Early reduction in plasma norepinephrine during beta-blocking therapy with metoprolol in chronic heart failure.

BACKGROUND: The possible role exerted by modulation of sympathetic outflow in the clinical effects of beta-blockade in chronic heart failure was tested during short- and long-term treatment. METHODS AND RESULTS: Oral metoprolol (30-150 mg/day) was added to conventional therapy in 14 patients with idiopathic dilated cardiomyopathy, left ventricular ejection fraction (LVEF) of <0.45, and New York Heart Association class II or III. Norepinephrine plasma levels, which are an index of sympathetic activation, decreased by 27.57 +/- 18.03% after 1 month (P < .005), but returned to pretreatment levels after 6 months. LVEF increased by 7.7 +/- 6.0 ejection fraction units after 6 months (P < .005 vs baseline and P < .05 vs 1 month). Long-term beta-blockade resulted in nonsignificant improvements in functional class, symptom score, and oxygen consumption at peak exercise. After 1 month, the reduction in plasma norepinephrine levels and the changes in LVEF were inversely correlated (P < .01). No other correlation emerged during short- or long-term treatment. CONCLUSION: In conclusion, the reduction in plasma norepinephrine levels during short-term beta-blockade was not proportional to the clinical benefits and may have been attributed to the direct inhibition of sympathetic outflow. The early reduction in circulating norepinephrine levels may decrease cardiac performance through withdrawal of sympathetic support when the favorable effects of beta-blockade have not had time to occur. The role that sympathetic modulation may exert in the long-term clinical benefits of metoprolol deserves further investigation.

[Hemodynamics and clinical data in chronic coronary disease with severe left ventricular systolic dysfunction]. / Emodinamica centrale e dati clinici nella coronaropatia cronica con grave disfunzione sistolica ventricolare sinistra.

To elucidate how symptoms and signs of chronic heart failure are related to the filling pressure and cardiac output at rest, 58 patients (55 males, 3 females, mean age 57 +/- 9 years, range 30-75) with left ventricular ejection fraction (LVEF) < or = 30% and a lesion > or = 50% on a major coronary branch have been selected from patients submitted in 1985-1993 to a complete right and left cardiac catheterization including ventriculography and coronary angiography. Patients with recent myocardial infarction (MI), unstable angina, associated heart diseases or recent changes in body weight and in diuretic therapy were excluded. Clinical data were obtained at cardiac catheterization time from history, physical examination, chest X-ray and ECG. Patients with angina as limiting symptom were excluded from NYHA functional classification. Pulmonary venous congestion (PVC) was defined on X-ray as: absent, venous redistribution, interstitial pulmonary edema (IPE). Mean pulmonary capillary wedge pressure (PCWP) was recorded under fluoroscopy and cardiac index was measured by the Fick method. On the whole group, 96% of patients had had one or more MI (on ECG necrosis was anterior in 58%, inferior in 9%, anterior and inferior in 26%), 69% were in NYHA functional class III or IV, 54% had IPE and 45% had mitral regurgitation. 71% were under treatment with digitalis, 74% with diuretics and 39% with ACE-inhibitors. PCWP was correlated with LVEDV (r = 0.34; p < 0.001) but neither with LV mass nor with LV mass/volume ratio. It was significantly higher (p < 0.01) in patients with mild-moderate mitral regurgitation, in patients with necrosis involving both anterior and inferior walls (26 +/- 6 vs 21 +/- 8 mmHg in patients with single wall necrosis, p < 0.05) and in patients with multiple MI (26 +/- 7 vs 20 +/- 8 mmHg in patients with no or single MI, p < 0.02). Moreover, it was neither correlated with functional classification nor with PVC: of patients with PCWP > 24 mmHg, 14% were in II NYHA functional class and 21% had no PVC while of patients with PCWP < 15 mmHg, 36% were in NYHA functional class IV and 7% had IPE. Cardiac index was reduced below 2.3 l/min/m2 in 21% of patients: these patients had increased pulmonary (p < 0.0002) and systemic (p < 0.0001) vascular resistance, increased systolic (p < 0.001) and diastolic (p < 0.01) pulmonary artery pressure and reduced LVEF (p < 0.01) and right ventricular ejection fraction (p < 0.03). Furthermore, on the whole patients an inverse correlation was found between cardiac index and functional classification (r = -0.42; p < 0.01). The reliability of NYHA functional class IV, physical signs of heart failure and IPE for estimating PCWP > 24 mmHg and cardiac index < 2.3 l/min/m2 was rather limited although high specificity was shown for gallop sounds (92 and 97%) and jugular vein distension (88 and 97%). In conclusion, in coronary patients with chronic severe LV systolic dysfunction a mismatch between clinical data and central hemodynamics is not rare. The reliability of functional class, X-ray PVC and physical signs to predict central hemodynamics in fairly limited.

Influence of beta-blockade with metoprolol on symptoms and functional capacity of patients with idiopathic dilated cardiomyopathy.

Long-term treatment with beta-adrenergic blocking drugs has been shown to induce clinical amelioration in patients with chronic heart failure. However, the efficacy of these agents has not been consistent, and the mechanisms of their beneficial effects remain to be established. The present study evaluated the influence of oral metoprolol on symptoms and exercise tolerance of patients with idiopathic dilated cardiomyopathy (3 women and 9 men, left ventricular ejection fraction < 0.45, NYHA functional class II or III). One patient did not tolerate metoprolol, whereas 11 patients terminated the study. After 6 months of beta-blocking therapy, detectable improvements of symptoms (NYHA class and questionnaire-derived symptom score) were observed in 6 patients. Six patients reported an increase in functional capacity [oxygen consumption at peak exercise (VO2p) during cardiopulmonary exercise test]. For the whole group, no significant changes in symptoms and exercise tolerance were detected. During exercise, oxygen pulse (VO2/heart rate) and VO2/RPP (VO2/heart rate/systolic pressure) were significantly increased after 6 months on metoprolol (+35, 9% and +27.1%, respectively; both p < 0.01 vs baseline). In conclusion, beta-blocking therapy was well tolerated by the majority of patients, some of which reported improvement of symptoms and functional capacity. The observed increase on oxygen pulse and Vo2/RPP suggests that beta-blockade may reduce myocardial oxygen requirements in proportion to cardiac work. An increase in the energy available to myocardial cells for synthetic and reparative processes may thus account, at least in part, for the beneficial influence of long-term beta-blockade in heart failure patients.

Programmed chest-wall stimulation to evaluate the progress of A-V block after pacemaker insertion in patients with trifascicular disease.

Twenty six patients (aged 46-80, mean age 64) with bifascicular block in the presence of prolonged H-V interval (trifascicular block), were followed for an average of 31 months after inserting an R-wave inhibited pacemaker (PM) because of syncope and/or dizzy attacks. The underlying rhythm was evaluated at 4-6-month intervals by three different techniques: 1) 12-lead ECG when intrinsic patient rate was faster than PM rate; 2) abrupt PM inhibition (APMI) by the rapid chest-wall stimulation technique, and 3) progressive PM inhibition (PPMI) using a programmed chest-wall stimulation technique capable of decreasing the PM rate gradually to 30 beats/min before complete PM inhibition. In addition, the PPMI allowed the underlying rhythm to be induced and sustained and properly evaluated without any discomfort to the patient. Following PM insertion, 4 patients (15%) developed complete heart block after a mean follow-up of 43 months, and one patient (4%) developed 2nd degree 2:1 A-V block (VX) after 83 months. The P-R interval increased in 5 patients (19%) and decreased in 2 (8%). No change of A-V conduction was found in 9 patients (34%). Three patients developed low atrial rhythm, atrial flutter and atrial fibrillation, respectively (12%). After PM insertion 2 patients still complained of dizziness. None reported syncope. Two patients died during follow-up, both of congestive heart failure (8%). By detection of intrinsic rhythm it was recognized that a long symptomatic paroxysmal phase may precede the development of chronic complete A-V block. Therefore, the insertion of a permanent PM is recommended in patients with unexplained neurologic symptoms and trifascicular disease, without waiting for documented episodes of complete A-V block.

Clinicopathologic assessment of arrhythmias in a case of scleroderma heart disease with sudden death.

Electrophysiologic and histopathologic correlation has been carried out in a patient with scleroderma heart disease, affected by syncopal seizures, who died of recorded ventricular fibrillation. The electrophysiological investigation disclosed dysfunction of sinoatrial conduction, revealed by sinoatrial blocks and by an abnormal return cycle pattern after premature atrial beats. Atrial effective and functional refractory periods were increased and an unusual 'pseudo-Wenckebach' phenomenon between artificial stimulus and atrium was observed during atrial pacing. Intra-AV nodal conduction time was at normal upper limits and Wenckebach-type AV block was obtained on pacing the atrium at 100 beats/min. HV conduction was moderately prolonged in the presence of left anterior hemiblock. The histopathologic substrates of these electrophysiologic disturbances were fibrosis of the sinus node, disrupted internodal pathways and atrio-AV nodal connections, and left bundle branch atrophy. As far as fatal tachyarrhythmia is concerned, myofibrillar degeneration may have contributed to its pathogenesis. It is suggested that both lesions of the ordinary myocardium and specialized conduction system account for the electrical instability of sclerodermic patients.

A pharmacological approach to the study of AV conduction in man.

Smooth and interrupted curves of AV conduction, generated with an atrial extrastimulus technique, are seen in man, suggesting the involvement of two physiological AV pathways named "alpha" and "beta" and leading to a final common pathway (FCP). In view of this knowledge, the effects of some representative antiarrhytmic agents (Atropine, Verapamil, Ajmaline) were studied in eight patients in order to elucidate the physiological role of the various components of AV junction. Verapamil decreased conduction velocity of both "alpha" and "beta" pathways and increased their refractoriness; Atropine decreased "alpha" and "beta" pathways' refractory periods and increased their conduction velocity; further studies are required to clarify the effects of Ajmaline on AV conduction.

[Electrophysiological demonstration of more structures in the atrioventricular node (author's transl)]. / Evidenziazione elettrofisiologica di piu' strutture nel nodo atrioventricolare.

Three types of atrioventricular nodal conduction curves, relating A1A2 to H1H2, generated with atrial extrastimulus technique, are known. The first type is smooth, suggesting the homogeneous structure of A-V node. The second type, with abrupt increase in H1H2 response over a critical range of A1A2 coupling intervals, suggests the presence of fast and slow A-V nodal pathways. We have found in five patients the third tipe of A-V conduction curve, giving evidence of an intranodal final common pathway, distal to the fast and slow A-V nodal pathways. The thyrd type of curve enables us to know also some alectrophysiological properties of final common pathway. Indeed we have defined effective and functional refractory periods of fast, slow and final common pathways as far as we can in this type of curve. Paced heart rate variations and atropine medications have led the third type of A-V conduction curve to change into the second type in three cases, into first type in one case. These changes of A-V nodal conduction curves are related to different influence of cardiac cycle lenghts and autonomic nervous system on refractory periods and conduction velocity of the outlined intranodal structures.

[The atrial stimulation programmed for the research of dual A-V nodal conduction pathways (author's transl)]. / La stimolazione atriale programmata nella ricerca della duplic conduzione A-V nodale.

Several techniques of premature atrial stimulation were used in a group of 28 not selected patients admitted to electrophysiological investigations of different rhythm troubles. The purpose of this study was the demonstration of dual A-V nodal pathways. The method consisted in the delivery of one or two atrial extrastimuli at every sixth beat, with or without atrial pacing at increasing rate, up to the either atrail or nodal refractory period. Then a curve of intranodal conduction was plotted. The different techniques led us to a curve reproducible in the 89% of the cases. Its main features are the steady increase of the A-H interval, the subsequent sudden "jump" of the same at critical shortening of the coupling stimulation interval and finally a third segment of steady increase until the atrial or nodal refractory period is reached. We believe that this behaviour is common in the man. The significance of the "jump", of the morphology of the curve and their possible relationship with the existence of dual A-V nodal pathways is discussed. Finally the different stimulation techniques are compared.