baseline to the last available 6-minute walk test was significantly greater in patients who received epoprostenol compared with patients assigned to standard therapy (72 +/- 40 vs -39 +/- 32 m, mean +/- SEM; p = 0.033). Our study suggests that long-term intravenous infusion of epoprostenol is feasible in patients with severe heart failure and our hemodynamic and functional results suggest clinical benefit as well. However, until recent results indicating an adverse effect of epoprostenol on survival are fully evaluated, the role of this drug in the treatment of advanced heart failure will remain uncertain.

Intra-aortic balloon (IAB) counterpulsation has been utilized as an effective "bridge" to transplantation in patients with end-stage heart failure. To determine if patients with heart failure with nonischemic cardiomyopathy (NICM) derive the same benefit from IAB support as those with ischemic cardiomyopathy (ISCM), we evaluated 27 patients with NICM and 16 patients with ISCM who required IAB support while awaiting transplantation. Hemodynamic changes, effects on organ function (renal and hepatic), frequency of complications, and clinical outcomes were analyzed. Baseline demographics and hemodynamics were comparable in both groups (p = NS). Hemodynamics improved in both groups, immediately (15 to 30 min) following IAB insertion, with greater improvement (p0.05) in cardiac index and a trend toward greater reduction in filling pressures in the NICM group. Systemic vascular resistance fell to a similar degree in both groups. During continued IAB support (0.13 to 38 days in NICM, 1 to 54 days in ISCM), all hemodynamic changes persisted in both groups, with larger decrease (p0.05) in systemic vascular resistance and greater increase (p0.05) in cardiac index in the patients with NICM. The reduction in filling pressures, however, tended to be greater in patients with ISCM. Renal and hepatic function parameters improved to a similar extent in both groups. The frequency of complications and clinical outcome during IAB support were also similar in the two groups. These data confirm that IAB counterpulsation is a safe and effective "bridge" in patients with both NICM and ISCM with end-stage heart failure. The mechanism of sustained benefit in the two groups, however, may be different; afterload reduction appears to be more important in patients with NICM whereas reduction in filling pressures (increased coronary perfusion pressure) may be the main mechanism in patients with ISCM.

The relationship between maximal exercise tolerance and resting radionuclide indexes of left ventricular systolic and diastolic function were evaluated in 20 ischemic and 44 idiopathic cardiomyopathy patients with New York Heart Association class 2-4 chronic congestive heart failure. Left ventricular ejection fraction, peak systolic ejection rate, peak diastolic filling rate, time to peak filling from end-systolic volume, and fractional filling in early diastole were measured from the radionuclide ventriculogram. All patients underwent symptom-limited exercise testing with on-line measurement of oxygen consumption. In the ischemic group, all of the radionuclide indexes correlated poorly with maximal exercise oxygen consumption (VO2max) except the peak systolic ejection rate which correlated modestly (r = 0.58, p0.05). Peak systolic ejection rate was significantly lower (p0.01) as were the peak diastolic filling rate and fractional filling in the first third of diastole (p0.05) in ischemic patients with marked exercise intolerance (VO2maxor = 14 mL/kg/min) compared with those with preserved exercise tolerance (VO2max14 mL/kg/min). In the idiopathic group, none of the radionuclide indexes correlated well with VO2max; and all indexes were similar in patients with and without marked exercise intolerance. These data suggest that (1) resting left ventricular ejection fraction poorly predicts maximal exercise capacity in both ischemic and idiopathic cardiomyopathy and (2) resting peak systolic ejection rate, peak diastolic filling rate, and fractional filling in early diastole may predict exercise tolerance in ischemic but not idiopathic cardiomyopathy.

The purpose of this study was to determine whether digoxin is effective in patients with chronic, stable mild to moderate heart failure.Digoxin has been a traditional therapy in heart failure, but methodologic limitations in earlier studies have prevented definitive conclusions regarding its efficacy.Withdrawal of digoxin (placebo group, n = 46) or its continuation (digoxin group, n = 42) was performed in a prospective, randomized, double-blind, placebo-controlled multicenter trial of patients with chronic, stable mild to moderate heart failure secondary to left ventricular systolic dysfunction who had normal sinus rhythm and were receiving long-term treatment with diuretic drugs and digoxin.Patients withdrawn from digoxin therapy showed worsened maximal exercise capacity (median change in exercise time -96 s) compared with that of patients who continued to receive digoxin (change in exercise time +4.5 s) (p = 0.003). Patients withdrawn from digoxin therapy showed an increased incidence of treatment failures (p = 0.039) (39%, digoxin withdrawal group vs. 19%, digoxin maintenance group) and a decreased time to treatment failure (p = 0.037). In addition, patients who continued to receive digoxin had a lower body weight (p = 0.044) and heart rate (p = 0.003) and a higher left ventricular ejection fraction (p = 0.016).These data provide strong evidence of the clinical efficacy of digoxin in patients with normal sinus rhythm and mild to moderate chronic heart failure secondary to systolic dysfunction who are treated with diuretics.

Patients with chronic heart failure frequently have pulmonary hypertension. Because severe preoperative pulmonary hypertension predicts a poor outcome after orthotopic transplantation, pulmonary vasoreactivity is evaluated frequently in the pretransplantation screening of heart failure patients. We prospectively evaluated the utility of the direct pulmonary vasodilator, prostaglandin E1, and compared it to the nonspecific vasodilators, nitroglycerin and sodium nitroprusside, in the evaluation of pulmonary hypertension in 39 heart transplantation candidates. Prostaglandin E1 significantly lowered pulmonary artery pressure, transpulmonary pressure gradient, and pulmonary vascular resistance. An adequate pulmonary vasodilator response (defined as a decline in transpulmonary pressure gradient to less than 15 mm Hg) occurred in 31 patients (79%). In a subgroup of nine patients also tested with nitroglycerin, greater reductions (p less than 0.01) in both transpulmonary pressure gradient and pulmonary vascular resistance occurred with prostaglandin E1, compared to nitroglycerin. Five of six patients who did not respond to nitroglycerin responded to prostaglandin E1. In another subgroup of 12 patients who were also evaluated with sodium nitroprusside, prostaglandin E1 produced a larger decline (p less than 0.05) in transpulmonary pressure gradient and pulmonary vascular resistance than did sodium nitroprusside. Six of eight patients who did not respond to sodium nitroprusside responded to prostaglandin E1. Based on pulmonary vasodilator response to prostaglandin E1, 27 patients were accepted on the transplantation waiting list, and eight patients underwent orthotopic transplantation. Postoperatively, acute right ventricular failure of the donor heart developed in none of these patients. Significant hemodynamic improvement occurred by 24 hours and persisted through 4 weeks of postoperative follow-up in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac events from graft arteriopathy, including myocardial infarction, heart failure resulting from previous myocardial infarction, and sudden death, may limit long-term survival after heart transplantation. To determine the incidence of cardiac events and the use of coronary arteriography in predicting these events, the long-term results (mean follow-up, 3.5 years; standard deviation +/- 2.0) of heart transplantation in 427 patients were reviewed. Cardiac events included 19 cases of myocardial infarction, 13 cases of sudden death, and 10 cases of congestive heart failure. All these events occurred after the first year except for three cases of sudden death and one case of myocardial infarction. Cumulative incidence of cardiac events per patient year was 0.9% within the first year, increasing to 1.9% by 5 years. Cardiac events accounted for 3.8% of the deaths by the end of the first year, rising to 18% of total mortality by 7 years after heart transplantation. In patients dying after the first year of transplantation, deaths from sequelae of coronary artery disease occurred in 36% (20/55). The relative risk ("odds ratio") of any cardiac event was 3.44 (p less than 0.05) in patients with angiographic evidence of obstructive disease compared with those without evidence of disease, risk of cardiac death 4.6 (p less than 0.05) and risk of sudden death, 2.4 (not significant). Of the 13 patients who died suddenly, five seen at autopsy were found to have had a recent myocardial infarction. Of all patients who died of heart disease, recent myocardial infarction was detected in nine who were seen at autopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Amyloid heart disease has been considered a contraindication for cardiac transplant based on the hypothesis that it is a systemic disease and that amyloid deposition would occur in the cardiac allograft. A survey was sent to all of the US centers and a limited number of Canadian and European centers listed with the International Registry. Twenty-four centers responded, and data were ultimately provided for a total of 10 patients (3 men, 7 women, mean age 48 years, range 30-60 years) who were transplanted for cardiac amyloid. The diagnosis of cardiac amyloidosis was made histologically on endomyocardial biopsy and/or examination of the explanted heart. Additional documented organ involvement included liver (two of 10), rectal (three of 10), renal (two of 10), gingiva (two of 10), and tongue (one of 10), although invasive biopsies were not performed in a majority of patients. A specific amyloid protein was identified in eight patients (seven lambda, one kappa immunoglobulin light chain). Although four of the surviving nine patients (one perioperative death) developed recurrent amyloid deposition in the allograft, it was detected solely by electron microscopy in two of these and had no clinical significance. There was, however, a progressive risk of major organ involvement with organ function impairment in this group (22% at 12 months, 50% at 24 months, 66% at 48 months). Although the immediate and early postoperative outcomes were not dissimilar between this group and patients undergoing transplantation for other cardiac diseases, late survival was reduced (39% at 48 months) compared with the larger population, but differences were not statistically significant due to the small amyloid sample size (p = 0.16).(ABSTRACT TRUNCATED AT 250 WORDS)

When examining survival rates following cardiac transplantation, it is important to examine the risk factors for both early (30-day) and late (greater than 30-day) survival as they may well be different. Factors affecting early survival appear related more to the preoperative condition of the patient (including degree of pulmonary hypertension) as well as advances that have been made in postoperative care. It is not immediately obvious why gender has such a profound effect on early survival and why primary graft failure rates appear higher in this group. Donor organ factors did not appear to relate to this difference. On the other hand, late survival appears to be influenced mainly by immunologic factors such as panel reactive antibody level and immunosuppressive protocol. A less dramatic effect of transpulmonary gradient appears to have a lasting effect on recipients even when they survive the initial 30-day period. Thus, pulmonary hypertension may have prolonged effects on the cardiac allograft which as yet we do not understand completely. The majority of late mortality is still due to graft atherosclerosis, infection, and acute cellular rejection, the latter 2 occurring most frequently within the first year after transplantation whereas death from graft atherosclerosis becomes most prominent beyond 5 years. Despite persistent improvements in 30-day survival, late survival following cardiac transplantation will only improve with the advent of better tissue matching and improved immunosuppression. The results with FK506, for example, are promising.

Amyloid heart disease has been considered a contraindication for heart transplant on the basis of the hypothesis that it is a systemic disease and that amyloid deposition would occur in the cardiac allograft. Despite these concerns, several centers have performed heart transplantation for amyloidosis in a limited number of cases. A survey was sent to all of the U.S. centers and a limited number of European centers listed with the Registry of the International Society for Heart Transplantation. Nineteen centers responded, and data were provided for a total of seven patients (three men and four women, with a mean age of 46 years, range, 30 to 60 years) who had transplants for cardiac amyloid. The diagnosis of cardiac amyloidosis was made histologically on endomyocardial biopsy and/or examination of the explanted heart. Additional organ involvement included liver (two cases), rectal (two cases), renal (one case), gingiva (one case), and tongue (one case). A specific amyloid protein was identified in five patients (four lambda, one kappa Ig light chain). Two patients developed recurrent amyloid in their allograft seen by electron microscopy at 3 1/2 and 4 months, respectively. One patient developed progressive diastolic dysfunction, but systolic function was preserved. This patient died 13 months after transplantation as a result of progressive liver infiltration with amyloid. One patient died immediately after operation. Five patients are alive and fully rehabilitated 32 +/- 12 months after transplant. On the basis of this small series, some patients with cardiac amyloidosis can undergo heart transplantation with good intermediate-term results.

This study was undertaken to investigate the impact of diabetes, which develops after heart transplantation, on infection and patient survival. Nondiabetic patients (366) underwent heart transplantation at our institution between June 1, 1980 and January 12, 1988. Of these patients, 29 (8%) developed posttransplantation diabetes (PTD), defined as a continued need for hypoglycemic agents. The PTD group did not differ significantly from the nondiabetic recipients in age, sex, or human leukocyte antigen type. The average age in the PTD group was 49 years. Average length of follow-up was 21 months (range 4 to 46 months). Eighteen patients are maintained on insulin. Eight patients are on oral hypoglycemic agents. Three patients died while on insulin. The average prednisone dosage in this group is 0.23 mg/kg/day. There have been 18 minor infections and four potentially serious nonlethal infections in the 27 PTD recipients. One lethal infection occurred 33 months after heart transplantation. The only other fatality was related to metastatic bladder cancer. This lethal infection rate of 3% compares with a rate of 11% in all nondiabetic recipients who have follow-up for 21 months. The 3-year actuarial survival of the PTD group is 75%, which compares favorably with the survival of nondiabetic patients. PTD cannot be predicted by sex, age, or human leukocyte type before transplantation, and it does not significantly increase the incidence of mortality or serious infection.

The hemodynamic and hormonal responses to dobutamine alone and with the addition of amrinone were studied in ten patients with severe heart failure. Dobutamine significantly increased heart rate, cardiac index, and stroke volume index and significantly decreased mean right atrial and systemic arterial pressures and systemic and pulmonary vascular resistance. The addition of amrinone further decreased significantly mean right atrial, pulmonary arterial, and pulmonary arterial wedge pressures and systemic vascular resistance, while heart rate rose. The response of the cardiac index was variable, increasing in seven and decreasing in three patients. Plasma renin activity rose significantly with dobutamine and further increased with amrinone. We conclude that in most patients with severe heart failure, amrinone, when combined with dobutamine, improves hemodynamics. The further increase in heart rate, variable effects on the cardiac index, and marked activation of the renin-angiotensin system suggest caution and potential limitations in the use of this combination.

Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

The positive inotropic/vasodilator agent MDL 17,043 was evaluated to determine its usefulness for both short-term support of the failing circulation and long-term treatment of patients with congestive heart failure. Both intravenous and oral administration of MDL 17,043 significantly increased cardiac output, stroke volume, stroke work index, and heart rate, and significantly decreased pulmonary arterial wedge, right atrial, and mean arterial pressures as well as systemic and pulmonary arteriolar resistance. Such hemodynamic responsiveness persisted in patients on long-term oral therapy with MDL 17,043. When compared with dobutamine, the peak hemodynamic effects of MDL 17,043 were similar except for somewhat greater increases in heart rate with dobutamine and somewhat greater decreases in mean pulmonary arterial and wedge pressures with MDL 17,043. Both intravenous and oral MDL 17,043 elevated plasma renin activity. Oral doses were rapidly absorbed, and the drug had an elimination half-life of about 20 hr. Although the majority of patients showed clinical improvement at 1 month, this effect tended to wane over time leading to either recurrent heart failure or death. Mortality rates at 1 year are about 46% in class III patients and 97% in class IV patients on long-term oral MDL 17,043. The results of these studies suggest that MDL 17,043 may be useful in the short-term management of the failing circulation; however, its value in the long-term management of patients with chronic heart failure remains unclear and requires further studies for resolution.

Rest and exercise hemodynamics with the beta agonist pirbuterol and a placebo preparation were studied in seven patients with severe chronic congestive heart failure. At rest, pirbuterol increased cardiac index (1.8 +/- 0.3 to 2.3 +/- 0.4 L/min/M2, p less than 0.01) and decreased systemic vascular resistance (1899 +/- 405 to 1419 +/- 257 dynes-sec-cm-5, p less than 0.01) without a significant change in heart rate, right atrial, pulmonary arterial, pulmonary arterial wedge, or systemic arterial pressures. Although there were slight increases in cardiac index at peak exercise with pirbuterol, neither total exercise time nor peak oxygen consumption were improved with this agent. No significant hemodynamic changes occurred with placebo at rest, nor was there improvement in exercise performance following placebo. Of three patients studied at six weeks, two showed total loss of hemodynamic effect of pirbuterol compared to the acute response. In conclusion, although acute rest hemodynamics improve with pirbuterol, the lack of improved acute exercise performance and the decrease in hemodynamic responsivity at six weeks appear to limit its usefulness in the treatment of heart failure.

ACCF : American College of Cardiology Foundation ACS : acute coronary syndrome AHA : American Heart Association CAD : coronary artery disease CABG : coronary artery bypass grafting CKMB : creatine kinase MB isoform cTn : cardiac troponin CT : computed tomography CV : coefficient of variation ECG : electrocardiogram ESC : European Society of Cardiology FDG : fluorodeoxyglucose h : hour(s) HF : heart failure LBBB : left bundle branch block LV : left ventricle LVH : left ventricular hypertrophy MI : myocardial infarction mIBG : meta-iodo-benzylguanidine min : minute(s) MONICA : Multinational MONItoring of trends and determinants in CArdiovascular disease) MPS : myocardial perfusion scintigraphy MRI : magnetic resonance imaging mV : millivolt(s) ng/L : nanogram(s) per litre Non-Q MI : non-Q wave myocardial infarction NSTEMI : non-ST-elevation myocardial infarction PCI : percutaneous coronary intervention PET : positron emission tomography pg/mL : pictogram(s) per millilitre Q wave MI : Q wave myocardial infarction RBBB : right bundle branch block sec : second(s) SPECT : single photon emission computed tomography STEMI : ST elevation myocardial infarction ST–T : ST-segment –T wave URL : upper reference limit WHF : World Heart Federation WHO : World Health Organization Myocardial infarction (MI) can be recognised by clinical features, including electrocardiographic (ECG) findings, elevated values of biochemical markers (biomarkers) of myocardial necrosis, and by imaging, or may be defined by pathology. It is a major cause of death and disability worldwide. MI may be the first manifestation of coronary artery disease (CAD) or it may occur, repeatedly, in patients with established disease. Information on MI rates can provide useful information regarding the burden of CAD within and across populations, especially if standardized data are collected in a manner that …