Early prediction of cardiac allograft vasculopathy and heart transplant failure.

Early risk-prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross-validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule-1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long-term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low-risk subgroup could possibly be followed with fewer invasive procedures.

Value of serum-soluble intercellular adhesion molecule-1 for the noninvasive risk assessment of transplant coronary artery disease, posttransplant ischemic events, and cardiac graft failure.

BACKGROUND: Adhesion molecules on arterial endothelium have been implicated in spontaneous atherosclerosis and transplant coronary artery disease (CAD). We studied whether elevated serum-soluble intercellular adhesion molecule-1 (sICAM-1) during the immediate posttransplant period was a risk factor for CAD, posttransplant ischemic events, or cardiac graft failure. METHODS AND RESULTS: We initially studied serum sICAM-1 in a subset of 16 cardiac allograft recipients (5.5+/-0.7 samples per patient) to determine a cutoff point that best correlated with presence of arterial and arteriolar endothelial ICAM-1 in matching endomyocardial biopsies. The cutoff value was 308 ng/mL. Subsequently, we prospectively evaluated serum sICAM-1 in serial samples (5.3+/-0.1 per patient) obtained during the first 3 months after transplantation in a validation subset of 130 recipients and correlated early sICAM-1 levels with long-term outcome. Serum sICAM-1 >308 ng/mL correlated significantly with ICAM-1 on arterial and arteriolar endothelium (P:=0.02). Cardiac allograft recipients with serum sICAM-1 >308 ng/mL had 2.67 (95% CI, 1.28 to 5.59, P:=0.009) times greater risk of CAD and 3.63 (95% CI, 1.05 to 12.5, P:=0.04) times greater risk of graft failure. Recipients with sICAM-1 >308 ng/mL also developed more severe CAD (P:=0.009) and more ischemic events (P:=0.03) after transplantation. CONCLUSIONS: Serum sICAM-1 levels can be used to noninvasively assess risk of transplant CAD, posttransplant ischemic events, and cardiac graft failure.

Short- and long-acting angiotensin-converting enzyme inhibitors: a randomized trial of lisinopril versus captopril in the treatment of congestive heart failure. The Multicenter Lisinopril-Captopril Congestive Heart Failure Study Group.

A randomized, parallel, double-blind study was performed with lisinopril, a long-acting angiotensin-converting enzyme inhibitor, versus captopril, a shorter-acting angiotensin-converting enzyme inhibitor, in the treatment of congestive heart failure. All patients were in New York Heart Association class II, III or IV and had remained symptomatic despite therapy with digoxin and diuretics. After a 4 to 14 day placebo baseline period, patients were randomized to receive either lisinopril, 5 mg orally once per day (n = 94), or captopril, 12.5 mg orally three times per day (n = 95), in addition to continuation of digoxin and diuretics. The dose of study drug could be doubled at 4 week intervals for a total of 12 weeks of double-blind therapy. The maximal dose was 20 mg once per day of lisinopril or 50 mg three times per day of captopril. The addition of either lisinopril or captopril to a regimen of diuretics or digoxin, or both, caused an increase in exercise duration as assessed on a motorized treadmill. When protocol violators were excluded, patients receiving lisinopril had a statistically greater increase in exercise duration than that of patients receiving captopril. In patients with renal impairment (serum creatinine greater than 1.6 mg/dl at baseline), lisinopril was superior to captopril in improving exercise duration. Lisinopril, but not captopril, increased left ventricular ejection fraction in patients with moderately to severely (less than 35%) decreased function (p less than 0.05). Improvement in functional capacity and quality of life, as assessed by the Yale Scale dyspnea/fatigue index, was significantly greater for the lisinopril group.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: a report from the Registry of Studies of Left Ventricular Dysfunction. SOLVD Investigators.

OBJECTIVES: This study examined the relation between neurohumoral activation and severity of left ventricular dysfunction and congestive heart failure in a broad group of patients with depressed left ventricular function who were not recruited on the basis of eligibility for a therapeutic trial. BACKGROUND: Previous studies have established the presence of neurohumoral activation in patients with severe congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to an impairment in left ventricular function. METHODS: From the 6,273 patients recruited into the Studies of Left Ventricular Dysfunction Registry (SOLVD), a subgroup of 859 patients were randomly selected, and their plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were correlated with clinical findings, New York Heart Association functional class, left ventricular ejection fraction and drug use. RESULTS: There was a weak but significant correlation between ejection fraction and an increase in plasma norepinephrine (rho = -0.18, p < 0.0001), plasma renin activity (rho = -0.24, p < 0.0001) and arginine vasopressin (rho = -0.12, p < 0.003). The only exception was atrial natriuretic peptide, which showed the best correlation to ejection fraction (rho = -0.37, p < 0.0001). Deterioration in functional class was associated more with increases in atrial natriuretic peptide (p = 0.0003) and plasma renin activity (p = 0.0003) and less with an increase in plasma norepinephrine. Of the clinical variables, elevated jugular venous pressure and third heart sound (S3) gallop were significantly associated with increased levels of plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. We then compared the relation of neurohormones with clinical signs, functional status, ejection fraction and drug therapy and controlled for mutual interactive effects. After adjustment, a decrease in ejection fraction was still significantly related to an increase in plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. In contrast, only a difference between functional classes I and III/IV was associated with an increase in plasma renin activity and atrial natriuretic peptide levels. CONCLUSIONS: Neurohumoral activation in patients with heart failure is related to severity of left ventricular functional depression, and this relation is independent of functional class or concomitant drug therapy.

Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: results of the Studies of Left Ventricular Dysfunction (SOLVD) Registry. The SOLVD Investigators.

OBJECTIVES: The aim of this study was to determine the differences in neurohumoral responses between patients with pulmonary congestion with and without impaired left ventricular ejection fraction. BACKGROUND: Previous studies have established the presence of neurohumoral activation in patients with congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to the impairment in systolic contractility. METHODS: The 898 patients recruited into the Studies of Left Ventricular Dysfunction (SOLVD) Registry substudy were examined to identify those patients with pulmonary congestion on chest X-ray film who had either impaired (< or = 45%, group I) or preserved (> 45%, group II) left ventricular ejection fraction. Plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were measured in these two groups of patients and compared with values in matched control subjects. RESULTS: Distribution of the New York Heart Association symptom classification was the same in the two groups of patients. Compared with control subjects, patients in group II with pulmonary congestion and preserved ejection fraction had no activation of the neurohumoral mechanisms, except for a small but statistically significant increase in arginine vasopressin and plasma renin activity. Compared with patients in group II, those in group I with pulmonary congestion and impaired ejection fraction had significant increases in plasma norepinephrine (p < 0.002), plasma renin activity (p < 0.02) and atrial natriuretic peptide levels (p < 0.0007). When we controlled for baseline differences between groups I and II, the between-group differences in plasma norepinephrine (p < 0.02) and atrial natriuretic peptide (p < 0.002) remained significant. However, plasma renin activity was not significantly different between groups I and II. When the effects of diuretic agents and angiotensin-converting enzyme inhibitors were adjusted, patients with lower ejection fraction were found to have significantly higher plasma norepinephrine and atrial natriuretic peptide levels. CONCLUSIONS: The results point to the importance of the decrease in left ventricular ejection fraction as one of the mechanisms for activation of neurohormones in patients with heart failure.

Discrepancy between first-dose converting enzyme inhibition at rest and subsequent inhibition during exercise in chronic heart failure.

Low-dose angiotensin-converting enzyme inhibition is thought to completely block the renin-angiotensin system. This study examined the hemodynamic and hormonal responses to initial low- and higher dose converting-enzyme inhibitor (lisinopril or captopril) at rest compared with the response during subsequent chronic therapy while treadmill exercise testing was performed in nine patients with chronic heart failure. At rest, similar changes in systemic arterial pressure, plasma renin activity, and plasma aldosterone concentration were found with initial low and higher doses. However, after at least 4 weeks of therapy, dose-dependent increases in plasma renin activity and decreases in plasma aldosterone concentration were noted during exercise without significant differences in exercise systemic arterial pressure or heart rate. This discrepancy suggests that initial low-dose converting enzyme inhibition does completely block the enzyme, but higher dose therapy is required for complete blockade during subsequent exercise in chronic heart failure.

Neurohumoral activation during exercise in congestive heart failure.

Neurohumoral factors were assessed in 14 subjects with chronic, stable New York Heart Association functional class II or III congestive heart failure and nine comparably aged normal subjects at rest and during moderate (50 W) and strenuous (100 W) upright exercise. Heart failure was associated with elevated plasma renin activity and plasma antidiuretic hormone (ADH) concentrations at rest. However, plasma renin activity almost doubled (from 4.7 +/- 0.6 to 8.4 +/- 1.1 ng/ml per hour) during strenuous exercise in subjects with heart failure, and changed only minimally in normal control subjects. Plasma ADH concentration did not change during exercise in the presence of heart failure, but rose in normal subjects during strenuous exercise to levels comparable to those of subjects with heart failure. Similar plasma osmolality values were present in both groups. Circulating norepinephrine concentrations were insignificantly elevated by heart failure both at rest and during exercise, and plasma epinephrine concentrations were similar. These findings suggest independent neurohumoral activation during exercise in the presence of congestive heart failure, with predominant activation of the renin-angiotensin-aldosterone axis.

Hemodynamic effects of intravenous prenalterol in severe heart failure.

Nine patients with chronic severe low output heart failure (radionuclide left ventricular ejection fraction 17 +/- 5 percent [mean +/- standard deviation], left ventricular filling pressure 26 +/- 6 mm Hg, cardiac index 1.9 +/- 0.4 liters/min per m2, left ventricular stroke work index 18 +/- 6 g-m/m2) from various causes were treated with intravenous prenalterol (a new catecholamine-like inotropic agent) in doses of 1,4 and 8 mg. Significant hemodynamic improvement occurred as measured by increased left ventricular ejection fraction (to 26 +/- 4 percent), decreased left ventricular filling pressure (to 21 +/- 8 mm Hg) and increased cardiac index (to 2.4 +/- 0.6 liters/min per m2) and left ventricular stroke work index (to 25 +/- 8 g-m/m2). Significant increases in heart rate (from 87 +/- 18 to 91 +/- 18 beats/min) and mean systemic arterial pressure (from 87 +/- 8 to 92 +/- 7 mm Hg) also occurred. Peak hemodynamic response occurred at various doses. Significant adverse effects associated with prenalterol consisted of increased ventricular ectopic beats in two patients and asymptomatic ventricular tachycardia in two patients. Thus, intravenous prenalterol produces hemodynamic improvement in patients with a chronic severe low output state but may be associated with increased ventricular ectopic activity.

Neurohumoral variability in left ventricular dysfunction. SOLVD Investigators. Studies of Left Ventricular Dysfunction.

The immediate and longer term variability of selected vasoactive- and volume-regulating neurohormones were measured in patients entering a substudy of the Studies of Left Ventricular Dysfunction--a randomized clinical trial in patients with left ventricular ejection fraction < or = 35%. The variability of these hormones has not been determined in a large cohort of patients. Immediate (short-term) variability was assessed by systematically comparing levels after 15 and 30 minutes of supine rest at the initial visit, and longer term variability was assessed by comparing 30-minute supine rest values at the initial visit with corresponding values taken at 30 minutes after 16 to 24 days of stable therapy. Initial values obtained at the first visit after 30-minute supine rest for all 209 patients were (mean +/- SEM) 512 +/- 21 pg/ml pg/ml for plasma norepinephrine, 1.9 +/- 0.2 ng/ml/hr for plasma renin activity, 3.0 +/- 0.1 pg/ml for plasma arginine vasopressin, and 129 +/- 5.3 pg/ml for plasma atrial natriuretic peptide. All variables were moderately increased relative to established normal values. There was a small but significant decrease from 15- to 30-minute supine posture in all neurohormones, except arginine vasopressin. In the presence of stable background therapy, no significant differences were found between measurements obtained after 30 minutes supine rest at the initial visit and 16 to 24 days later. Spearman correlation coefficients corresponding to immediate and longer term variability were high (range 0.55 to 0.79) (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular antithrombin and clinical outcome in heart transplant patients.

A procoagulant microvasculature is associated with accelerated development of coronary artery disease (CAD) and failure in heart transplant patients. This study was performed to evaluate how changes in natural anticoagulation within cardiac allografts affect outcome. We prospectively studied 141 consecutive cardiac allograft recipients who underwent transplantation between 1988 and 1997. Serial endomyocardial biopsy specimens (6.5 +/- 0.1 biopsy specimens/patient) obtained during the first 3 months after transplantation were studied immunohistochemically to evaluate vascular antithrombin, and annual coronary angiograms (3.8 +/- 0.2 angiograms/patient) were studied to evaluate CAD. Antithrombin was present in arteries and veins, but not in capillaries, of all donor heart biopsy samples. Allografts that maintained vascular antithrombin had the best prognosis. Allografts with early and persistent loss of vascular antithrombin (n = 21) developed CAD earlier (p < 0.001), developed more severe disease (p < 0.001), showed more disease progression (p < 0.001), and failed more often (p = 0.003) and earlier (p < 0.001) than allografts retaining normal vascular antithrombin (n = 45). However, allografts that lost and recovered vascular antithrombin while developing unusual capillary antithrombin binding (n = 75) had less CAD, developed CAD later, had less severe disease and less disease progression (p < 0.01), and failed less often (p = 0.01) and later (p = 0.03) than allografts with persistent loss of vascular antithrombin. The persistent lack of a thromboresistant microvasculature increases risk of subsequent CAD and graft failure. However, recovery of vascular antithrombin and development of unusual capillary antithrombin binding improves allograft outcome.

Characteristics of peak aerobic capacity in symptomatic and asymptomatic subjects with left ventricular dysfunction. The Studies of Left Ventricular Dysfunction (SOLVD) Investigators.

Expired gas analysis was used to determine the aerobic exercise performance of subjects with depressed left ventricular (LV) systolic function and congestive heart failure (CHF). To determine whether subjects with no or minimal CHF have better aerobic exercise performance than do those with overt CHF, oxygen consumption (VO2) at anaerobic threshold (AT) and peak exercise was measured in 184 subjects with LV ejection fraction less than or equal to 0.35 who participated in the Studies of Left Ventricular Dysfunction. Subjects were divided into those with overt CHF needing treatment (treatment trial; n = 20) and those who had neither overt CHF nor treatment for CHF (prevention trial; n = 164). Treatment trial subjects had a lower LV ejection fraction (0.25 +/- 0.07) than did prevention trial ones (0.29 +/- 0.05; p = 0.001), but there were no differences in age, gender, body weight, resting heart rate and blood pressure. Treadmill exercise testing was performed after 2 to 3 weeks of placebo (no angiotensin-converting enzyme inhibitor) treatment. Treatment trial subjects exercised for a shorter time (493 +/- 160 seconds) and attained a lower peak VO2 (13 +/- 4 ml/kg/min) and VO2 at AT (11 +/- 4 ml/kg/min) than did prevention trial ones (842 +/- 277 seconds, and 20 +/- 6 and 16 +/- 5 ml/kg/min, respectively). Analysis of covariance showed that the differences in peak VO2 and VO2 at AT were statistically significant between the 2 trials after adjusting for age, gender, LV ejection fraction and New York Heart Association functional class.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of long-term enalapril therapy on neurohormones in patients with left ventricular dysfunction. SOLVD Investigators.

The aim of this study was to compare the long-term effects of treatment with enalapril or placebo on plasma neurohormones in patients with left ventricular (LV) dysfunction. Elevated neurohormonal levels are associated with increased mortality in patients with congestive heart failure. Multiple studies have shown that angiotensin-converting enzyme inhibitors decrease mortality and morbidity in these patients. In Studies of Left Ventricular Dysfunction (SOLVD), enalapril significantly reduced mortality in patients with symptomatic LV dysfunction (treatment trial). In contrast, in patients with asymptomatic LV dysfunction (prevention trial), there was no significant reduction in mortality with enalapril therapy. The effect of enalapril was examined in 333 prevention trial and 129 treatment trial patients. Plasma norepinephrine (NE) and plasma renin activity were measured in these patients at baseline, and at 4 and 12 months of follow-up. In a subset of these patients, atrial natriuretic peptide (ANP) and arginine vasopressin were also measured. Analysis of covariance models were used to determine the effect of enalapril on each neurohormone. Participants in the treatment trial had significantly higher neurohormonal levels when compared with those in the prevention trial or normal control subjects. In the treatment trial, patients taking enalapril had a greater decrease in plasma NE levels than patients taking placebo (p < 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Neurohumoral and cardiopulmonary response to sustained submaximal exercise in the dog.

Neurohumoral, cardiovascular, and respiratory parameters were evaluated during sustained submaximal exercise (3.2 km/h, 15 degrees elevation) in normal adult mongrel dogs. At the level of activity achieved (fivefold elevation of total body O2 consumption and threefold elevation of cardiac output), significant (P less than 0.05) increases in plasma norepinephrine and epinephrine concentration (from 150 +/- 23 to 341 +/- 35 and from 127 +/- 27 to 222 +/- 31 pg/ml, respectively) were present, as well as smaller but significant increases in plasma renin activity and plasma aldosterone concentration (from 2.2 +/- 0.3 to 3.1 +/- 0.6 ng X ml-1 X h-1 and from 98 +/- 8 to 130 +/- 6 pg/ml, respectively). Plasma arginine vasopressin increased variably and insignificantly. The cardiovascular response (heart rate, systemic arterial and pulmonary arterial pressures, left ventricular filling pressure, and calculated total peripheral and pulmonary arteriolar resistance) closely paralleled that of human subjects. Increased hemoglobin concentration was induced by exercise in the dogs. The ventilatory response of the animals was characterized by respiratory alkalosis. These data suggest similarities between canine and human subjects in norepinephrine, plasma renin activity, and plasma aldosterone responses to submaximal exercise. Apparent species differences during submaximal exertion include greater alterations of plasma epinephrine concentration and a respiratory alkalosis in dogs.

Chronic alpha-adrenoceptor blockade with trimazosin in congestive heart failure.

We evaluated chronic adjunctive alpha-1 receptor blockade with trimazosin in congestive heart failure. This agent produced hemodynamic effects consistent with venodilation (reduced left ventricular volume and filling pressure with increased left ventricular ejection fraction), but only during exercise. Resting hemodynamic parameters and exercise duration were not significantly altered by chronic alpha-1 receptor blockade.

The exercise response in idiopathic dilated cardiomyopathy.

In order to more clearly define the exercise response of idiopathic dilated cardiomyopathy (IDC), 20 patients in this study with strictly defined IDC were evaluated with radionuclide ventriculography and invasive hemodynamic monitoring. Severe cardiovascular impairment was present at rest, and peak supine exercise produced progressive left ventricular (LV) dilatation in both diastole and systole (mean +/- SEM from 172 +/- 14 to 212 +/- 22 ml/m2 at end-diastole and from 137 +/- 14 to 170 +/- 22 ml/m2 at end-systole; both p less than 0.03). There were marked increases in LV and right ventricular filling pressure (from 17 +/- 2 to 36 +/- 3 mmHg and from 7 +/- 2 to 15 +/- 2 mmHg, respectively; both p less than 0.0001) and increased pulmonary artery pressure. Mean LV ejection fraction did not change significantly with exercise (22 +/- 2 to 23 +/- 3%; p greater than 0.8), but individual patients demonstrated substantial variability. Cardiac output rose less than in normals and increases were brought about primarily by subnormal heart rate increases. High resting and exercise systemic and pulmonary vascular resistance were indicative of limited vasodilator reserve. Despite marked hemodynamic abnormalities, 10 of the 20 subjects had well preserved exercise capacity (greater than or equal to 12 min exercise duration). These patients as a group had significantly lower resting heart rate and higher exercise cardiac output and lower exercise systemic vascular resistance. However, they did not differ from the other patients with respect to resting LV function.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of prenalterol and dobutamine in a canine model of acute ischemic heart failure.

The hemodynamic effects of the inotropic agents prenalterol and dobutamine were compared in a canine model of acute ischemic heart failure following two-vessel coronary artery constriction. Intravenous infusions of both inotropic agents resulted in improvement of cardiac output, left ventricular maximum dP/dt, and contractile force in the nonischemic zone and in a decrease in systemic vascular resistance. No significant changes occurred in ischemic zone contractile force or left ventricular end-diastolic pressure following either inotropic agent compared to saline controls. Significant differences between the two inotropic agents consisted of prenalterol's markedly longer duration of action (hemodynamic half life of 3 hr after discontinuation compared to a value of 1.7 min after dobutamine discontinuation) and greater augmentation of cardiac output at high-dose dobutamine due to greater increases in heart rate. However, similar hemodynamic effects were noted with prenalterol and dobutamine at doses which increased nonischemic contractile force 50%. Both inotropic agents were associated with ventricular arrhythmias in the acute ischemic state. Implications regarding the use of prenalterol and dobutamine in clinical acute ischemic low-output states are discussed.

Regional myocardial contractile response to the beta-adrenergic stimulant prenalterol in the conscious dog following myocardial infarction. Mechanism of hemodynamic effect.

In order to assess regional myocardial contractile responses to the beta-adrenergic stimulant prenalterol after recent myocardial infarction, 9 male mongrel dogs underwent left circumflex coronary artery (LCX) occlusion after implantation of miniature subendocardial sonomicrometer crystals in normal, marginally ischemic (border) and central ischemic zones. 90-min LCX occlusion with reperfusion resulted in substantial infarction (mean +/- SEM 24 +/- 3% of total left ventricular area) and characteristic regional functional alterations. In conscious, unsedated animals 72 h after infarction, intravenous prenalterol (30 micrograms/kg) significantly decreased end-diastolic and end-systolic segment length and increased percent systolic shortening in normal and border zones, but did not alter ischemic zone function. Heart rate increased significantly with prenalterol. Regional myocardial function before drug administration correlated closely with response to the inotropic agent. These results indicate that the mechanism by which prenalterol improves cardiac function 72 h after myocardial infarction is stimulation of normal and marginally ischemic myocardium.