Daratumumab for the treatment of multiple myeloma.

Since its initial approval in 2015, daratumumab has had a tremendous impact on the treatment of multiple myeloma. It is a monoclonal antibody that targets CD38, an antigen with high surface expression on multiple myeloma cells. While it initially received approval as a monotherapy for multiply relapsed multiple myeloma, its favorable toxicity profile allowed for combinations with other novel myeloma therapies leading to numerous indications as a component of triplet and quadruplet regimens. These indications now span relapsed/refractory populations and both transplant-eligible and transplant-ineligible patients with newly diagnosed myeloma. Further investigations are underway to continue to expand the reach of daratumumab, including large phase III collaborative trials to assess the efficacy of daratumumab as part of post-transplant maintenance and its impact on smoldering myeloma. The recent introduction of a subcutaneous formulation of daratumumab with proven noninferiority will improve the convenience and accessibility of the drug. In this review, we examine the preclinical development of daratumumab, its pharmacology and clinical investigations that demonstrated its safety and efficacy. Furthermore, we discuss the outstanding questions related to daratumumab and ongoing clinical trials seeking to answer them.

Isatuximab for the treatment of multiple myeloma.

Isatuximab is an IgG1 monoclonal antibody targeting CD38 that has received regulatory approval in combination regimens for patients with relapsed/refractory multiple myeloma. CD38 is an antigen with high surface expression on multiple myeloma cells. While daratumumab holds most of the market share for this drug class, isatuximab offers several unique aspects including a mechanism of action that may involve more direct myeloma-cell inhibition and killing and less reliance on cross-linking and immune effector cells, as well as subgroup data from pivotal trials showing notable efficacy in populations with renal impairment, high-risk cytogenetics and the elderly. While the administration of the drug remains intravenous, studies of fixed-volume infusion and rapid infusion may improve drug administration convenience. Ongoing studies are examining isatuximab in combination with other immune therapies and cellular therapies, conventional chemotherapy and across other disease entities.

Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy.

On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.

Donor-lymphocyte infusion following haploidentical hematopoietic cell transplantation with peripheral blood stem cell grafts and PTCy.

Donor-lymphocyte infusion (DLI) for relapse following haploidentical hematopoietic cell transplantation (haploHCT) with post-transplant cyclophosphamide (PTCy) has been described in recipients of bone marrow grafts, but not recipients of G-CSF mobilized peripheral blood (PB) grafts. We retrospectively identified patients who underwent DLI following PB-haploHCT with PTCy for relapse, or loss of chimerism (LOC). Twelve patients (57%) received DLI for hematologic relapse/persistent disease, seven (33%) for extramedullary relapse and two (10%) for LOC. Sixteen (76%) received chemotherapy prior to DLI, which did not correlate with response. The most common first dose was 1 × 106 CD3+ cells/kg. Two patients developed grade I aGvHD post DLI, one had grade II and two had grade III. One developed mild skin cGvHD 1361 days post DLI. Pre-DLI aGvHD predicted post-DLI aGvHD (P=0.025). Six patients achieved CR after DLI for overt relapse, one achieved full donor chimerism after LOC. Patients with LOC or EM relapse had superior relapse-free survival following DLI (P=0.029). DLI following PB-haploHCT with PTCy is a viable salvage therapy for overt relapse or LOC without a substantial increase in GvHD, and donor lymphocytes may be collected simultaneously with graft collection to facilitate availability in patients at high risk of relapse.

Baroreflex loading maneuvers do not suppress increased plasma arginine vasopressin in patients with congestive heart failure.

Nonspecific baroreflex loading maneuvers such as head-down tilt readily suppress stimulated arginine vasopressin levels in normal humans. To test the hypothesis that the increased arginine vasopressin levels in patients with congestive heart failure would not respond normally to baroreflex loading, 12 patients with congestive heart failure had arginine vasopressin levels and osmolality determined in the supine position and after 15 min of 30 degrees head-down tilt. Arginine vasopressin was increased to 6.5 +/- 2.0 pg/ml at control measurement and did not decrease. Eight patients underwent further study after osmotic stimulation with mannitol. Mannitol increased osmolality from 287 +/- 9.2 to 294 +/- 7.8 mOsm/kg (p less than 0.001) and from 288 +/- 9 to 299 +/- 8.2 mOsm/kg (p less than 0.01) on two occasions. No significant suppression of arginine vasopressin was seen during head-down tilt after mannitol infusion compared with values in a time control period. These results are consistent with an abnormality in baroreflex suppression of arginine vasopressin secretion in chronic congestive heart failure and suggest that such a defect may contribute to long-term high levels of arginine vasopressin in this condition.

Angiotensin II inhibits the forearm vascular response to increased arterial pressure in humans.

OBJECTIVES: This study tested the hypothesis that angiotensin II may inhibit the forearm vascular resistance response to an increase in arterial pressure in normal humans. BACKGROUND: Angiotensin II inhibits baroreflex-mediated reductions in heart rate and peripheral sympathetic activity during increases in arterial pressure in experimental animals. If present in humans, such effects could contribute to the pathophysiologic role of angiotensin II in hypertension and heart failure. METHODS: Two investigations were performed. In the first, forearm vascular resistance responses were compared during equipressor infusions of angiotensin II and phenylephrine. In the second, heart rate, forearm vascular resistance and systemic venous norepinephrine spillover responses were compared during head-down tilt and head-down tilt plus phenylephrine with concomitant angiotensin II or vehicle infusions. RESULTS: In the first study, forearm vascular resistance increased from 44 +/- 12 (mean +/- SD) to 54 +/- 13 U (p < 0.05) during angiotensin II but did not change during phenylephrine infusions (39 +/- 8.5 to 40 +/- 14 U) that increased mean arterial pressure comparably (88 +/- 9.8 to 103 +/- 14 mm Hg during angiotensin II, p < 0.001; 91 +/- 7.6 to 104 +/- 9.2 mm Hg during phenylephrine, p < 0.001). In the second study, the decrease in heart rate and forearm vascular resistance during the combination of head-down tilt and phenylephrine were both attenuated during concomitant angiotensin II compared with vehicle infusions: delta HR/delta MAP = -2.2 beats/min per mm Hg during vehicle and -0.87 beats/min per mm Hg during angiotensin II (p = 0.07); delta FVR/delta MAP = -2.8 U/mm Hg during vehicle and -0.19 U/mm Hg during angiotensin II (p = 0.01), where delta HR = change in heart rate; delta MAP = change in mean arterial pressure; and delta FVR = change in forearm vascular resistance. Norepinephrine spillover declined during vehicle infusions (612 +/- 367 to 418 +/- 196 ng/min, p < 0.05) but not during angiotensin II infusions despite a greater increase in mean arterial pressure when the subpressor angiotensin II was combined with head-down tilt and phenylephrine (6.0 +/- 7.0 mm Hg during vehicle; 14 +/- 9.4 mm Hg during angiotensin II, p < 0.01). CONCLUSIONS: Both pressor and nonpressor infusions of angiotensin II immediately inhibit the forearm vascular response to mild baroreflex loading in normal humans. If present over the long term, such effects could contribute to inappropriate peripheral resistance in diseases such as hypertension and congestive heart failure.

Angiotensin II and sympathetic activity in patients with congestive heart failure.

OBJECTIVES: This study was designed to determine the effects of intravenous angiotensin II infusions and the short-term effects of enalaprilat on venous plasma norepinephrine and norepinephrine spillover in patients with stable chronic congestive heart failure. BACKGROUND: Angiotensin II has been shown experimentally to stimulate norepinephrine release. Such effects, if present in humans with congestive heart failure, could be of pathophysiologic and pharmacologic importance. METHODS: In study 1, 60-min angiotensin II (5 ng/kg per min) infusions were administered in eight patients with chronic New York Heart Association functional class II and III congestive heart failure. Heart rate, arterial pressure, forearm venous plasma norepinephrine, norepinephrine clearance (estimated from the clearance of tritiated norepinephrine) and norepinephrine spillover were measured after 30 min in the supine position and after 15 min each of head-up and head-down tilt. All patients were studied in a double-blind manner on two occasions with vehicle control infusions. In study 2, 14 patients comparable to those in the first study had similar measurements made in the supine position before and 30 and 60 min after the administration of enalaprilat (1 mg intravenously). Eight patients received a double-blind vehicle control. RESULTS: In study 1, there were no effects of angiotensin II on heart rate, plasma norepinephrine, norepinephrine clearance or norepinephrine spillover compared with the vehicle control when the patient was in the supine position. Mean arterial pressure increased from 85 +/- 13 to 95 +/- 10 mm Hg with angiotensin II. During upright tilt, plasma norepinephrine and norepinephrine spillover increased comparably with angiotensin II and the vehicle control. During head-down tilt, plasma norepinephrine decreased with both angiotensin II and the vehicle control. Norepinephrine spillover remained elevated relative to control values on both study days during head-down tilt. In study 2, both enalaprilat and vehicle control administration were associated with a slight decrease in mean arterial pressure (5 +/- 2 vs. 3 +/- 4 mm Hg, p = NS), but no changes were seen in plasma norepinephrine. Norepinephrine clearance and spillover decreased comparably with time after both enalaprilat and vehicle control. CONCLUSIONS: Neither the infusion of angiotensin II nor the acute administration of enalaprilat significantly alters the activity of the sympathetic nervous system as reflected by plasma norepinephrine or systemic venous norepinephrine spillover in patients with chronic congestive heart failure. These data weaken the hypothesis that angiotensin II is an important regulator of sympathetic activity in congestive heart failure.

Effect of digitalis on norepinephrine kinetics in congestive heart failure.

OBJECTIVE: The aim of this study was to test the hypothesis that digitalis glycosides would reduce sympathetic activity as reflected by forearm venous norepinephrine kinetics in patients with congestive heart failure. BACKGROUND: Digitalis glycosides have been reported to decrease sympathetic nervous system activity with baroreceptor sensitization in experimental animals. Such effects could be of therapeutic importance in congestive heart failure. METHODS: Double-blind randomized assessment was made of the effects of low dose intravenous deslanoside (Cedilanid-D, 0.002 mg/kg body weight) and vehicle on heart rate, arterial pressure, forearm blood flow, plasma norepinephrine, norepinephrine clearance and norepinephrine spillover in nine patients with stable congestive heart failure, New York Heart Association functional class II or III. Open label assessment of the responses to 0.6 mg of deslanoside was made in an overlapping group of seven patients. All measurements were made 30 and 60 min after intravenous injection of drug or vehicle and after 15 min of 30 degrees head-down tilt as a test of the sympathetic response to baroreceptor loading. RESULTS: Heart rate, arterial pressure and forearm blood flow were unchanged by low dose deslanoside. Heart rate decreased slightly with the 0.6 mg dose with the patients in the supine position. Norepinephrine spillover and clearance decreased with time on each study day in the supine position, but no effect was attributable to digitalis. Plasma norepinephrine and norepinephrine clearance and spillover all remained unchanged during head-down tilt on each study day. CONCLUSIONS: Nonpressor doses of deslanoside do not suppress sympathetic activity as reflected by venous norepinephrine and norepinephrine spillover in patients with congestive heart failure. Further, deslanoside did not normalize the sympathetic response to mild baroreceptor loading produced by head-down tilt. These data do not support sympathoinhibition through baroreceptor sensitization as a likely effect of digitalis in congestive heart failure.

Regional blood flow response to orthostasis in patients with congestive heart failure.

To investigate the central and regional circulatory response to orthostasis in congestive heart failure, hemodynamic variables and forearm and hepatic blood flow were measured in 22 patients at supine rest and during a 65 degrees head-up tilt. Results were compared with those in nine normal subjects. Heart rate and mean arterial blood pressure increased during tilt in normal subjects, but not in patients with heart failure. Forearm blood flow decreased in normal subjects from 3.7 +/- 1.1 to 2.7 +/- 1.5 ml/min per 100 g (probability [p] less than 0.02), but did not change from a lower baseline (1.65 +/- 0.78 ml/min per 100 g) in patients. Forearm vascular resistance increased in normal subjects but not in patients. Hepatic blood flow did not change during tilt in either group, but hepatic vascular resistance increased in normal subjects from 0.37 +/- 0.13 to 0.47 +/- 0.15 U, (p less than 0.02). The increase was not seen in patients (1.2 +/- 1.1 to 1.4 +/- 1.0 U, p = not significant [NS] ). Total systemic resistance increased in patients from 1,848 +/- 560 to 2,132 +/- 731 dynes.s.cm-5 (p less than 0.005) indicating that resistance did increase in some vascular beds. Plasma norepinephrine also increased modestly in these patients from 665 +/- 377 to 761 +/- 379 pg/ml (p = 0.035), but individual changes in plasma norepinephrine did not correlate with changes in hepatic or forearm resistance. Thus, both the overall hemodynamic response and the regulation of regional blood flow and resistance differ in several respects in patients with congestive heart failure when compared with normal subjects. Changes in heart rate, blood pressure, forearm flow and forearm and hepatic vascular resistance are all blunted in patients. Reasons for the differences are not yet clear, but may be associated with abnormalities in reflex control of the circulation in patients with congestive heart failure.

Hemodynamic effects of infused arginine vasopressin in congestive heart failure.

The hemodynamic effects of exogenously administered arginine vasopressin were assessed in 11 patients with chronic congestive heart failure. Infusion rates of 0.1 to 0.8 pmol/kg per min increased plasma arginine vasopressin from 6.5 +/- 2.7 (SD) pg/ml at control to 63 +/- 39 pg/ml at the highest infusion rate. There were progressive decreases in cardiac output and stroke volume, with increases in systemic vascular resistance and pulmonary capillary wedge pressure, but only minimal changes in heart rate and blood pressure. Changes in cardiac output, stroke volume and systemic resistance were evident from the first infusion rate, which increased plasma arginine vasopressin from 6.5 +/- 2.7 to 9.9 +/- 4.6 pg/ml. A paired analysis of baseline hemodynamic data with those measured during infusions producing an arginine vasopressin level averaging 15 +/- 2.6 pg/ml yielded the following changes: cardiac output decreased from 4.6 +/- 1.2 to 4.2 +/- 0.96 liters/min (p less than 0.01), stroke volume decreased from 60 +/- 19 to 54 +/- 16 ml (p less than 0.005) and systemic vascular resistance increased from 1,329 +/- 396 to 1,443 +/- 395 dynes X s X cm-5 (p = 0.01). Thus, small increases in circulating arginine vasopressin cause modest but significant adverse circulatory effects in patients with congestive heart failure. A fall in cardiac output, probably as a result of increased afterload, is seen at levels of arginine vasopressin within the basal range found in congestive heart failure. These data demonstrate that circulating arginine vasopressin in physiologic concentrations is capable of influencing hemodynamics in patients with congestive heart failure and suggest that therapy for this condition directed at inhibition of the vascular effect of arginine vasopressin may be potentially useful.

Relative attenuation of sympathetic drive during exercise in patients with congestive heart failure.

Patients with congestive heart failure have been considered to have augmented sympathetic drive both at rest and during dynamic exercise. The augmentation observed during exercise may be related to the state of near exhaustion experienced by patients with heart failure at relatively low work loads. To compare the response of the sympathetic nervous system to exercise in normal subjects and patients with heart failure when they are working in a comparable physiologic frame of reference, the data for both groups can be expressed as percent peak oxygen consumption achieved (percent peak VO2) rather than as a function of absolute oxygen consumption (VO2). Ten healthy control subjects and 31 patients with chronic clinical class II and III heart failure were studied during upright maximal bicycle exercise. Eighteen of the 31 patients had primary cardiomyopathy and 13 had ischemic cardiomyopathy. The average ejection fraction at rest was 24 +/- 10% (+/- SD) in the group with heart failure. Heart rate, systolic blood pressure, VO2 and plasma norepinephrine levels were measured at rest and throughout exercise. When the data were expressed as a function of percent peak VO2 achieved, patients with heart failure demonstrated a flatter slope (p = 0.004) than normal in the response of plasma norepinephrine to exercise, indicating a relative blunting of sympathetic drive. This was accompanied by attenuated heart rate (p = 0.001) and blood pressure (p less than 0.001) responses. These differences were not apparent when the data are expressed as a function of absolute VO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired response of plasma vasopressin to orthostatic stress in patients with congestive heart failure.

Arginine vasopressin, a potent vasoconstrictor and regulator of body water, is frequently increased in the plasma of patients with congestive heart failure. Other neurohumoral control networks, such as the sympathetic nervous system and the renin-angiotensin system, also demonstrate increased activity in congestive heart failure, but fail to respond normally to physiologic stress, such as orthostatic tilt. To assess the response of plasma vasopressin to orthostasis in heart failure, vasopressin was measured before and at 10 and 45 minutes during passive upright tilt in 15 patients with congestive heart failure and their response was compared with that in 9 normal control subjects. Arginine vasopressin was measured by radioimmunoassay. In the normal subjects, plasma arginine vasopressin was 5.3 +/- 2.3 pg/ml at control, was unchanged at 10 minutes, but significantly increased to 7.0 +/- 2.5 pg/ml at 45 minutes (p less than 0.05). In contrast, patients with congestive heart failure showed no significant changes in arginine vasopressin levels from the control levels of 11.6 +/- 5.5 pg/ml. Both plasma norepinephrine and renin activity increased in the normal subjects, but failed to increase from higher baselines in patients with congestive heart failure. Thus, plasma arginine vasopressin, like plasma norepinephrine and renin activity, does not increase in response to upright tilt in patients with congestive heart failure. The explanation is not evident but could involve either abnormalities in reflex control of plasma vasopressin in congestive heart failure or in clearance of the hormone during orthostasis.

Effect of angiotensin II on noradrenaline release in the human forearm.

OBJECTIVE: The aim was to test the hypothesis that in normal humans angiotensin II would stimulate local release of noradrenaline under basal conditions or during a sympathetic stimulus provided by lower body negative pressure (LBNP). METHODS: Nine healthy volunteers received intra-arterial infusions of angiotensin II, 5 ng.min-1, into the non-dominant forearm. Forearm blood flow (strain gauge plethysmography) and regional noradrenaline spillover (using the tracer methodology of Esler) were measured during angiotensin II alone, LBNP alone, and LBNP plus angiotensin II. RESULTS: Angiotensin II and LBNP decreased forearm blood flow comparably: from 3.1(SD 1.5) to 2.4 (0.9) ml.100 g-1.min-1 during angiotensin II, p < 0.05; and from 3.3(1.5) to 2.5(1.0) ml.100 g-1.min-1 during LBNP, p < 0.05 (p = NS, A-II v LBNP). Angiotensin II had no effect on forearm venous noradrenaline or regional noradrenaline spillover. LBNP increased venous noradrenaline outflow from the forearm, from 1.6(0.40) to 2.1(0.6) nmol.min-1 (p < 0.05), while regional noradrenaline spillover tended to increase, rising from 1.5(0.8) to 2.0(1.0) nmol.100 ml-1.min-1. Angiotensin II did not enhance forearm blood flow or noradrenaline responses to LBNP. CONCLUSIONS: In the human forearm, mildly vasoconstrictor infusions of angiotensin II do not increase local release of noradrenaline, either alone or during mild LBNP. At least under these conditions, angiotensin II would not appear to be a potent influence on local sympathetic activity.

Response of plasma arginine vasopressin to nicotine in normal man.

The response of plasma arginine vasopressin (AVP) to nicotine administered by chewing gum (Nicorette, 2 mg) was examined in nine healthy volunteers. Heart rate, mean arterial pressure, serum osmolality, plasma AVP level, and plasma nicotine level were measured at baseline (control) and at 30, 45, and 60 minutes after initial administration of the gum. There were small increases in heart rate (72 +/- 6.3 to 82 +/- 5.1 beats/min, p less than 0.05) and mean arterial pressure (88 +/- 8.2 to 93 +/- 10 mm Hg, p = NS), while the plasma nicotine level increased to a maximum of 16 +/- 2.0 ng/ml (p less than 0.001). No changes were seen in either osmolality (283 +/- 3.4 mOsm/kg) or AVP level (4.3 +/- 2.0 pg/ml) in eight of the nine subjects who remained asymptomatic. In one subject whose hemodynamic and plasma nicotine responses were similar to the others but who became nauseated, the plasma AVP level increased from 4.2 to 26 pg/ml. These data suggest that nicotine at the plasma concentrations achieved in this study is not associated with stimulation of plasma AVP secretion in normal man. Other factors in association with nicotine use, in this case nausea, may be required for AVP stimulation to occur.

Differentiating systolic from diastolic heart failure: pathophysiologic and therapeutic considerations.

PURPOSE: To compare and contrast the pathophysiology and therapy of heart failure with normal and abnormal systolic ventricular function. METHODS: Review of basic pathophysiologic mechanisms, clinical data, and therapeutic trials. CONCLUSIONS: The clinical features of heart failure may be similar regardless of whether ventricular function is normal or abnormal. However, the pathophysiologic mechanisms leading to heart failure with normal ventricular function differ considerably from those producing heart failure with abnormal systolic function. The key problems in heart failure with abnormal systolic function involve impaired contractility, neuroendocrine activation, increased intracardiac volume and pressure, and enhanced sensitivity to change in afterload. With normal systolic function, the key problem is an abnormal diastolic pressure/volume relationship, which may be due to a variety of active and passive processes affecting diastole. Assessing left ventricular systolic function is crucial before initiating therapy in a patient with heart failure, since treatment for systolic dysfunction may be ineffective or even counterproductive if symptoms are due to abnormal diastolic properties with preserved systolic function.

Response of plasma vasopressin to ethanol in congestive heart failure.

Plasma arginine vasopressin (AVP) levels are frequently increased in patients with congestive heart failure (CHF). Further, AVP does not respond normally to certain osmotic and nonosmotic manipulations in this condition. As a test of the central suppressibility of AVP in CHF, an oral ethanol challenge was given (0.7 ml/kg body weight) to 10 patients with CHF and 10 normal control subjects, and the response of AVP, osmolality, heart rate and blood pressure was measured over the next 2 hours. In the CHF group, AVP was 9.6 +/- 3.9 pg/ml (+/- standard deviation) at control and remained unchanged throughout the protocol. In the normal group, AVP was 6.9 +/- 2.9 pg/ml at control and declined significantly to 4.9 +/- 2.0 pg/ml at 20 minutes (p less than 0.05). Osmolality and blood ethanol changes were similar in the 2 groups, as were those in mean arterial pressure. The administration of ethanol therefore did not result in an acute decrease in plasma AVP in patients with CHF, but did so in normal subjects. Differences in the response of blood pressure and osmolality do not explain the abnormality; hence, a defect in the central control of AVP release may exist in CHF. This observation may have implications for the mechanisms involved in the generation or maintenance of elevated AVP levels in patients with this disease.

Dissociation of sympathetic responses to baroreceptor loading and unloading in compensated congestive heart failure secondary to ischemic or nonischemic dilated cardiomyopathy.

This study tested the hypothesis that abnormalities of baroreceptor-mediated suppression of sympathetic activity may persist in chronic congestive heart failure (CHF) despite pharmacologic treatment and clinical stability. Plasma norepinephrine and norepinephrine kinetics (using 3HNE infusions) were measured during head-up and head-down tilt in 8 patients with chronic CHF and 6 normal control subjects. In response to upright tilt, normal subjects increased plasma norepinephrine (270 +/- 45 to 413 +/- 60 pg/ml, p less than 0.001) and norepinephrine spillover (540 +/- 103 to 781 +/- 124 ng/min, p less than 0.001). Patients also increased plasma norepinephrine (436 +/- 105 to 600 +/- 112 pg/ml, p less than 0.05) and norepinephrine spillover (802 +/- 180 to 1,037 +/- 370 ng/min). During head-down tilt, plasma norepinephrine decreased in normal subjects (from 413 +/- 60 to 256 +/- 26 pg/ml, p less than 0.001). The decrease was due entirely to a decrease in norepinephrine spillover (781 +/- 124 to 466 +/- 40 ng/min, p less than 0.001). In contrast, there was no significant change in norepinephrine spillover (1,037 +/- 370 to 949 +/- 338 ng/min) during head-down tilt in patients with CHF. These data suggest that suppression of sympathetic activity during baroreceptor loading may be defective in CHF despite relative preservation or correction of the response to baroreceptor unloading.

Arginine vasopressin and the renal response to water loading in congestive heart failure.

Previous studies have shown on the basis of isolated comparisons that plasma arginine vasopressin (AVP) levels are inappropriately increased for a given serum osmolality in patients with CHF. To explore further the osmoregulation of AVP in this condition, the response of plasma AVP to a 15- to 20-ml/kg oral water load was compared in 26 patients with CHF and 14 normal subjects. In the normal subjects, serum osmolality decreased from 289 +/- 5.0 to 282 +/- 5.0 mOsm/kg (p less than 0.001) and AVP from 3.6 +/- 1.1 to 2.1 +/- 0.78 pg/ml (p less than 0.001). In the patients with CHF, osmolality decreased from 289 +/- 7.0 to to 281 +/- 7.0 mOsm/kg and AVP from 7.1 +/- 3.6 to 5.8 +/- 3.4 pg/ml (p less than 0.001). As a percentage of the control value, the decrease in AVP was much greater in the normal group, 41 +/- 15% vs 18 +/- 10% (p less than 0.001). Urinary osmolality levels were measured before and after water loading in 11 patients and in 7 normal subjects. Normal subjects diluted from 812 +/- 130 to 133 +/- 26 mOsm/kg (p less than 0.001) and CHF patients from 599 +/- 218 to 253 +/- 170 mOsm/kg, a statistically significant (p less than 0.01) but smaller (p less than 0.05) level of suppression. There were, however, 2 distinct groups within the CHF population: one in which urine osmolality was appropriately decreased (from 594 +/- 269 to 144 +/- 37 mOsm/kg, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure.

The activity of the sympathetic nervous system is increased at rest in patients with congestive heart failure. To determine whether this augmentation is carried over during dynamic upright exercise, 14 patients with congestive heart failure were stressed maximally during upright bicycle ergometry. Plasma norepinephrine and epinephrine levels were measured in the basal upright (sitting) posture before and during maximal exercise. The results were compared with those in six healthy control subjects before and during maximal exercise. Plasma norepinephrine increased during exercise from a mean (+/- standard error of the mean) of 650 +/- 95 to 1,721 +/- pg/ml in the group with heart failure. This increase was significantly less (p less than 0.001) than that in the control group (from 318 +/- 36 to 3,230 +/- 418 pg/ml). However, for equivalent levels of total body oxygen consumption (VO2), the group with heart failure had higher levels of plasma norepinephrine than the control group. Plasma epinephrine was similar in the two groups in the basal upright position (92 +/- 18 and 92 +/- 26 pg/ml), but it increased more during exercise in the normal subjects (743 +/- 210 pg/ml) than in the group with heart failure (167 +/- 67 pg/ml) (p less than 0.001). The percent increase in norepinephrine correlated with the percent change in VO2 in the group with heart failure (r = 0.62, p less than 0.02), but the percent change in epinephrine did not. There is, therefore, a disturbance in the sympathetic nervous system during exercise in patients with congestive heart failure. Although norepinephrine increases in such patients to a greater extent than in normal subjects at lower levels of exercise, the extremely high levels of norepinephrine and epinephrine generated by normal subjects during maximal upright exercise do not occur in patients with heart failure.

Effect of amlodipine and felodipine on sympathetic activity and baroreflex function in normal humans.

Baroreflex sensitization and direct sympatholytic effects have been suggested as contributing mechanisms to the effects of dihydropyridine calcium channel blockers in hypertension and heart failure. In this study, we tested the hypothesis that either amlodipine or felodipine would decrease norepinephrine levels and enhance cardiac, peripheral vascular, or sympathetic responses to baroreflex perturbation in healthy humans. Six healthy male volunteers aged 21 to 40 participated. Heart rate, forearm blood flow, arterial pressure, and norepinephrine kinetics were assessed in the supine position, after 15 min of 60 degrees head-up tilt, after 15 min of 30 degrees head-down tilt, and after 15 min head-down tilt with phenylephrine infused to raise mean arterial pressure 10 to 15 mm Hg. Studies were conducted double-blind on 3 different days 8 to 12 h after placebo, 5 mg amlodipine, and 10 mg felodipine. Resting heart rate, mean arterial pressure, forearm vascular resistance, plasma norepinephrine, and norepinephrine spillover were not affected by amlodipine or felodipine. During upright tilt, head-down tilt, and phenylephrine, each variable increased and decreased as expected after placebo. There was no effect of either amlodipine or felodipine on any response to any maneuver. Baseline sympathetic activity as reflected by plasma norepinephrine and norepinephrine spillover are not altered by either amlodipine or felodipine. Neither drug acutely sensitizes baroreflex function in normal humans over the degree of perturbation produced in these protocols.