Sundt, Thoralf M.

Abstract Background: Patients with AL and congestive heart failure have a median survival of less than one year. Methods: Between 1994 and 2005, 11 patients underwent sequential heart transplant followed by autologous peripheral blood stem cell transplant (SCT) for treatment of AL. Patients had heart dominant AL with minimal/no other organ impairment and no evidence of multiple myeloma. Results: Patients ranged in age from 35 to 63 years (median 54). All had biopsy proven amyloidosis and monoclonal protein detectable in serum (73%) or urine (100%). Free light chain assay was available prior to SCT in 6 and was abnormal in all. All patients presented with NYHA Class III or IV heart failure. All but two patients had no other organ involved at the time of heart transplant. One patient had his heart transplant at another facility and had renal involvement at the time of heart transplant. One patient had peripheral nerve involvement documented prior to heart transplant. Five patients had progression of amyloid to involve other organs by the time of SCT. These included: renal (6), peripheral nerve (2), macroglossia (3), gastrointestinal (2). The median time from diagnosis to heart transplant was 3 months (range 1 to 5). The median time from heart transplant to SCT was 8 months, (range 3 to 24). Conditioning chemotherapy consisted of melphalan 200 mg /m2 (6 patients) or melphalan 140 mg/m2 (5 patients). Two patients died of complications before day +100, (TRM of 18%). Hematologic remissions were seen in 8 and organ responses in 3. Five were unable to be evaluated for organ response due to the heart transplant. Three died from progressive amyloidosis at 66, 56.7, and 55 months following SCT. The median survival is 56.7 months from SCT. Six are alive with a median follow-up of 24 months, range 9 to 90 months. Among the 6 surviving patients, one patient relapsed and one patient has failed to improve, but 4 patients are in continued remission. One patient developed secondary myelodysplastic syndrome. Conclusions: Heart transplant followed by SCT is feasible and offers durable remissions for carefully selected patients with cardiac AL. Figure Figure

The natural history of penetrating atherosclerotic ulcers (PAUs) of the descending thoracic aorta remains unclear. Between January 1996 and June 2000, PAU was diagnosed in 36 patients (16 men, 20 women; mean age 74.9 ± 1.5 years) at Washington University. Imaging studies and hospital records were reviewed. Late follow-up was by search of the Social Security Death Index and telephone interview. None of 16 asymptomatic patients underwent operation. At follow-up (median 457 days), 6 patients had died of unrelated and 2 of unknown causes. Among 20 symptomatic patients, 10 had associated intramural hematoma (5) or dissection (5), of whom 3 underwent operation. At median follow-up (448 days), the 7 unoperated patients remained alive without an aortic operation. Among the remaining 10 symptomatic patients, 3 had an aortic operation and 2 died of unknown causes during follow-up (median 586 days). These data suggest that, in selected cases, PAU may be managed expectantly with careful observation.

Endothelium-dependent relaxations are inhibited during chronic vasospasm after subarachnoid hemorrhage in the canine basilar artery, although the luminal release of endothelium-derived relaxing factor (EDRF) is maintained. The present study investigated the mechanisms underlying the impaired vascular reactivity and in particular whether the loss of responsiveness of the smooth muscle to EDRF is due to an impaired production of cGMP. Bradykinin and nitric oxide evoked concentration-dependent relaxations in isolated canine basilar arteries with and without endothelium, respectively, which were reduced in the subarachnoid hemorrhage group. Relaxations evoked by M&B22,948 (an inhibitor of cGMP phosphodiesterases) were smaller, but those evoked by the lipophilic cGMP analogue 8-bromo-cGMP were potentiated slightly in the subarachnoid hemorrhage group. The resting levels of cGMP in rings with endothelium (reflecting the effect of spontaneous release of EDRF) and those evoked by bradykinin in rings with endothelium and by nitric oxide in rings without endothelium were diminished in the subarachnoid hemorrhage group. These data indicate that the altered endothelium-mediated relaxations of the smooth muscle after subarachnoid hemorrhage is due, at least in part, to an impaired activation of soluble guanylate cyclase leading to a reduced production of cGMP in the smooth muscle.

Cerebral adenosine triphosphate and lactate concentrations were measured in the squirrel monkey ( Saimiri sciureus ) before, during, and at selected times after various periods of middle cerebral artery occlusion. The gradual decrease in ATP to 55, 35, and 20%, of normal and the increase in lactate to 7, 8, and 10 times normal after 2, 3, and 4 hours of occlusion, respectively, were reversible with restoration of flow. Electrocorticograms recorded in acute preparations indicated potential for recovery. The correlation of lactate levels with previous determinations of blood flow in this preparation supports the theory that loss of autoregulation and "luxury perfusion" in cerebral ischemia results from localized metabolic acidosis due to accumulation of lactic acid. In a separate group of monkeys, the ischemic lesions were found to be largely reversible after 2 or 3 hours and irreversible after 4 hours of middle cerebral artery occlusion; the cause of death in the monkeys subjected to 4 hours of occlusion was edema, which progressed even after restoration of flow.

Correlative studies of cortical blood flow measured by the 85 Kr washout technique and observations of the cortical blood vessels of 10 squirrel monkeys subjected to temporary occlusion of the middle cerebral artery are described. During occlusion, cortical blood flow in core areas of ischemia decreased to 0.12 to 0.90 ml/g/min (20 to 50% of preocclusion values) and became pressure dependent with failure of autoregulation. After release of the occluding clip, cortical blood flow was restored. Correlation between degree of vascular reaction judged by observation of the cortex and degree of hyperemia as determined by cortical blood flow was poor. There was incomplete correlation between the degree of hyperemia and the degree of preceding ischemia. Hyperemia, or "luxury perfusion," manifested by red venous blood, appears to be related to failure of cerebral tissue to utilize available oxygen as well as to "reactive" hyperemia, or supernormal blood flow, in regions previously ischemic. There was no demonstrable gradual failure of collateral circulation during occlusion. Cerebral edema was progressive and even progressed after restoration of cortical blood flow; it was incompletely correlated with the degree of ischemia and degree of hyperemia.

Cerebral blood flow (CBF) was measured during 28 carotid endarterectomies in 25 patients, by injection of 133 Xe into the exposed internal carotid artery (ICA). Twenty-three patients had episodic cerebral or retinal ischemia and five had neurologic deficits before operation. Initial CBF values were variable. Increases of Pa Co Co2 caused CBF to increase in four of six patients, to increase slightly in one, and to decrease in one. In each of 19 procedures, CBF decreased during surgical occlusion of the ICA, 11 times to less than 30 ml/100 g/min, but absence of postoperative worsening indicated that decreased ICA blood flow is not a major risk of the procedure; embolization from the site of operation may be a greater threat to the patient. CBF increased after 14 endarterectomies, perhaps due to failure of autoregulation or to reactive hyperemia. Measurements of jugular PV o o2 and lactate concentration were of little value.