MRI-based abnormalities in young adults at risk of adverse bone health due to childhood-onset metabolic & endocrine conditions.

OBJECTIVE: Traditional methods of bone densitometry may not provide a comprehensive assessment of bone health. We aimed to assess bone micro-architecture and bone marrow adiposity (BMA) by MRI in adults with osteogenesis imperfecta (OI) and endocrinopathy including GH deficiency and/or hypogonadism. MEASUREMENTS: High-resolution micro-MRI images were acquired at the tibia using 3T MRI to calculate parameters of bone micro-architecture in seven adults with OI and 10 adults with endocrinopathies. MR Spectroscopy was performed in participants to calculate vertebral BMA, which was expressed as percentage fat fraction (%FF). Lumbar spine DXA was performed to assess bone mineral density. The MRI data were compared with a group of 22 healthy adults who were divided into two age-matched control groups. RESULTS: Intra-operator repeatability was high, with an average CoV of 1% for micro-MRI and 2·5% for MRS. The ratio of apparent bone volume to total volume (appBV/TV) in the endocrinopathy and OI groups was lower than in age-matched control groups (P = 0·003 and P = 0·008 respectively). A weak association between DXA BMD and appBV/TV was also observed (r = 0·5, P = 0·045). %FF was higher in the endocrinopathy group than in the age-matched control group (P = 0·005), but no difference in %FF was observed between the OI group and their age-matched control group (P = 0·26). CONCLUSIONS: MRI provides valuable detailed information on the micro-architecture and adiposity of bones and is capable of showing clear differences in bone parameters in a range of clinical conditions associated with abnormal bone health.

186Re-labeled antibodies to p185HER2 as HER2-targeted radioimmunopharmaceutical agents: comparison of physical and biological characteristics with 125I and 131I-labeled counterparts.

Overexpression of the HER2/neu protooncogene has been shown to correlate with poor clinical prognosis. A murine monoclonal antibody (4D5) directed against the extracellular domain (ECD) of p185HER2 has been shown to inhibit in vitro and in vivo growth of carcinomas overexpressing HER2 and has been humanized (rhuMAb HER2). The objective of the study was the identification of an agent which might be useful for in vitro studies, tumor imaging and/or radioimmunotherapy by linking beta-emitting radionuclides to these HER2-targeted antibodies. Murine 4D5 and humanized rhuMAb HER2 were radiolabeled with 125I, 131I or 186Re. Physical characteristics (TCA precipitability, SDS-PAGE, size exclusion chromatography), binding affinities to the HER2 ECD (in an ELISA and on SK-BR-3 cells) and antiproliferative activities of the radiolabeled antibodies were determined. Although 131I-4D5 and 131I-rhuMAb HER2 usually retained > 85% ECD binding, they exhibited increased aggregation and fragment content, drastically reduced antiproliferative activities and poor stability upon storage at 4 degrees C. For these antibody preparations, conservation of binding did not necessarily correlate with preservation of bioactivity indicating the importance of bioactivity determinations in radiolabeled antibody studies. Conversely, 4D5 and rhuMAb HER2 labeled with 125I or 186Re maintained physical properties, ECD binding, antiproliferative activities and were stable upon storage at 4 degrees C for at least 8 days. The superior retention of physical and biological characteristics of 186Re-labeled 4D5 and rhuMAb HER2 compared with their 131I-labeled counterparts suggests the potential for their use as radioimaging and radioimmunotherapeutic agents in the treatment of HER2 overexpressing tumors.

Echocardiographic findings in autosomal dominant polycystic kidney disease.

Echocardiography, including Doppler analysis, was performed to assess the prevalence of cardiac abnormalities in 163 patients with autosomal dominant polycystic kidney disease, 130 unaffected family members, and 100 control subjects. In these three groups, the prevalence of mitral-valve prolapse was 26, 14, and 2 percent, respectively (P less than 0.0005). A higher prevalence of mitral incompetence (31, 14, and 9 percent, respectively; P less than 0.005), aortic incompetence (8, 3, and 1 percent, respectively; P less than 0.05), tricuspid incompetence (15, 7, and 4 percent, respectively; P less than 0.02), and tricuspid-valve prolapse (6, 2, and 0 percent, respectively; P less than 0.02) was also found in the patients with polycystic kidney disease. These findings reflect the systemic nature of polycystic kidney disease and support the hypothesis that the disorder involves a defect in the extracellular matrix and the cardiac abnormalities are an expression of that defect.

Aerobic responses to low level exercise testing following an acute myocardial infarction.

Thirty-four patients who had recently sustained an acute myocardial infarction performed low-level exercise testing with analysis of expired gas 7.1 +/- 2.6 days after the event. They were classified as finishers (F) and nonfinishers (NF) of the low-level protocol. The ejection fraction in the NF was 39 +/- 14% vs 56 +/- 17% in the F (p less than 0.01), and the NF had 2.6 +/- 0.8 vessels stenosed vs 1.8 +/- 0.9 vessels stenosed in the F (p less than .05). Ten normal subjects also performed the exercise test. At the same workload, patients with recent myocardial infarction had significantly lower oxygen consumption (NF less than F), significantly higher minute ventilation (NF greater than F), ventilatory equivalent for oxygen (NF greater than F), and higher respiratory exchange ratio (NF greater than F) than did normal subjects. The heart rate responses were higher in the post infarction patients than in normal subjects. The oxygen pulse was significantly lower in the cardiac patients compared to normals. These findings suggest that during the early recovery phase from an acute myocardial infarction, patients, particularly the NF, utilize less oxygen at submaximal work loads than do normal subjects. This suggests that in these patients part of the energy requirements for exercise are met anaerobically. This could be due to abnormal extraction of oxygen by the working muscles or as a result of poor delivery of oxygen due to abnormal left ventricular function.

Predictive value of M-mode echocardiography in patients with congestive heart failure.

The M-mode echocardiogram (ECHO) is widely used to follow patients with congestive heart failure (CHF), but the value of ECHO for this purpose is unclear. In 49 patients with symptomatic CHF, we obtained ECHO during baseline evaluation to determine the value of ECHO for predicting 1-year survival or maximal oxygen uptake during exercise (VOmax). The cause of CHF was coronary artery disease in 12 patients and idiopathic dilated cardiomyopathy in 37 patients. Overall mortality at 1 year was 10 of 49 (20%), but was higher in patients with coronary artery disease (42%) compared to those with idiopathic dilated cardiomyopathy (14%), p less than 0.001. ECHO indices of left ventricular contractility were greater in survivors (S) in whom shortening fraction averaged 16 +/- 8 (SD)% vs 10 +/- 4% in nonsurvivors (NOS), p less than 0.025. Velocity of circumferential fiber shortening averaged 0.53 +/- 0.25 Hz in S vs 0.35 +/- 0.15 Hz in NOS, p less than 0.05. No left ventricular dimensions, including systolic and diastolic diameters, volume, wall thickness, and mass differed significantly between S and NOS. No ECHO measure of left ventricular dimensions or contractility correlated significantly with VOmax. Thus, ECHO may be useful to predict survival but not functional capacity in patients with CHF.

Minoxidil in patients with chronic left heart failure: contrasting hemodynamic and clinical effects in a controlled trial.

Minoxidil, a potent predominant arterial dilator, improves hemodynamics over the short term in patients with heart failure. In random double-blind fashion 17 patients with chronic left heart failure were given minoxidil (nine patients) or placebo (eight patients) in addition to digoxin and diuretics for 3 months. Cardiac index and heart rate increased and mean arterial pressure and systemic vascular resistance fell within 4 hr of minoxidil administration. Right heart and pulmonary arterial pressures were unchanged over the short term but rose after long-term minoxidil. After 3 months of minoxidil treatment, systemic vascular resistance was still reduced (11.7 +/- 6.3[SD] vs 17.1 +/- 3.1 U at baseline; p less than .05). Hemodynamics were similar at baseline and remained unchanged during placebo treatment. Mean left ventricular ejection fraction rose from 29.6 +/- 17.7% to 42.7 +/- 22.3% (p less than .05) after 3 months of minoxidil treatment (this result was influenced largely by responses in two patients), and remained unchanged (at 25.1 +/- 16.6%) after 3 months of placebo. Exercise duration and maximal oxygen uptake during exercise were unchanged during minoxidil or placebo treatment. Total clinical events, including increased need for diuretics, angina, ventricular arrhythmias, worsening heart failure, and death were all more frequent during minoxidil vs placebo administration (21 vs seven total events; p less than .01). Thus, despite improving hemodynamics and left ventricular function, long-term minoxidil administration was associated with a poorer clinical course in patients with chronic left ventricular failure. Furthermore, this experience demonstrates that improvement of left ventricular function alone cannot be reliably interpreted as proof of clinical efficacy of therapeutic interventions in patients with heart failure.

Hemodynamic effects of vasodilators and long-term response in heart failure.

Hemodynamic responses to vasodilators are commonly assessed when starting long-term vasodilator treatment in patients with chronic left ventricular failure, although the relation between short- and long-term responses is not established. Thus, short- and long-term hemodynamic responses to placebo and vasodilators (isosorbide dinitrate, minoxidil and enalapril or captopril) were measured and long-term clinical efficacy was assessed by changes in exercise capacity after 1 to 5 months of vasodilator administration (plus digitalis and diuretic agents) in 46 patients with New York Heart Association functional class II to IV heart failure caused by cardiomyopathy. There were no significant changes in hemodynamics or exercise capacity during placebo treatment. After initial doses and during long-term administration of vasodilator drugs, hemodynamics were significantly improved. After long-term vasodilator treatment, maximal oxygen uptake during exercise increased by 2.9 +/- 5.7 ml/min per kg from a control value of 14.1 +/- 5.6 ml/min per kg (p less than 0.01), and exercise duration also increased by 1.8 +/- 3.5 minutes (p less than 0.01). Changes in maximal oxygen uptake, however, did not correlate with short-term changes in pulmonary wedge pressure (correlation coefficient [r] = -0.14), cardiac index (r = -0.01) or systemic vascular resistance (r = -0.20). Long-term hemodynamic changes also failed to correlate with changes in exercise capacity. Baseline hemodynamics, cardiac dimensions and left ventricular ejection fraction before vasodilator administration all failed to correlate with baseline exercise capacity or with long-term changes in exercise capacity. Thus, hemodynamic measurements at initiation or during follow-up of vasodilator therapy do not relate to long-term clinical efficacy assessed by exercise capacity in patients with chronic left ventricular failure. Therefore, the rationale for making invasive hemodynamic measurements before initiating long-term vasodilator therapy for heart failure is questioned.

Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure.

The cause of exercise intolerance in congestive heart failure is unclear. Hemodynamic and ventilatory responses were measured during symptomatic maximal upright bicycle exercise in 28 patients with chronic severe left ventricular failure who achieved a maximal oxygen uptake of only 12 +/- 4 ml/min/kg (+/- standard deviation). All patients reached anaerobic metabolism as the respiratory exchange ratio rose and arterial pH fell significantly. Pulmonary capillary wedge pressure increased from 20 +/- 10 mm Hg at rest to 38 +/- 9 mm Hg at peak exercise and cardiac index increased from 2.51 +/- 0.73 to 4.54 +/- 1.65 liters/min/m2 (both p less than 0.001). Systemic vascular resistance decreased, but pulmonary vascular resistance did not change during exercise. Despite the marked pulmonary venous hypertension at peak exercise, blood gases were unchanged (PaO2, 96 +/- 15 mm Hg; PaCO2, 35 +/- 7 mm Hg). Systemic arterial oxygen content increased from 16 +/- 2 to 17 +/- 2 vol% (p less than 0.01). Changes in pulmonary capillary wedge pressure did not correlate with changes in arterial oxygen content. Results were similar whether patients were limited by dyspnea or fatigue. Thus, exercise intolerance in patients with severe left ventricular failure is associated with marked elevation of pulmonary capillary wedge pressure and anaerobic metabolism without hypoxemia or altered carbon dioxide tension. These findings suggest that exercise ability in congestive heart failure is more dependent on cardiac output than on ventilatory consequences of pulmonary congestion.

Effects of a new angiotensin converting enzyme inhibitor, enalapril, in acute and chronic left ventricular failure in dogs.

Enalapril (MK-421) is a new angiotensin converting enzyme inhibitor which effectively lowers elevated blood pressure and might also be useful in heart failure. Enalapril was infused into six awake dogs 2 hours after left circumflex coronary artery embolization (acute failure group) and into six other awake dogs two to six months after coronary embolization (chronic failure group). In the acute failure group 2 hours after embolization, increased left ventricular end-diastolic pressure and reduced cardiac output remained unchanged during enalapril infusion. In the chronic failure group, increased left ventricular end-diastolic pressure also remained unchanged during enalapril infusion, but cardiac output, which had fallen to 131.8 +/- 11.9 (S.D.) from 165.8 +/- 17.9 ml/min/kg (P less than 0.01) by two to six months in this group rose during enalapril infusion to 154.5 +/- 27.7 ml/min/kg (P less than 0.05). Heart rate and blood pressure were not changed during enalapril in either group, but stroke volume rose (26.0 +/- 5.9 to 29.2 +/- 6.9 ml, P less than 0.01) and systemic vascular resistance fell (58.5 +/- 10.3 to 39.3 +/- 4.3 units, P less than 0.01) during enalapril only in the chronic failure group. Plasma renin activity after embolization was slightly but not significantly higher in the acute failure group. Thus, enalapril appears to be an arterial vasodilator in dogs with chronic but not acute left ventricular failure.

Importance of venodilation during long-term vasodilator therapy of chronic left ventricular failure.

Vasodilators with different sites of action are used for long-term therapy of congestive heart failure, and selection of agents based on acute hemodynamic effects has been recommended. We compared the acute hemodynamic effects (by Swan-Ganz catheterization) and long-term responses (maximal oxygen uptake during exercise) associated with isosorbide dinitrate, a predominant venodilator, captopril, an arterial and venous dilator, and minoxidil, an arterial dilator, in 22 patients with congestive heart failure. In eight patients isosorbide dinitrate reduced pulmonary wedge pressure by 29% +/- 8% acutely (p less than .001) without significantly changing cardiac index or systemic vascular resistance. In eight patients captopril acutely reduced pulmonary wedge pressure by 42% +/- 22% (p less than .001) and systemic vascular resistance by 27% +/- 12% (p less than .01), while raising cardiac index by 19% +/- 18% (p less than .02). In six patients minoxidil raised cardiac index acutely by 38% +/- 30% (p less than .05) and reduced systemic vascular resistance by 35% +/- 12% (p less than .05) without changing pulmonary wedge pressure. After 2-5 months vasodilator administration maximal exercise oxygen uptake was increased by 7 +/- 3 ml/min/kg on isosorbide dinitrate (p less than .01), by 3 +/- 2 ml/min/kg on captopril (p less than .01), and by only 1 +/- 2 ml/min/kg on minoxidil (ns). Thus exercise capacity improved only during administration of drugs with venodilating action, failing to change during treatment with the arterial dilator despite a reduction in systemic vascular resistance. Predominantly arterial dilators alone may not be suitable for long-term vasodilator therapy for heart failure, and the regimens used should include venodilating agents.

Diagnostic implications of atrial vulnerability.

Extrastimulation in the atrial vulnerable zone may result in atrial fibrillation or flutter (AFF), especially with stimulation of multiple atrial sites. However, the clinical relevance of such vulnerability to AFF is unknown. Therefore, single twice-threshold extrastimuli were applied at three disparate right atrial sites in 45 consecutive unmedicated patients without overt heart failure. Group I consisted of 12 patients with documented spontaneous paroxysms of AFF. AFF was duplicated in 9 to 12 patients using extrastimulation in the vulnerable zone (5 in sinus rhythm, 4 requiring atrial pacing at 120 beats/min). Group II consisted of 33 patients without documented AFF dispite monitoring. Vulnerability to AFF was found in 12 of 33 patients (4 in sinus rhythm, 8 requiring atrial pacing). The duration of induced AFF did not discriminate between the two groups. Among the 12 Group II patients vulnerable to AFF, 3 had rapid palpitations, 2 had undiagnosed rapid tachycardias, 1 had atrial tachycardias and 1 junctional tachycardias. In vulnerable patients, the pause after AFF correlated with the pause after atrial pacing, but only 1 of 11 Group II patients with sick sinus syndrome was vulnerable. Thus, paroxysmal AFF may be duplicated with the extrastimulus technique if sufficient arial sites are stimulated, providing a model for evaluation of these arrhythmias. But atrial vulnerability, even to extrastimulation at normal heart rates, may be seen in patients suspected of atrial tachyarrhythmia in the absence of documented AFF, and does not contribute to the diagnosis of sinoatrial dysfunction.

Electrophysiologic effects of hydralazine on sinoatrial function in patients with sick sinus node syndrome.

The electrophysiologic effects of hydralazine were evaluated in nine hypertensive patients with sinoatrial dysfunction. Intravenous hydralazine, 0.15 mg/kg, caused no significant reduction in arterial blood pressure. Yet this dose of hydralazine increased heart rate from 61.9 +/- 4.1 beats/min (mean +/- standard error of the mean) to 68.6 +/- 4.9 (P less than 0.001). Sinus nodal recovery time upon termination of atrial pacing shortened from 3,207 +/- 1,098 to 2,064 +/- 573 msec (P less than 0.05) and second escape cycles shortened as well (P less than 0.025). Acceleration of heart rate and abbreviation of recovery time did not closely correlate with change in blood pressure (r = 0.41 and 0.18, respectively). Junctional escape beats became more frequent and junctional escape time shortened from 2,525 +/- 692 to 1,705 +/- 382 msec (P less than 0.05). Sinoatrial conduction time tended to shorten, but a significant change was not observed. Atrial tachyarrhythmias did not occur and atrial refractoriness was unchanged. Thus, a minimal blood pressure response to hydralazine was associated with enhanced automaticity. Hydralazine merits clinical trial for treatment of sick sinus syndrome with concomitant hypertension.