Maria Teresa Olivari

Plasma Norepinephrine as a Guide to Prognosis in Patients with Chronic Congestive Heart Failure

Hemodynamics, plasma norepinephrine, and plasma renin activity were measured at supine rest in 106 patients (83 men and 23 women) with moderate to severe congestive heart failure. During follow-up lasting 1 to 62 months, 60 patients died (57 per cent); 47 per cent of the deaths were sudden, and 45 per cent were related to progressive heart failure. Statistically unrelated to the risk of mortality were cause of disease (60 patients had coronary disease, and 46 had cardiomyopathy), age (mean, 54.8 years), cardiac index (mean, 2.11 liters per minute per square meter of body-surface area), pulmonary wedge pressure (mean, 24.5 mm Hg), and mean arterial pressure (mean, 83.2 mm Hg). A multivariate analysis of the five significant univariate prognosticators--heart rate (mean, 84.4 beats per minute), plasma renin activity (mean, 15.4 ng per milliliter per hour), plasma norepinephrine (mean, 700 pg per milliliter), serum sodium (mean, 135.7 mmol per liter), and stroke-work index (mean, 21.0 g-meters per square meter)--found only plasma norepinephrine to be independently (P = 0.002) related to the subsequent risk of mortality. Norepinephrine was also higher in patients who died from progressive heart failure than in those who died suddenly. These data suggest that a single resting venous blood sample showing the plasma norepinephrine concentration provides a better guide to prognosis than other commonly measured indexes of cardiac performance.

The Neurohumoral Axis in Congestive Heart Failure

The incidence of congestive heart failure is increasing in the United States. This common syndrome is characterized not only by impaired ventricular function but also by an increase in some endogenous vasoconstrictor substances, including norepinephrine, angiotensin II, and arginine vasopressin. Although activation of the systems that release these substances is presumed to be compensatory (to maintain perfusion pressure during inadequate flow), the sympathetic nervous system, renin-angiotensin-aldosterone system, and arginine vasopressin may contribute to the pathogenesis of the syndrome. The excessive vasoconstriction present in heart failure likely produces a further burden on the failing myocardium. New strategies in therapy are being developed to counteract the activation of vasoconstrictor forces in congestive heart failure. Data indicate that selective blockade of the renin-angiotensin system is useful. Preliminary data suggest that inhibition of the sympathetic nervous system may be helpful, and inhibition of vasopressin in animals with heart failure is being studied. New and more selective therapy for heart failure may come from these studies.

Acute Vasoconstrictor Response to Intravenous Furosemide in Patients with Chronic Congestive Heart Failure: Activation of the Neurohumoral Axis

Hemodynamic and neurohumoral responses to acute diuretic therapy were measured in 15 patients with severe chronic heart failure given intravenous furosemide, 1.3 +/- 0.6 (SD) mg/kg body weight. Left ventricular pump function deteriorated by 20 minutes, as indicated by a fall in stroke volume index (27 +/- 8 to 24 +/- 7 mL/min X m2 body surface area, p less than 0.01) and an increase in left ventricular filling pressure (28 +/- 7 to 33 +/- 9 mm Hg, p less than 0.01). Increases occurred in heart rate (87 +/- 13 to 91 +/- 16 beats/min, p less than 0.01), mean arterial pressure (90 +/- 15 to 96 +/- 15 mm Hg, p less than 0.01), systemic vascular resistance (1454 +/- 394 to 1676 +/- 415 dynes X s X cm-5, p less than 0.01), plasma renin activity (9.9 +/- 8.5 to 17.8 +/- 16 ng/mL X h, p less than 0.05), plasma norepinephrine level (667 +/- 390 to 839 +/- 368 pg/mL, p less than 0.01), and plasma arginine vasopressin level (6.2 +/- 1.3 to 8.3 +/- 2.0 pg/mL, p less than 0.01). During the next 3.5 hours the patients had diuresis (2085 +/- 1035 mL) and the expected fall in filling pressure (28 +/- 7 to 22 +/- 10 mm Hg, p less than 0.01). Neurohumoral indicators also returned toward the control levels. Intravenous furosemide, in patients with severe chronic heart failure, is associated with acute pump dysfunction temporally related to activation of the neurohumoral axis.

Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection

Coronary artery disease (CAD) is now the major limitation to long-term survival after cardiac transplantation. Its etiology remains unclear. The possible role of viral infection in the genesis of CAD stimulated the review of 102 patients transplanted since the introduction of triple drug immunosuppression (cyclosporine, azathioprine and prednisone) to assess the importance of posttransplant cytomegalovirus infection in the development of CAD in the cardiac graft. CAD occurred in 16 patients (16%). Recipient age and sex, donor age, pretransplant diagnosis, frequency of acute rejection episodes, HLA mismatch, cytomegalovirus infection, incidence of posttransplant systemic hypertension and diabetes mellitus, and mean triglyceride, cholesterol and cyclosporine levels were analyzed to assess their influence on the development of CAD. Only the occurrence of cytomegalovirus infection was found to be a significant factor (p = 0.007): infection occurred in 62% of patients with CAD and in only 25% of those without. These data support the existence of an association between cytomegalovirus infection and CAD after cardiac transplant. It is possible that the virus contributes to the initial injury to the coronary endothelium.

Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans

BackgroundCardiac transplantation (CT) causes total cardiac denervation. Methods and ResultsTo test directly for sympathetic reinnervation in humans, we measured the cardiac release of norepinephrine (NE) in response to tyramine (an agent that causes NE release from intact sympatheticnerve terminals) and sustained handgrip exercise (a reflex sympathetic stimulus) in 12 patients less than 5 months after CT, in 50 patients 1 year or more after CT, and in eight patients without CT. Plasma [NE] was measured in the aorta ([NE]A0) and coronary sinus ([NE]cs) at rest, after tyramine administration (55 μg/kg, i.v.), and during sustained handgrip exercise. Cardiac NE release was determined by subtracting [NE]AO from [NE]cs ([NE]cs-AO). NE release was defined as [NE]cs-AO during the intervention — [NE]cs-AO at rest (Δ[NE]cS-AO). In patients studied within 5 months of CT, no significant NE release occurred after tyramine administration (Δ[NE]cS-AO, 33±18 pg/ml; range, -98 to 117 pg/ml) or handgrip exercise (Δ[NE]cs-Ao, -34±10 pg/ml; range, -46 to 8 pg/ml; n = 10). Conversely, in 39 of 50 patients studied 1 year or more after CT, tyramine administration caused a significant cardiac NE release (Δ[NE]cs-AO, 500±59 pg/ml; range, -11 to 1,918 pg/ml), and handgrip exercise caused a significant NE release in 17 of 41 patients (Δ[NE]cs-Ao, 189±34 pg/ml; range, -211 to 949 pg/ml). In normally innervated patients, tyramine caused an even larger NE release (Δ[NE]AO-cs, 1,943±210 pg/ml; range, 1,152 to 2,977 pg/ml), and handgrip exercise caused a significantNE release in two of seven patients (Δ[NE]cs-AO, 143±51 pg/ml; range, -15 to 338 pg/ml). ConclusionsEarly after CT, neither tyramine nor handgrip exercise caused a significant cardiac release of NE, suggesting sympathetic denervation. Late after CT, most patients had a significant, but subnormal, NE release in response to pharmacological or reflex stimuli, suggesting that limited sympathetic reinnervation occurs in most patients after orthotopic CT.

Clinical use of a calcium antagonistic agent (nifedipine) in acute pulmonary edema

Nifedipine induces vascular smooth muscle relaxation through a calcium antagonistic action. The possibility of clinical use of the drug as a ventricular unloading agent has been explored in this study. In patients with hypertensive (seven cases), primary (seven cases) or rheumatic (aortic insufficiency five cases, mitral regurgitation five cases) cardiac disease, nifedipine, administered in a single sublingual dose (10 mg), relieved acute pulmonary edema. Circulatory variations from control were the following: decrease of systemic and pulmonary arterial pressures, and of vascular resistances, of pulmonary wedge pressure, of left ventricular diastolic and systolic dimensions (echocardiography); increase of cardiac and stroke index, of left ventricular mean rate of circumferential fiber shortening, of left and right mean pre-ejection delta P/delta t and mean rate of ejection; improvement of forward output in primary and rheumatic disease. Nifedipine benefits acute congestive heart failure by sustained fall of both preload and afterload and, possibly, by an enhanced contractility. It seems to have an appropriate indication in cases in which left ventricular afterload reduction is desirable.

Negative influences of ascites on the cardiac function of cirrhotic patients

Right and left ventricular function was evaluated in 21 men with cirrhosis and tense ascites during staged removal of ascitic fluid. During paracentesis it was observed (1) that there was a significant increase in cardiac output, stroke volume, right and left ventricular stroke work and mean rate of systolic ejection; (2) that up to a certain stage of drainage (about 5,000 ml), there was a relationship between the amount of fluid removed and the intraabdominal and right atrial pressures and (3) that there was a direct relationship between improvement of cardiac function and normalization of right atrial pressure. It is believed that the increased intra-abdominal hydrostatic pressure acting upon the diaphragm affects the intrathoracic pressure to such an extent that the transmural filling pressure of the heart is reduced, and the mean pressure and respiratory pulsations of the right atrium increased, all of which impede venous return. Improved cardiac function during paracentesis appears to be due to an augmented filling of the heart and to a larger venous return.

Hemodynamic and Hormonal Response to Transdermal Nitroglycerin in Normal Subjects and in Patients With Congestive Heart Failure

The hemodynamic and hormonal responses to nitroglycerin administered transdermally in a gel-like matrix were evaluated in nine patients with severe congestive heart failure and in nine normal subjects. In normal subjects, peripheral vasodilation was accompanied by reflex sympathetic stimulation as reflected by an increase in heart rate and plasma norepinephrine. In patients with heart failure, nitroglycerin produced sustained hemodynamic effects that began 30 minutes after the application and fully persisted for at least 6 hours. A significant decrease in right and left ventricular filling pressures was associated with an increase in stroke index and a significant decrease in forearm and pulmonary vascular resistances. There was no change in heart rate and systemic arterial pressure or in plasma norepinephrine or plasma renin activity. After 24 hours, pressures had partially returned to control levels, but mean pulmonary artery pressure was still significantly lower than in the control period. After removal of the nitroglycerin, each patient exhibited a decrease in cardiac index and an increase, above the control values, in pulmonary and systemic arterial pressures and pulmonary, systemic and forearm vascular resistances. This transient rebound appeared to be unrelated to stimulation of the sympathetic or renin-angiotensin systems. Thus, transdermal absorption of this new form of nitroglycerin appears to provide a nitrate vascular effect that is sustained for 24 hours, but an endogenous vasoconstrictor effect may influence the hemodynamic response over the first 24 hours.

Abnormal neurohumoral response to nitroprusside infusion in congestive heart failure

Vasodilator drugs produce tachycardia and an increase in circulating plasma norepinephrine in normal subjects. In contrast, heart rate does not change when the same drugs are given to patients with congestive heart failure. To assess if this difference could be related to a different reflex activation of the sympathetic nervous system, the response of plasma norepinephrine to nitroprusside infusion and to head-up tilt was studied in 5 normal subjects and in 46 patients with chronic congestive heart failure. Norepinephrine and heart rate increased significantly during both stimuli in normal subjects but were unchanged during nitroprusside infusion for the entire group of patients with heart failure, with considerable variability in individual responses. In 21 patients (Group I) norepinephrine increased during nitroprusside infusion, while in the remaining 25 (Group II) norepinephrine decreased. The hemodynamic response to nitroprusside was similar in the two groups, thus suggesting that the different changes in plasma norepinephrine could not be explained on the basis of a different hemodynamic response to the drug. Plasma norepinephrine also did not change significantly in Group II during tilt, although the decrease in intracardiac pressure and the increase in peripheral resistance were similar to those in Group I who increased norepinephrine normally by 56%. These data indicate that a subset of patients with severe ventricular dysfunction have an abnormal humoral, reflex sympathetic response to changes in arterial or intracardiac pressure, or both. The higher mortality in Group II suggests that this alteration in the sympathetic response may be a marker of the severity and prognosis of heart failure.

Anti-beta-receptor antibodies in human dilated cardiomyopathy and correlation with HLA-DR antigens

The mechanisms responsible for the decline in the density of beta-adrenoceptors in the failing myocardium have not been adequately defined. It is a possibility that the nature of the process leading to heart failure may determine, in large part, the pathogenesis of this decline. Sera of some patients with dilated cardiomyopathy contain antibodies directed against the beta-adrenoceptor, as judged by ligand binding inhibition, immunoprecipitation and immunoblotting assays. Because deranged immune function is thought to play a role in dilated cardiomyopathy, immunogenetic markers of the propensity to develop anti-beta-receptor antibodies were sought. The prevalence of HLA-DR4 was significantly higher in dilated cardiomyopathy patients (40 vs 24% in 511 normal subjects, pc less than 0.001). In contrast, no association was found between HLA phenotypes and alcoholic cardiomyopathy. Furthermore, 72% (13 of 18) of the HLA-DR4 dilated cardiomyopathy patients had anti-beta-receptor antibodies compared to 22% (7 of 33) HLA-DR4-negative patients; in the latter, presence of antibody was linked to the HLA-DR1 phenotype. Conversely, 67% (15 of 23) of the antibody-positive patients were typed as HLA-DR4 compared to only 10% of the antibody-negative patients. Interestingly, none of the 23 antibody-positive patients were typed as HLA-DR3 while 37% of the antibody-negative did. Only 25% of alcoholic cardiomyopathy patients had anti-beta-receptor antibodies and no preponderant HLA association could be demonstrated. These results suggest that the presence of anti-beta-receptor antibodies in patients with idiopathic dilated cardiomyopathy may be under the control of the major histocompatibility locus.