Fred L. Anderson

Clinical Use of the Total Artificial Heart

We report here our first experience with the use of a total artificial heart in a human being. The heart was developed at the University of Utah, and the patient was a 61-year-old man with chronic congestive heart failure due to primary cardiomyopathy, who also had chronic obstructive pulmonary disease. Except for dysfunction of the prosthetic mitral valve, which required replacement of the left-heart prosthesis on the 13th postoperative day, the artificial heart functioned well for the entire postoperative course of 112 days. The mean blood pressure was 84 +/- 8 mm Hg, and cardiac output was generally maintained at 6.7 +/- 0.8 liters per minute for the right heart and 7.5 +/- 0.8 for the left, resulting in postoperative diuresis and relief of congestive failure. The postoperative course was complicated by recurrent pulmonary insufficiency, several episodes of acute renal failure, episodes of fever of unidentified cause (necessitating multiple courses of antibiotics), hemorrhagic complications of anticoagulation, and one generalized seizure of uncertain cause. On the 92nd postoperative day, the patient had diarrhea and vomiting, leading to aspiration pneumonia and sepsis. Death occurred on the 112th day, preceded by progressive renal failure and refractory hypotension, despite maintenance of cardiac output. Autopsy revealed extensive pseudomembranous colitis, acute tubular necrosis, peritoneal and pleural effusion, centrilobular emphysema, and chronic bronchitis with fibrosis and bronchiectasis. The artificial heart system was intact and uninvolved by thrombosis or infectious processes. This experience should encourage further clinical trials with the artificial heart, but we emphasize that the procedure is still highly experimental. Further experience, development, and discussion will be required before more general application of the device can be recommended.

Age-related changes in beta-adrenergic neuroeffector systems in the human heart.

BackgroundAging decreases cardiac β–adrenergic responsiveness in model systems and in humans in vivo. The purpose of this study was to comprehensively evaluate the age-related changes in the β-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts. Methods and ResultsTwenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of β-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total β-receptor density assessed by maximum [125I]ICYP binding (βmax) was reduced in older hearts by 37% in left ventricles and 31 % in right ventricles (both P<.05), and the downregulation was confined to the β1 subtype (r= −.78 left ventricle β1 density versus donor age). Older donor hearts exhibited a 3- to 4-fold rightward shift of ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer receptors in a high-affinity agonist binding state (P<.05). Older hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol (β2-agonist), and by the G protein–sensitive probes forskolin, Gpp(NH)p, and NaF. In contrast, there was no change in response to manganese, a specific activator of the adenylyl cyclase catalytic subunit. Toxin-catalyzed ADP ribosylation in membranes prepared from older versus younger hearts revealed a 29% to 30% reduction (P<.05) with cholera toxin (Gβs) but no difference with pertussis toxin (Gβi). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC50 in older relative to younger donor hearts. ConclusionsThere is a profound decrease in cardiac β-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of β1-receptors, uncoupling of β2-receptors, and abnormal G protein-mediated signal transduction.

Myocardial catecholamine and neuropeptide Y depletion in failing ventricles of patients with idiopathic dilated cardiomyopathy. Correlation with beta-adrenergic receptor downregulation.

BackgroundMyocardial adrenergic neurotransmitters and β-adrenergic receptor levels were measured in left and right ventricular myocardial specimens obtained from 30 patients with biventricular failure resulting from idiopathic dilated cardiomyopathy. Methods and ResultsNonfailing myocardium obtained from 12 organ donors provided control data. Norepinephrine, dopamine, and neuropeptide Y concentrations were significantly decreased in failing compared with nonfailing control hearts. The mean ratio of dopamine to norepinephrine and of dopamine to neuropeptide Y in failing hearts was also significantly decreased compared with nonfailing control hearts. Compared with nonfailing control hearts, Bmax and β-receptor density were significantly decreased in failing hearts and there were weak but significantly positive correlations of Bmax and β-adrenergic receptors with norepinephrine, dopamine, and neuropeptide Y ConclusionsNorepinephrine and its cotransmitter neuropeptide Y are depleted in failing human ventricular myocardium. Decreased norepinephrine stores correlate weakly with β-adrenergic receptor downregulation consistent with the hypothesis that norepinephrine depletion occurs in response to increased adrenergic drive. Decreased dopamine relative to norepinephrine implies that an abnormality of dopamine conversion to norepinephrine is not present in failing human heart.

Vasoactive intestinal peptide receptor in failing human ventricular myocardium exhibits increased affinity and decreased density.

We investigated vasoactive intestinal peptide (VIP)-receptor pharmacology in failing and nonfailing human ventricular myocardium by examining [125I]VIP binding in membrane fractions of left ventricle and inotropic effects of VIP in isolated right ventricular trabeculae mounted in tissue baths. [125I]VIP binding demonstrated upwardly concave, curvilinear Scatchard plots consistent with two classes of binding sites. Only the high-affinity (dissociation constant [Kd] 400-800 pM) site could be regulated by guanine nucleotides. Compared with nonfailing heart, membranes derived from failing heart exhibited a twofold reduction in the Kd of the high-affinity VIP binding site, whereas the receptor density (Bmax) was decreased by 62%. In concordance with this decreased receptor density and increased affinity, the maximal contractile response of right ventricular trabeculae from failing right ventricles was decreased by 61%, and the dose-response curve to VIP was left-shifted approximately threefold. We conclude that the VIP receptor in failing human ventricular myocardium exhibits novel regulatory behavior consisting of increased receptor affinity and decreased receptor density.

Effect of Vasoactive Intestinal Peptide on Myocardial Contractility and Coronary Blood Flow in the Dog: Comparison with Isoproterenol and Forskolin

The effects of intracoronary injections of vasoactive intestinal peptide (VIP) on left ventricular (LV) dp/dt, coronary blood flow (CBF), and myocardial oxygen consumption (MVO2) were compared with isoproterenol (ISO) and forskolin in 18 dogs using a preparation in which cardiac output, mean systemic arterial pressure, and heart rate were fixed. In eight dogs in which the effects of VIP and ISO were compared using doses ranging from 2 × 10−12 to2 × 10−8 mol, both agents significantly increased LV dp/dt at doses ≥6.6 × 10−10 mol. At maximal doses (2 × 10−9 to 2 × 10−8 mol) the effect of ISO was significantly greater than VIP. Both VIP and ISO significantly increased CBF at all doses, but at maximal doses the effect of VIP on CBF was significantly greater than ISO. The increase in CBF relative to the increase in MVO2, an index of direct coronary vasodilation, was significantly greater for VIP compared with ISO. In 10 additional dogs the effects of VIP and ISO were compared with forskolin given in doses ranging from 2 × 10−9 to 2 × 10−7 mol. At maximal doses (2 × 10−7 mol) the increase in LV dp/dt was similar to VIP but significantly less than ISO, whereas the increase in CBF was similar to ISO but significantly less than VIP. The increase in CBF relative to the increase in MVO2 was significantly greater for forskolin compared with ISO, indicating a direct vasodilator effect. These data indicate that VIP has a greater coronary vasodilator/inotropic ratio than either ISO or forskolin, agents that also activate the adenylate cyclase pathway. This distribution of the VIP effects may confer favorable therapeutic properties on agents that activate the VIP receptor pathway.

Hemodynamic effects of exercise in patients with aortic stenosis

Abstract Hemodynamic data obtained by right and left heart catheterization at rest and during exercise in thirty-two patients with aortic stenosis were reviewed. Eighteen patients had either minimal or no aortic regurgitation (group I) and fourteen patients had moderate to moderately severe aortic regurgitation (group II). The mean systolic pressure gradient (ΔP) across the aortic valve decreased or remained unchanged during exercise in eleven of eighteen patients in group I and in nine of fourteen patients in group II. Net forward aortic valve systolic flow (AVSF) increased during exercise in fourteen of eighteen patients in group I and in thirteen of fourteen patients in group II. Thus, in some patients the change in ΔP during exercise appears to be at variance with the predictability implied by the Gorlin equation which states that ΔP should be directly related to (AVSF) 2 . It is unlikely that this discrepancy can be explained on the basis of a systematic measuring error involving one or more of the various factors in the equation. This suggests that the aortic valve may not behave as a fixed orifice under all hemodynamic conditions, and that orifice hydraulics might be different depending on the mechanics of contraction. Average cardiac index (CI) was 2.5 L. per minute per M 2 . at rest and 3.8 L. per minute per M 2 . during exercise for patients in group 1, and 2.2 L. per minute per M 2 . at rest and 3.9 L. per minute per M 2 . during exercise for patients in group 2. Arterial and left ventricular systolic and diastolic pressures increased, and systemic resistance decreased during exercise. Thus, resting cardiac output is maintained and it increases during exercise at the expense of marked elevation in both systolic and diastolic pressures in the left ventricle. An analysis of the relationship between stroke work index (SWI) and left ventricular end diastolic pressure (LV edp ) in patients from group I revealed, in general, two types of responses to exercise. Six patients had an increase in SWI averaging 39 per cent associated with a 67 per cent increase in LV edp . In sharp contrast, ten other patients demonstrated an increase in SWI averaging only 1.3 per cent whereas LV edp increased by an average of 129 per cent. It is apparent therefore that the response to exercise makes it possible to separate patients with remaining myocardial reserve from those without. Thus, exercise data in patients with aortic stenosis provide objective, quantitative information useful in making a decision when and if to perform corrective surgery.

Evaluation of total artificial heart performance in man

This report describes the method whereby total artificial heart (TAH) performance was evaluated in the first human implantation, the operating characteristics of the TAH and the accompanying circulatory response. The patient survived for 112 days. Weekly averages (+/- standard deviation) for left-heart drive pressure ranged from 146 +/- 5 to 171 +/- 10 mm Hg, right-heart drive pressure from 46 +/- 4 to 79 +/- 17 mm Hg, heart rate from 77 +/- 8 to 98 +/- 3 beats/min, diastolic vacuum from 0 to 7 +/- 0.5 mm Hg and percent systole 40 +/- 1 to 44 +/- 0. Left-sided cardiac output ranged from 3.0 +/- 0.4 to 3.9 +/- 0.2 liters/min/m2, and was consistently greater than right-sided cardiac output, which ranged from 2.6 +/- 0.4 to 3.6 +/- 0.1 liters/min/m2. Drive line air pressure and flow signals and cineradiography of the TAH demonstrated complete filling and ejection for the left ventricle and complete filling but partial ejection for the right ventricle. There was no significant change in cardiac index during variation in right atrial pressure between 4 and 14 mm Hg. During 21 days of invasive hemodynamic monitoring, daily average of mean systemic arterial pressure ranged from 81 +/- 5 to 107 +/- 11 mm Hg, pulmonary artery pressure from 22 +/- 2 to 28 +/- 8 mm Hg and left atrial pressure from 8 +/- 2 to 22 +/- 4 mm Hg. Prominent V waves on the left atrial pressure tracing suggested mitral regurgitation as a cause of the difference between the outputs of the 2 ventricles.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of prostaglandins F2a and E2 on the bovine circulation.

Summary The effects of PGF2α and PGE2 on the pulmonary and systemic circulations were studied in unanesthetized calves. PGF2α, average dose 2.1 μg/kg, injected into the pulmonary artery resulted in a significant increase in PA pressure and fall in CO whereas FA pressure, LV end diastolic pressure, HR, blood gases and pH were not significantly altered. PGE2, average dose 1.9 μg/kg, injected into the pulmonary artery resulted in a significant decrease in FA pressure, increase in HR and a small but significant increase in PA pressure whereas LV end diastolic pressure, CO, blood gases and pH were not significantly altered. Thus, this study indicates that in the bovine PGF2α causes pulmonary vasoconstriction and PGE2 causes systemic vasodilatation. The authors are indebted to Dr. J. E. Pike of the Upjohn Company for generous supplies of prostaglandins. The technical assistance of Mr. Don Anton and Filimon Ukradyha, PhD, is greatly appreciated.

Effect of Therapeutic Dopamine Administration on Myocardial Catecholamine and Neuropeptide Y Concentrations in the Failing Ventricles of Patients with Idiopathic Dilated Cardiomyopathy

Summary: The purpose of this study was to investigate the relationship between dopamine (DA) exposure and myocardial catecholamine and neuropeptide Y (NPY) concentrations in patients with severe congestive heart failure due to idiopathic dilated cardiomyopathy (IDC). Both nonfailing (NF) and failing (F) hearts were obtained in collaboration with the Utah Cardiac Transplantation Program and the Intermountain Organ Recovery System. The patients were stratified into five groups according to their preoperative exposure to dobutamine (DBT) and/or DA. Compared to 12 untreated, NF control hearts, norepinephrine (NE) concentrations were significantly decreased in 30 untreated F hearts obtained from patients with IDC. Norepinephrine concentrations were also significantly decreased in DA-treated NF hearts and in DAtreated F hearts compared to untreated NF and untreated or DBT-treated failing hearts, respectively. NPY concentrations were significantly decreased in untreated F hearts and were further decreased in dopamine-treated NF and DA-treated F hearts compared to untreated NF and untreated or DBT-treated F hearts. Thus, NE and NPY depletion related to DA administration was evident in both NF and F myocardium and was specific for DA in that it was not evident in patients who received the direct-acting β-agonist inotrope DBT. These data suggest that the major inotropic mechanism of action of DA is through cardiac adrenergic neurotransmitter release. The data also provide further support for the concept that indirect acting inotropes such as DA may have limited inotropic potential in F hearts where neuronal NE has been depleted

Pulmonary Vasoconstriction Elicited by Stimulation of the Hypothalamic Integrative Area for the Defense Reaction

Changes in the pulmonary circulation evoked by stimulation of the hypothalamic integrative area for the defense reaction were studied in 22 cats anesthetized with a chloralose-urethane mixture. Pulmonary arterial pressure and flow, left and right atrial pressures, aortic pressure, arterial flow to the skinned hind limb, and heart rate were all significantly increased. The calculated pulmonary vascular resistance was also significantly increased. The rise in pulmonary vascular resistance was abolished by bilateral stellectomy or by hexamethonium infusion; it was not affected by bilateral cervical vagotomy. Therefore, the increase in pulmonary vascular resistance was mediated by the thoracic sympathetic nerves. The increase in pulmonary arterial flow was mainly caused by an increase in heart rate; a small rise in calculated stroke volume also occurred.