Antioxidant vitamins attenuate oxidative stress and cardiac dysfunction in tachycardia-induced cardiomyopathy.

OBJECTIVES: We administered antioxidant vitamins to rabbits with pacing-induced cardiomyopathy to assess whether antioxidant therapy retards the progression of congestive heart failure (CHF). BACKGROUND: Although oxidative stress is increased in CHF, whether progression of heart failure could be prevented or reduced by antioxidants is not known. METHODS: Rabbits with chronic cardiac pacing and sham operation were randomized to receive a combination of beta-carotene, ascorbic acid and alpha-tocopherol, alpha-tocopherol alone or placebo over eight weeks. Echocardiography was used to measure cardiac function weekly. Resting hemodynamics and in vivo myocardial beta-adrenergic responsiveness were studied at week 8. Animals were then sacrificed for measuring myocardial beta-receptor density, norepinephrine (NE) uptake-1 site density, sympathetic neuronal marker profiles, tissue-reduced glutathione/oxidized glutathione (GSH/GSSG) ratio and oxidative damage of mitochondrial DNA (mtDNA). RESULTS: Rapid cardiac pacing increased myocardial oxidative stress as evidenced by reduced myocardial GSH/GSSG ratio and increased oxidized mtDNA and produced cardiac dysfunction, beta-adrenergic subsensitivity, beta-receptor downregulation, diminished sympathetic neurotransmitter profiles and reduced NE uptake-1 carrier density. A combination of antioxidant vitamins reduced the myocardial oxidative stress, attenuated cardiac dysfunction and prevented myocardial beta-receptor downregulation and sympathetic nerve terminal dysfunction. Administration of alpha-tocopherol alone produced similar effects, but the effects were less marked than those produced by the three vitamins together. Vitamins produced no effects in sham-operated animals. CONCLUSIONS: Antioxidant vitamins reduced tissue oxidative stress in CHF and attenuated the associated cardiac dysfunction, beta-receptor downregulation and sympathetic nerve terminal abnormalities. The findings suggest that antioxidant therapy may be efficacious in human CHF.

Selegiline improves cardiac sympathetic terminal function and beta-adrenergic responsiveness in heart failure.

Selegiline is a centrally acting sympatholytic agent with neuroprotective properties. It also has been shown to promote sympathetic reinnervation after sympathectomy. These actions of selegiline may be beneficial in heart failure that is characterized by increased sympathetic nervous activity and functional sympathetic denervation. Twenty-seven rabbits with rapid cardiac pacing (360 beats/min, 8 wk) and twenty-three rabbits without pacing were randomly assigned to receive selegiline (1 mg/day, 8 wk) or placebo. Rapid pacing increased plasma norepinephrine (NE) and decreased left ventricular fractional shortening, baroreflex sensitivity, cardiac sympathetic nerve terminal profiles, cardiac NE uptake activity, and myocardial beta-adrenoceptor density. Selegiline administration to animals with rapid ventricular pacing attenuated the increase in plasma NE and decreases in fractional shortening, baroreflex sensitivity, sympathetic nerve profiles, NE uptake activity and beta-adrenoceptor density. Thus selegiline appears to exert a sympatholytic and cardiac neuroprotective effect in pacing-induced cardiomyopathy. The effects are potentially beneficial because selegiline not only improves cardiac function but also increases baroreflex sensitivity in heart failure.

Alterations by norepinephrine of cardiac sympathetic nerve terminal function and myocardial beta-adrenergic receptor sensitivity in the ferret: normalization by antioxidant vitamins.

BACKGROUND: Chronic excessive norepinephrine (NE) causes cardiac sympathetic nerve terminal abnormalities, myocardial beta-adrenergic receptor downregulation, and beta-adrenergic subsensitivity. The present study was carried out to determine whether these changes could be prevented by antioxidants. METHODS AND RESULTS: Ferrets were administered either NE (1.33 mg/d) or vehicle by use of subcutaneous pellets for 4 weeks. Animals were simultaneously assigned to receive either antioxidant vitamins (beta-carotene, ascorbic acid, and alpha-tocopherol) or placebo pellets. NE increased plasma NE 4- to 5-fold but had no effect on heart rate, heart weight, arterial pressure, or left ventricular systolic function. However, myocardial NE uptake activity and NE uptake-1 site density were reduced, as well as cardiac neuronal NE, tyrosine hydroxylase, and neuropeptide Y. In addition, there was a decrease in myocardial beta-adrenergic receptor density with a selective decrease of the beta(1)-receptor subtype, reduction of the high-affinity site for isoproterenol, decreased basal adenylyl cyclase activity, and the adenylyl cyclase responses to isoproterenol, Gpp(NH)p, and forskolin. All of these changes were prevented by antioxidant vitamins. The effects of NE on myocardial beta-adrenergic receptor density, NE uptake-1 carrier site density, and neuronal NE were also prevented by superoxide dismutase or Trolox C. CONCLUSIONS: The toxic effects of NE on the sympathetic nerve terminals are mediated via the formation of NE-derived oxygen free radicals. Preservation of the neuronal NE reuptake mechanism is functionally important, because the antioxidants also prevented myocardial beta-adrenergic receptor downregulation and postreceptor abnormalities. Thus, antioxidant therapy may be beneficial in heart failure, in which cardiac NE release is increased.

[The influence of electrical time interval indices and aging on the left atrial systolic time intervals].

The influence of aging and heart rate on left ventricular systolic time intervals is well known, but the effects on left atrial systolic time intervals, a new index of left atrial function, remain unknown. The influence of aging and heart rate on left atrial systolic time intervals was investigated in 43 normal subjects (13-72 years of age) by Doppler echocardiography. Atrial pre-ejection period, atrial ejection time, and corrected atrial pre-ejection period were obtained by transmitral Doppler echocardiography. Simple regression analysis showed atrial pre-ejection period significantly correlated with P wave duration (PP; r = 0.78), and PR interval (PR; r = 0.60), but not with RR interval (RR). However, multiple regression analysis showed atrial pre-ejection period significantly correlated only with PP. Simple regression analysis found atrial ejection time significantly correlated with PP (r = 0.38), and PR (r = 0.39), but not with RR. However, multiple regression analysis found atrial ejection time did not correlate with any factor significantly. Aging was significantly correlated with corrected atrial pre-ejection period (r = -0.37), but not with corrected atrial ejection time and atrial pre-ejection period. Atrial ejection time significantly correlated with corrected atrial pre-ejection period (r = -0.37), but not with atrial pre-ejection period. Corrected atrial pre-ejection period is a clinically useful index of left atrial systolic function.

[Pulsed Doppler findings of the pulmonary vein flow in mitral stenosis].

Left atrial function was assessed by transesophageal echocardiography in 8 patients with mitral stenosis and sinus rhythm (MS group), and 16 age-matched normal controls (C group). Pulsed Doppler findings of left upper pulmonary vein flow were classified into first and second forward waves during systole (S1, S2), forward wave during diastole (D), and backward flow during left atrial contraction (PVA). Peak velocity (P) and time-velocity integral (TVI) of each wave and acceleration and deceleration slope of S2 wave (S2-Ac, S2-Dc) were obtained. TVI-S2 and P-D in the MS group were significantly lower than those in the C group (TVI-S2: 4 +/- 2 vs 12 +/- 3 cm, P-D: 27 +/- 13 vs 41 +/- 12 cm/sec). S2-Ac and S2-Dc in the MS group were significantly higher than those in the C group (S2-Ac: 456 +/- 116 vs 323 +/- 118 cm/sec2, S2-Dc: 380 +/- 102 vs 165 +/- 48- cm/sec2). There were no differences in S1 and PVA. Lower TVI-S2 in the MS group suggests decreased reservoir function of the left atrium. Lower TVI-S2 in the MS group was caused by increased S2-Ac and S2-Dc which suggests increased left atrial preload and deterioration of left atrial compliance. Decreased P-D in the MS group reflects dysfunction of mitral valve opening.

Heterogeneity and time course of improvement in cardiac function after cardioversion of chronic atrial fibrillation: assessment of serial echocardiographic indices.

OBJECTIVE: To assess the clinical characteristics of patients in whom cardiac function improved after cardioversion of atrial fibrillation and the time course of the improvement. DESIGN: A prospective serial study of echocardiograms recorded before cardioversion and one day, seven days, one month, and three months after cardioversion. SETTING: Echocardiography laboratory of a university hospital. PATIENTS: 23 patients with chronic atrial fibrillation in whom cardioversion was successful. MAIN OUTCOME MEASURES: M mode indices of the left ventricular wall motion and pulsed Doppler indices of the left ventricular inflow. RESULTS: Three months after cardioversion percentage fractional shortening had increased by more than 5% in 14 patients (improved group) and by less than 5% in nine patients (non-improved group). Those in whom cardiac function improved had significantly higher heart rates and a greater reduction in ventricular filling during atrial fibrillation and a more prominent atrial filling wave three months after cardioversion than those patients in the non-improved group. Over the three months of follow up the mean (1SD) percentage fractional shortening increased from 22 (3)% to 30 (4)% in the improved group and in this group heart rate fell one day after cardioversion. A month after cardioversion the percentage fractional shortening had increased to 35 (5)% and the atrial systolic contribution to left ventricular filling increased from 30 (9)% on day 1 to 47 (12)%. CONCLUSIONS: Cardioversion improved cardiac function in patients with tachycardia and reduced ventricular filling during atrial fibrillation. Because both an immediate reduction of heart rate and a delayed recovery of atrial booster pump function played an important part in the improvement of cardiac function the long-term effects of cardioversion should be assessed at least a month after cardioversion.

[Left atrial ejection performance in heart failure as assessed by transesophageal Doppler echocardiography].

To investigate the left atrial ejection performance in heart failure, we observed both the transmitral (TMF) and pulmonary venous flow waves (PVF) by transesophageal Doppler echocardiography in 20 patients with heart failure (16 males, 4 females, 56 +/- 13 years old). In 7 of 20 patients, pulmonary capillary wedge pressures (PC) were also obtained within 72 hours after the transesophageal Doppler echocardiographic examinations. A reversal flow on PVF during atrial systole (atrial backward ejection flow) was observed in all of the 20 patients. Corrected atrial pre-ejection period correlated significantly with PC (r = -0.76, p < 0.05), indicating that the period was shortened in accordance with left atrial Starling's law. This period correlated significantly with both the duration and the time velocity integral of atrial backward flow (r = -0.72, p < 0.005; r = -0.55, p < 0.05, respectively), but not with the atrial ejection time nor with the time velocity integral of atrial systole. These results suggest that in some cases of heart failure, left atrial contractile function is preserved despite the marked augmentation of left atrial afterload, resulting in a decrease of the left atrial forward ejection and an increase of the left atrial backward ejection. Thus, the observations of TMF and PVF by transesophageal Doppler echocardiography are useful for assessing the left atrial ejection performance in patients with heart failure.

[Clinical and echocardiographic evaluation of the effects of atrial defibrillation in patients with idiopathic cardiomyopathy].

To elucidate the effects of atrial defibrillation in patients with idiopathic cardiomyopathy, we clinically and echocardiographically assessed 6 patients with hypertrophic cardiomyopathy (HCM) and 7 patients with dilated cardiomyopathy (DCM). Their mean age was 57 +/- 14 years and the mean duration of their atrial fibrillation (Af) was 47 +/- 29 days. There were no differences in age and the duration of Af between the HCM and DCM groups. We assessed the effects of defibrillation on the NYHA functional classification, heart rate (HR), systolic blood pressure (S-BP), M-mode echocardiographic data (LVDd, LVDs, %FS, LAD) and transmitral pulsed Doppler echocardiographic findings (peak velocity, time-velocity integral of rapid and atrial filling waves). These indices were obtained before and 52 +/- 22 days after defibrillation, and were compared with each other. 1. HR decreased (HCM: 87 +/- 16-->58 +/- 7/min, DCM: 93 +/- 19-->70 +/- 14/min) and total left ventricular filling increased (HCM: 6 +/- 1-->11 +/- 4 cm, DCM: 6 +/- 1-->10 +/- 2 cm) after defibrillation, and the increment of %FS (HCM: 36 +/- 6-->41 +/- 6%, DCM: 16 +/- 6-->25 +/- 11%) was observed. Four of 6 HCM patients and 5 of 7 DCM patients also improved with regard to the NYHA classification. 2. After defibrillation, LVDd increased in HCM (42 +/- 4-->47 +/- 4 mm), but not in DCM. However, LVDs decreased in DCM (52 +/- 9-->44 +/- 12 mm), but not in HCM. We concluded that atrial defibrillation had a beneficial effect on the recovery of the left ventricular function both in HCM and DCM due to the reduction in HR and increase in left ventricular filling. The mode of LV functional improvement after defibrillation varied depending on the state of patient's basal pathophysiology .

[Long-term effect of medical treatment in patients with chronic aortic regurgitation].

We often experience patients with chronic severe aortic regurgitation (AR) whose cardiac function significantly improves by medications, especially by vasodilator therapy. To find the factors determining the response to pharmacologic treatment, we studied 20 patients with chronic AR with dilated left ventricle (end-diastolic dimension > or = 55 mm) using echocardiography; 9 patients with significant improvement (delta Ds < or = -3 mm: improved group) and 11 without improvement (unchanged group). In the initial evaluation, systolic blood pressure and left ventricular relative wall thickness (Thd/Dd) were greater and left ventricular end-diastolic dimension was smaller in the improved group than in the unchanged group. During the follow-up period, systolic blood pressure and end-systolic wall stress decreased significantly and absolute and relative wall thickness increased significantly in the improved group, however, they remained nearly the same in the unchanged group. Significant negative correlation was observed between Thd/Dd and delta Ds. In conclusion, cardiac function in some patients with chronic AR can be improved by pharmacologic treatment, and in such cases, the Thd/Dd ratio could be a parameter of the response to pharmacologic treatment.

[Effects of PTCR and PTCA on serial changes in left and right ventricular wall motion in acute myocardial infarction].

To evaluate the effects of early recanalization on left and right ventricular wall motion in acute myocardial infarction (AMI), we serially observed their degrees in 66 patients with AMI. The patients were categorized as Group 1:17 with spontaneous recanalization within 6 hours of onset of the chest pain; Group 2:34 with effective recanalization within 6 hours (10 by PTCR, 10 by PTCR+ PTCA, and 14 by direct PTCA), and Group 3:21 without effective recanalization. The Group 2 patients were classified in 3 subgroups according to the time intervals from onset of symptoms to recanalization; 11 patients with recanalization within 2 hours (Group 2a), 10 between 2 and 4 hours (Group 2b), and 13 between 4 and 6 hours (Group 2c). The left and right ventricular wall motion abnormality indexes (WMAI) were defined as the means of point scores for the degrees of regional wall motion abnormality at 11 segments of the left ventricle and seven segments of the right ventricle on serial two-dimensional echocardiograms. Results were as follows: 1. The LV-WMAI of Group 1 was smaller on day 1, and improved on day 28 as compared to those of the other groups (0.63 +/- 0.35 to 0.18 +/- 0.18, p less than 0.001). 2. The improvements of the LV-WMAI from days 1 to 28 in Group 2a (WMAI: 1.01 +/- 0.57 to 0.26 +/- 0.26, delta WMAI: 82 +/- 14%) and Group 2b (1.03 +/- 0.38 to 0.52 +/- 0.48, 54 +/- 36%) were greater than that in Group 2c (1.01 +/- 0.46 to 0.64 +/- 0.52, 38 +/- 47%).(ABSTRACT TRUNCATED AT 250 WORDS)