Chronic treatment with sulfhydryl angiotensin-converting enzyme inhibitors reduce susceptibility of plasma LDL to in vitro oxidation, formation of oxidation-specific epitopes in the arterial wall, and atherogenesis in apolipoprotein E knockout mice.

The effects of chronic treatment with the new sulfhydryl angiotensin-converting enzyme (ACE)-inhibitor, zofenopril, in comparison with the classical sulfhydryl ACE-inhibitor captopril or enalapril or placebo on the development of atherosclerosis were determined in apolipoprotein-E knockout (apoE(-/-)) mice. Groups of 2-month-old male mice received either placebo (N=10), 0.05 mg/kg/day of zofenopril (N=10), 1 mg/kg/day of zofenopril (N=10), 5 mg/kg/day of captopril (N=10) or 0.5 mg/kg/day of enalapril (N=8). After 29 weeks of treatment, computer-assisted imaging analysis revealed that zofenopril reduced the aortic cumulative lesion area by 78% at 0.05 mg/kg/day and by 89% at 1 mg/ml/day of zofenopril compared to that of the placebo (P<0.0001). Captopril reduced by 52% aortic lesions compared to placebo (P<0.01 vs. placebo; P<0.05 vs. zofenopril at both doses). Enalapril did not reduce aortic lesions. Furthermore, 0.05 mg/kg/day of zofenopril reduced susceptibility of plasma LDL to in vitro oxidation compared to captopril, enalapril or placebo, as shown by significant reduction of malondialdehyde content (P<0.001 vs. placebo or enalapril; P<0.05 vs. captopril), as well as by the prolongation of lag-time (P<0.01 vs. placebo or enalapril P<0.05 vs. captopril). More importantly, mice treated with 1 mg/ml/day of zofenopril had a significant decrease in the intimal immunohistochemical presence of oxidation-specific epitopes on oxLDL (NA59 monoclonal antibody, P<0.01), macrophages derived foam cells (F4/80 monoclonal antibody, P<0.05) and native LDL (NP monoclonal antibody, P<0.01) compared to placebo, captopril or enalapril. Thus, chronic treatment with the new sulfhydryl ACE-inhibitor zofenopril has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic apoE(-/-) mice. This protection was significantly higher than that reached with captopril and at lower doses of the drug. Treatment with 0.5 mg/kg/day of enalapril did not provide any protective effect.

Effect of glycaemic control and age on low-density lipoprotein susceptibility to oxidation in diabetes mellitus type 1.

BACKGROUND: Although individuals with diabetes mellitus frequently have dyslipidaemias and high blood pressure, much of the increased risk for coronary heart disease is not explained by these and other classical risk factors. Thus, other less widely recognized risk factors, including increased susceptibility of low-density lipoprotein (LDL) to oxidation, might enhance vascular dysfunction and atherogenesis in diabetes. AIMS: We compared both the rate and extent of LDL oxidation ex vivo between 78 poorly controlled individuals with type 1 diabetes and 78 age- and sex-matched non-diabetic controls. We then initiated intensive insulin therapy for 3 months to determine the impact of improved glucose control on LDL composition and oxidation. RESULTS: Diabetic and non-diabetic individuals did not have significantly different body weights, dietary intake, blood pressure, renal function or plasma lipid levels. LDL composition was also similar in both groups. In contrast, vitamin E content in LDL was significantly lower in diabetic patients. Measures of LDL lipid oxidation, including conjugated diene, lipid peroxide and thiobarbituric acid reactive substances formation, as well as measures of LDL protein modification, were significantly greater in diabetic patients. Levels of hyperglycaemia correlated strongly with each measure of LDL lipid oxidation (r ranges from 0.60-0.81, P<0.05 for each correlation). After improved glucose control (average reduction in % Hb(Alc)of 5.5 units) all measures of LDL oxidation improved dramatically and approached values for non-diabetics. Absolute values of LDL oxidation increased among all categories of age in both diabetic and control individuals, and this relationship persisted even after adjustment for differences in glucose concentrations. CONCLUSIONS: We demonstrate that hyperglycaemia has a potent but reversible effect on LDL oxidation and that age may independently enhance LDL susceptibility to oxidation. These pathophysiological effects may play an important role in determining vascular complications and atherogenesis in poorly controlled type 1 diabetic patients.

Cardiovascular haemodynamics and cardiac autonomic control in patients with subclinical and overt hyperthyroidism.

OBJECTIVE: To characterize cardiac structure and function and cardiac autonomic control in patients with subclinical and overt hyperthyroidism. DESIGN: Thirty patients with subclinical hyperthyroidism and 30 with overt disease were selected from patients never previously treated for endocrinological disease in the outpatient clinic of our institution. Twenty normal individuals were studied as control group. METHODS: Left ventricular structure and function and cardiac autonomic control were evaluated, respectively, by two-dimensional Doppler echocardiography and by 24-h Holter recording with heart rate variability analysis. RESULTS: Patients with overt hyperthyroidism showed greater values of left ventricular end-diastolic volume (P<0.05) and left ventricular mass (P<0.05) than patients with subclinical disease. In addition, the mean velocity of left ventricular fibre shortening (P<0.05) and left ventricular ejection fraction (P<0.05) were greater in patients with overt hyperthyroidism than in patients with subclinical disease. No difference in any of these parameters was detectable between normal subjects and patients with subclinical disease. The isovolumic relaxation period was shorter in patients with subclinical hyperthyroidism than in control individuals (P<0.05) and in patients with overt hyperthyroidism (P<0.05). As regards cardiac autonomic control, all time and frequency domain measures decreased progressively from control individuals to patients with subclinical hyperthyroidism and those with overt disease (P<0.001). CONCLUSIONS: Thyrotoxic patients show changes in left ventricular structure and increased echocardiographic indexes of myocardial contractility, whereas the only echocardiographic feature detectable in patients with subclinical hyperthyroidism is an increased velocity of left ventricular relaxation. Cardiac parasympathetic withdrawal is evident in patients with overt hyperthyroidism and in patients with subclinical disease.

A multicenter, randomized double-blind study of valsartan/hydrochlorothiazide combination versus amlodipine in patients with mild to moderate hypertension.

OBJECTIVE: To compare the antihypertensive efficacy and tolerability of a once-daily fixed valsartan/hydrochlorothiazide (HCTZ) combination and amlodipine in subjects with mild-to-moderate hypertension. SUBJECTS AND SETTING: In this multicentre, double-blind, randomized, comparative trial, 690 patients with sitting systolic blood pressure (BP) > or = 160 mmHg and sitting diastolic BP > or = 95 mmHg at the end of a 2-week placebo wash-out period were randomized to valsartan-based treatment (n = 342) or amlodipine (n = 348). METHODS: The patients received valsartan 80 mg o.d. or amlodipine 5 mg o.d for 4 weeks; in the case of an unsatisfactory blood pressure response, the treatments could be respectively changed to the fixed combination of valsartan 80 mg + HCTZ 12.5 mg o.d. or amlodipine 10 mg o.d. for a further 8 weeks. RESULTS: Both treatment approaches decreased systolic blood pressure and diastolic blood pressure to the same extent. The rate of responders to treatment at the end of fourth week (before up-titration) was 57.4% among the valsartan-treated patients and 61.9% among the amlodipine-treated patients (ns). At the end of the study, the rate of responders was not significantly different between the two groups (74.9 versus 72.1%). Valsartan-based treatment had a slightly lower incidence of adverse events (1.5 versus 5.5%; P = 0.006). CONCLUSIONS: The results of this trial demonstrate that the valsartan/hydrochlorothiazide combination and amlodipine are equally effective in lowering BP, and that the combination is better tolerated.

Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients with GH deficiency.

Adult GH deficiency (GHD) is associated with increased cardiovascular morbidity and mortality due to unfavorable lipid profile, hyperfibrinogenemia, and impairment of cardiac performance. This prospective controlled cohort study evaluated the effects of 12-month GH replacement on lipid profile, fibrinogen levels, cardiac mass by echocardiography, and performance by equilibrium radionuclide angiography. To this end we studied 20 patients (11 men and 9 women, aged 19-40 yr), 10 with childhood-onset (co-) and 10 with adult-onset (ao-) disease, and 20 sex- and age-matched healthy subjects. At study entry, insulin-like growth factor I (IGF-I; P < 0.0001) and high density lipoprotein (HDL) cholesterol (P < 0.0001) levels, left ventricular mass index (LVMi; P < 0.0001), ejection fraction (LVEF) at rest (P = 0.001) and at peak exercise (P < 0.0001), peak ejection rate (P = 0.005), and exercise duration (P < 0.0001) and capacity (P = 0.002) were lower, whereas total cholesterol (P = 0.02), triglycerides (P = 0.003), and fibrinogen (P = 0.005) levels were higher in patients than in controls. After 12 months, increases in IGF-I (P < 0.0001) and HDL cholesterol levels (P = 0.04), LVMi (P < 0.0001), LVEF at peak exercise (P < 0.0001), and exercise duration (P = 0.009) and capacity (P = 0.003) and decreases in total cholesterol (P < 0.0001), low density lipoprotein cholesterol (P < 0.0001), triglycerides (P < 0.0001), and fibrinogen (P = 0.01) levels were found in all patients, without any difference between co- and ao-GHD. At the end of treatment, however, total cholesterol, triglycerides, and fibrinogen levels were still higher, and HDL cholesterol levels, IGF-I levels, and LVEF at rest and at peak exercise were lower in patients than in controls. In conclusion, GH replacement for 12 months significantly improved lipid profile, decreased fibrinogen levels, and increased LVMi and LVEF in young adults with co- or ao-GHD. However, lipid profile, fibrinogen levels, and systolic function remained abnormal compared with those in age- and sex-matched controls, suggesting that a longer period of GH replacement is necessary to normalize cardiovascular parameters and reverse the cardiovascular risk of these patients.

Circulating levels of cytokines and their site of production in patients with mild to severe chronic heart failure.

BACKGROUND: Patients with chronic heart failure have elevated levels of proinflammatory cytokines; however, the mechanism for their increased expression and the site of their production are unknown. METHODS: Twenty-two patients with heart failure, New York Heart Association functional class II to IV, underwent hemodynamic evaluation and echocardiographic study. Blood samples for cytokine evaluation were performed in the ascending aorta, coronary sinus, inferior vena cava, and hepatic vein. Levels of tumor necrosis factor-alpha (TNF-alpha), its soluble receptors sTNF-RI and sTNF-RII, interleukin-6 (IL-6), IL-6 soluble receptor, soluble gp130, interleukin-2 soluble receptor, and soluble Fas were measured with enzyme-linked immunosorbent assay kits. RESULTS: IL-6 concentrations were higher in class IV patients than in class III patients, which in turn were higher than those in class II. TNF-alpha, sTNF-RI, and sTNF-RII were higher in class IV patients than in class III and II patients. Significant correlations were found between IL-6 concentrations and left ventricular end-systolic volume (r = 0.64; P <.001), pulmonary wedge pressure (r = 0.56; P <.01), and left ventricular ejection fraction (r = -0.56; P <.01). No correlation was found between TNF-alpha and its soluble receptors and left ventricular volumes or hemodynamic measures. Finally, no difference in cytokine concentrations was found among the different sample sites. CONCLUSIONS: Among inflammatory cytokines, IL-6 concentrations better reflect the hemodynamic derangement in patients with heart failure. No cardiac or gut production of cytokines occurs in patients with mild to severe heart failure.

Cardiovascular effects of depot long-acting somatostatin analog Sandostatin LAR in acromegaly.

Cardiovascular disease is the most severe complication of acromegaly accounting for the increased mortality of these patients. Recently, the slow-release form of octreotide (OCT; Sandostatin LAR, OCT-LAR), for im injection every 28 days, was reported to induce suppression of GH levels below 7.5 mU/L (2.5 microg/L) in 39-75% of patients, and normalization of insulin-like growth factor (IGF)-I levels for age in 64-88% of patients, with an excellent patients' compliance. The aim of the present study was to investigate the early effect of OCT-LAR treatment on the left ventricular (LV) structure and performance in 15 somatostatin analog-naive patients with acromegaly (GH, 94.8 +/- 24.9 mU/L; IGF-I, 757.9 +/- 66.6 microg/L), focusing on the early effect of GH and IGF-I suppression on the heart. Cardiac structure was investigated by echocardiography, whereas LV performance was investigated by gated-blood-pool scintigraphy, before and after 3 and 6 months of treatment with OCT-LAR. OCT-LAR was initially administered im, at a dose of 20 mg every 28 days, for 3 months. In six patients, the dose was then increased to 30 mg every 28 days to achieve disease control, which was considered when fasting and/or glucose-suppressed GH values were below 7.5 and 3.0 mU/L, respectively, together with IGF-I values within the normal range for age. The treatment with OCT-LAR for 6 months induced a significant decrease of GH (to 12.9 +/- 3.0 mU/L) and IGF-I levels (to 340.3 +/- 40.2 microg/L) in all 15 patients. After 6 months of treatment, the percent IGF-I suppression was 52.8 +/- 4.4%, and serum GH/IGF-I levels were normalized in 9 patients. A significant decrease of LV mass index (LVMi), interventricular septum thickness, and LV posterior wall thickness was observed in all 15 patients after 3 and 6 months of OCT-LAR treatment: LVMi was decreased by 19.1 +/- 2.0% without any difference in patients with (19.9 +/- 2.7%) or without disease control (17.8 +/- 3.3%). Among the 11 patients with LV hypertrophy, 6 normalized their LVMi after treatment. At study entry, an inadequate LV ejection fraction (LVEF) at rest (<50%) was found in 5 patients (33.3%), whereas an impaired response of LVEF at peak exercise (<5% increase of basal value) was found in 9 patients (60%). A significant increase in LVEF, both at rest (from 51.6 +/- 2.6 to 58.1 +/- 1.7%, P < 0.01) and at peak exercise (from 51.6 +/- 2.3 to 60.2 +/- 2.4%, P < 0.001) was found in patients with (as compared with those without) disease control (from 55.2 +/- 3.8 to 58.0 +/- 4% and from 61.8 +/- 4.6 to 61.8 +/- 3.4%, respectively). Among the 5 patients with inadequate LVEF at rest, all but 1 regained a normal LVEF after 6 months of treatment; whereas, among the 9 patients with an impaired response of the LVEF at peak exercise, 3 patients normalized, 4 improved, and 2 impaired their responses after treatment. The percent of IGF-I suppression was significantly correlated with the percent increase of resting LVEF (r = 0.644, P < 0.01). Exercise duration (from 6.0 +/- 0.7 to 7.3 +/- 0.7 min) and capacity (from 69.0 +/- 8.2 to 80 +/- 7.8 watts) were increased in the 15 patients considered as a whole, but the improvement in the exercise response was significant only in patients with disease control (P < 0.01 and P < 0.05, respectively) who also had an increase in the peak ejection rate (P = 0.03). No change in hemodynamic parameters, either at rest or at peak exercise, was found after treatment with OCT-LAR in the 15 patients. In conclusion, the results of the present study demonstrate that OCT-LAR im injections every 28 days induces a sustained suppression of GH levels and IGF-I levels in all acromegalic patients, allowing achievement of disease control in 60% of patients after 6 months of treatment. The sustained suppression of IGF-I levels was followed by a significant reduction of LVMi in all patients already after 3 months of treatment, with recovery of LV hypertrophy in 6 of 11 patients. (ABSTRACT TRUN

Effects of losartan treatment on cardiac autonomic control during volume loading in patients with DCM.

This study evaluated the effect of angiotensin II receptor blockade on cardiac autonomic control adaptation and urine output in response to acute isotonic volume load in patients with idiopathic dilated cardiomyopathy (DCM) and asymptomatic to mildly symptomatic heart failure. Left ventricular volumes and heart rate variability measurements were assessed at baseline and during intravenous saline load in 14 patients before and after 2 mo of losartan treatment. After losartan treatment, blood pressure values were lower, whereas left ventricular ejection fraction was higher (F = 79, P < 0.001), than before treatment. During saline load, ejection fraction decreased before losartan treatment (F = 5.6, P < 0.05) but did not change after treatment. Urinary volume, unchanged during saline load in untreated patients, increased after losartan (F = 9.38, P < 0. 001). Time-domain measurements that represent vagal modulation of heart rate (root-mean-square successive differences and percentage of differences between successive R-R intervals >50 ms) decreased during saline load in untreated patients (F = 3.1, P < 0.05 and F = 6.5, P < 0.01, respectively), but not after losartan. Similarly, a decrease in very low frequency (F = 3.2, P < 0.05), low-frequency (F = 2.9, P < 0.05), and high-frequency power (F = 6.1, P < 0.01) after saline load was observed only in untreated patients. In patients with DCM, losartan treatment improves the cardiac autonomic adaptation and increases urine output in response to volume overload.

Prediction of recovery of left ventricular dysfunction after acute myocardial infarction: comparison between 99mTc-sestamibi cardiac tomography and low-dose dobutamine echocardiography.

UNLABELLED: The aim of this study was to evaluate the role of 99mTc-sestamibi cardiac imaging and dobutamine echocardiography in detecting myocardial viability early after acute myocardial infarction. METHODS: Forty-nine patients (mean age 52 +/- 10 y) underwent coronary angiography, low-dose dobutamine echocardiography, radionuclide angiography and rest 99mTc-sestamibi imaging within 10 d after myocardial infarction. Of these patients, 19 were revascularized and 30 were treated medically. Resting echocardiogram and radionuclide angiography were repeated 8 mo later to evaluate segmental functional recovery and changes in left ventricular (LV) ejection fraction, respectively. RESULTS: In revascularized patients, 61 of 108 akinetic or dyskinetic segments showed functional recovery. In these patients, sensitivity in predicting segmental functional recovery was 87% for sestamibi imaging and 66% for dobutamine echocardiography (P < 0.001), whereas specificity and accuracy were comparable. Sestamibi activity (> or =55% of peak) was the strongest predictor of segmental functional recovery (P < 0.001) and of LV ejection fraction improvement > or =5% (P < 0.01) after revascularization. In medically treated patients, 60 of 149 akinetic or dyskinetic segments showed functional recovery. In these patients, the majority (94%) of segments with contractile reserve on dobutamine were viable on sestamibi imaging and 86% of them improved function at follow-up. Functional recovery was poor in segments without contractile reserve either with (38%) or without (62%) preserved sestamibi uptake. Inotropic response was the best predictor of segmental (P < 0.001) and global (P < 0.01) LV functional improvement in medically treated patients. CONCLUSION: Dobutamine echocardiography predicts spontaneous functional recovery after acute myocardial infarction. However, sestamibi imaging is useful to identify patients with dysfunctional myocardium without contractile reserve who may benefit from coronary revascularization.

Cardiac autonomic responses to volume overload in normal subjects and in patients with dilated cardiomyopathy.

This study evaluated the effects of acute isotonic volume expansion on heart rate variability (HRV) in 10 patients with dilated cardiomyopathy (DCM) and in 10 age- and sex-matched normal volunteers. Echocardiographic left ventricular volumes and HRV measurements by continuous Holter recording were assessed at baseline, at 60 and 120 min during intravenous saline load (0.9% NaCl, 0.25 ml. kg(-1). min(-1)), and 60 min after infusion was terminated. Data analysis was performed by repeated-measures ANOVA. After volume expansion, left ventricular ejection fraction increased (F = 9.8; P < 0.001) in normal subjects and decreased (F = 8.7; P < 0.001) in DCM patients. During volume expansion a significant difference was also detectable between the two groups in root-mean-square successive difference (F = 25.2; P < 0.001), percentage of differences between successive normal R-R intervals >50 ms (F = 97.6; P < 0.001), high-frequency power (F = 50.1; P < 0.001), and low-frequency power (F = 41.6; P < 0.001), all of which reflect parasympathetic modulation of heart rate; in fact, these measurements increased in normal subjects and decreased in DCM patients. In normal subjects, the increase in HRV measurements during volume expansion suggests a parasympathetic activation, mediated by stimulation of cardiopulmonary and arterial mechanoreceptors. On the contrary, in DCM patients the parasympathetic withdrawal, already detectable at baseline, increases during volume expansion.

Independent and incremental prognostic value of heart rate variability in patients with chronic heart failure.

BACKGROUND: Decreased heart rate variability (HRV), indicating derangement in cardiac autonomic control, has been reported in patients with chronic heart failure. However, the independent and incremental prognostic value of HRV over clinical data and measures of left ventricular dysfunction has been less thoroughly investigated. This study was designed to evaluate the predictive value of HRV and Poincaré plots as assessed by 24-hour Holter recording in patients with chronic heart failure. METHODS: Ninety-seven patients, mean age 55 +/- 13 years, with radionuclide left ventricular ejection fraction 50 ms (hazard ratio 0.93), and age (hazard ratio 1.06). Furthermore, HRV analysis improved (P <. 001) the prognostic power of a model including clinical and echocardiographic data, left ventricular ejection fraction, and ventricular arrhythmias at Holter recording, whereas the inclusion of Poincaré plots did not add further predictive value. CONCLUSIONS: Our investigation demonstrated that HRV has independent and incremental prognostic value in patients with chronic heart failure and seems useful to stratify patients at high risk of cardiac death.

Comparison of verapamil versus felodipine on heart rate variability in hypertensive patients.

OBJECTIVE: We evaluated the effect of two calcium channel blockers, verapamil and felodipine, on heart rate variability in hypertensive patients. DESIGN: Time and frequency domain measures of heart rate variability were obtained from 24 h Holter recording in 25 previously untreated hypertensive patients without left ventricular hypertrophy, before and after 3 months of verapamil slow-release treatment (240 mg once daily) or felodipine extended-release treatment (10 mg once daily). RESULTS: Blood pressure values decreased with both drugs. Measures of heart rate variability, comparable at baseline in the two groups, were unchanged after felodipine. After verapamil, the average RR interval, the square root of the mean of the squared differences between all adjacent normal RR intervals (r-MSSD) and the percentage of differences between all adjacent normal RR intervals > 50 ms (pNN50), measures of vagal modulation of heart rate, increased (from 735 +/- 67 to 827 +/- 84 ms, P < 0.001; from 30 +/- 10 to 44 +/- 15 ms, P < 0.001; and from 3 +/- 2 to 7 +/- 6%, P < 0.01, respectively) and were higher than after felodipine. The coefficient of variation, a measure that compensates for heart rate effects, increased only after verapamil (from 5.8 +/- 1.3% to 6.6 +/- 1.0%; P < 0.05). High frequency power and its coefficient of component variance, both representing the vagal modulation of heart rate, increased after verapamil (from 5.33 +/- 0.29 to 5.80 +/- 0.27 In units, P < 0.001 and from 1.9 +/- 0.3 to 2.2 +/- 0.25%; P < 0.05). Finally, the low to high frequency power ratio, an indicator of sympathovagal balance, with a high value suggesting a sympathetic predominance, decreased after verapamil (from 2.16 +/- 0.41 to 1.36 +/- 0.35; P < 0.001), confirming the improvement in vagal modulation of heart rate. CONCLUSION: In hypertensive patients, despite a comparable anti-hypertensive effect, verapamil, but not felodipine, has favourable effect on cardiac autonomic control.

Wavelet transform analysis of heart rate variability during dipyridamole-induced myocardial ischemia: relation to angiographic severity and echocardiographic dyssynergy.

BACKGROUND: Analysis of heart rate variability (HRV) is a valuable noninvasive method for quantifying autonomic cardiac control in humans and has been utilized during dipyridamole echocardiographic test to differentiate positive from negative test results. HYPOTHESIS: We aimed to evaluate, by means of HRV analysis, the influence of the angiographic severity of coronary artery disease on cardiac autonomic control during dipyridamole-induced myocardial ischemia. METHODS: We analyzed RR interval variability changes during dipyridamole-induced myocardial ischemia in 31 selected patients (mean age 54 +/- 9 years) with available coronary angiography and positive dipyridamole echocardiographic test. Spectral components of HRV were assessed by means of wavelet transform analysis for the last 5 min before the beginning of the test (baseline) and for 5 min after the onset of ischemia-related events (peak dipyridamole effect). RESULTS: Patients were divided into three groups according to the number of coronary diseased vessels (Group A, single-vessel disease; Group B, double-vessel disease; Group C, triple-vessel disease). No difference was detectable at baseline among the three groups. After dipyridamole, low-frequency power, a measure of sympathetic modulation of heart rate, increased and echocardiographic wall motion score index worsened in all groups (p < 0.001). The increase in low-frequency power was more evident in Group C patients than in the other two groups (p < 0.005). Furthermore, after dipyridamole, a direct correlation was found between low-frequency power and wall motion score index (r = 0.59; p < 0.001). CONCLUSIONS: These data suggest that HRV analysis performed during dipyridamole echocardiographic test provides useful information to assess the severity of coronary artery disease.

Combined assessment of left ventricular function and rest-redistribution regional myocardial thallium-201 activity for prognostic evaluation of patients with chronic coronary artery disease and left ventricular dysfunction.

BACKGROUND: This study evaluated the prognostic value of combined assessment of left ventricular (LV) function and regional myocardial thallium activity in patients with nonrecent myocardial infarction and LV dysfunction. METHODS AND RESULTS: Eighty-two patients with previous myocardial infarction (>8 weeks) and echocardiographic evidence of LV dysfunction underwent thallium-201 rest-redistribution tomography and cardiac catheterization. During the follow-up period (mean 25 months) there were 18 cardiac events (14 deaths and 4 nonfatal myocardial infarctions). Multivariate Cox regression analysis on clinical, angiographic, and thallium variables showed that the number of echocardiographic dysfunctional segments with preserved thallium uptake (> or =50% of peak activity; chi-square 11.03; p<0.005) and age (chi-square 8.12, p<0.01) were predictive of poor outcome. At incremental analysis, combined echocardiographic and thallium data provided significant additional information to clinical, thallium, and LV functional data, increasing global chi-square value from 22.4 to 31.5 (p< 0.01). Similarly, combined data gave additional information after considering clinical, echocardiographic, and LV functional data, increasing global chi-square from 17.8 to 22.3 (p <0.05). Differently, the number of diseased vessels at coronary angiography did not add further prognostic information. CONCLUSIONS: In patients with previous myocardial infarction and chronic LV dysfunction, the combination of echocardiographic and thallium rest-redistribution imaging data gives prognostic information incremental to those of clinical and LV functional data and to those of each technique considered separately.

Intensive training and cardiac autonomic control in high level athletes.

PURPOSE: We aimed to evaluate in a longitudinal study the effect of intensive training on cardiac autonomic control in athletes using 24-h heart rate variability analysis. METHODS: Time and frequency domain measures of heart rate variability were calculated from 24-h Holter monitoring in 15 high level bicyclists (mean age 21 +/- 4 yr) after 1 month of detraining and after 5 months of vigorous training. At the same times echocardiographic left ventricular mass and dimensions and maximal oxygen consumption (VO2max) were assessed. RESULTS: In detrained athletes, VO2max values, left ventricular mass and dimensions, and time and frequency domain measures of vagal modulation of heart rate were higher than in a group of untrained subjects of similar age while heart rate and the low-to-high frequency ratio were lower, indicating an enhanced vagal modulation of heart rate in athletes as compared with that in control subjects. After 5 months of vigorous training, left ventricular mass and dimensions and VO2max increased in athletes, while heart rate decreased further. In contrast, no changes were detectable in time and frequency domain measures of heart rate variability over the entire 24-h and in both waking and sleeping hours. CONCLUSIONS: This study demonstrates that an increased cardiac vagal control is detectable in detrained athletes; however, after intensive training, despite a significant decrease in heart rate, time and frequency domain measures of heart rate variability reflecting cardiac vagal control remain unchanged. Thus, other mechanisms than changes in cardiac autonomic control could be involved in determining the profound bradycardia of athletes.

Successful coronary revascularization improves prognosis in patients with previous myocardial infarction and evidence of viable myocardium at thallium-201 imaging.

The role of coronary revascularization of dysfunctional myocardium with preserved thallium-201 uptake in determining the prognosis in patients after myocardial infarction remains to be defined. This study was designed to evaluate the effects of successful revascularization on survival and left ventricular (LV) function in patients with previous myocardial infarction and evidence of dysfunctional but still viable myocardium at rest-redistribution 201Tl imaging. Seventy-six consecutive patients with LV dysfunction related to previous myocardial infarction and evidence of viable myocardium at rest-redistribution 201Tl tomography were followed for 17+/-8 months. LV ejection fraction (EF) was assessed by radionuclide angiography at baseline and after 13+/-2 months. Thirty-nine patients were revascularized (group A) and 37 treated medically (group B). During the follow-up there were nine cardiac deaths. Survival rate was 97% in group A and 66% in group B (P<0.01). By Cox multivariate analysis, the extent of viable myocardium was the best predictor of cardiac death (chi2=8.67, P<0.01) and provided additional information to clinical and functional data (P<0.01). The inclusion of revascularization as a variable improved the global chi2 of the model from 14.1 to 21.9 (P<0.01). At follow-up, EF had improved by >/=5% in 16 patients. By multivariate logistic analysis, the extent of viable myocardium was the best predictor of EF improvement (chi2=15.49, P<0.001) and provided additional information to clinical and functional data (P<0.01). The inclusion of revascularization as a variable improved the global chi2 of the model from 16.8 to 22.5 (P<0.01). These results demonstrate that the total extent of dysfunctional myocardium with preserved 201Tl uptake is the strongest predictor of cardiac death in patients after myocardial infarction. Successful revascularization of dysfunctional but viable myocardium improves survival and LVEF in such patients.

Prognostic value of coronary angiography in patients with chronic ischemic left ventricular dysfunction and evidence of viable myocardium on thallium reinjection imaging.

BACKGROUND: We evaluated the independent and incremental prognostic value of cardiac catheterization and coronary angiographic data over thallium reinjection after stress redistribution imaging in patients with myocardial infarction and left ventricular dysfunction. METHODS AND RESULTS: Sixty-nine patients with a first myocardial infarction (> 8 weeks) and left ventricular ejection fraction < or = 40% underwent thallium-201 reinjection after stress redistribution tomographic imaging and cardiac catheterization. During follow-up (mean 26 months) 11 cardiac events (8 cardiac deaths and 3 nonfatal myocardial infarctions) occurred. On Cox regression analysis independent predictors of cardiac events were the sum of reversible and moderately irreversible defects at thallium reinjection (chi 2, 16.4, p < 0.005) and the number of reversible defects at stress redistribution (chi 2, 5.1, p < 0.05). Moreover, thallium reinjection imaging improved the prognostic power of clinical, exercise, and stress redistribution data (p < 0.01). The inclusion of left ventricular ejection fraction produced a borderline improvement (p = 0.06), whereas the number of vessels with coronary disease did not. In contrast, in patients at high risk such as those with at least 25% of viable myocardium at reinjection, the number of diseased vessels provided additional prognostic information (p < 0.05). CONCLUSIONS: In patients with chronic ischemic left ventricular dysfunction, left ventricular ejection fraction, but not the number of diseased vessels, provides additional prognostic information to thallium imaging. Therefore coronary angiography seems unnecessary in these patients, unless a significative amount of viable myocardium is detectable.

Heart rate variability in patients with hypertrophic cardiomyopathy: association with clinical and echocardiographic features.

Autonomic dysfunction has been reported in patients with hypertrophic cardiomyopathy. To evaluate the influence of different clinical and echocardiographic features of the disease on sympathovagal balance, as assessed by heart rate variability, 33 patients with hypertrophic cardiomyopathy and 33 healthy volunteers underwent echocardiographic examination and 24-hour electrocardiogram Holter recording. Measures of vagal modulation of heart rate were lower in patients with hypertrophic cardiomyopathy than in controls, particularly in those exhibiting syncope, exertional chest pain, dyspnea, or moderate or severe mitral regurgitation. Furthermore, the age-corrected multiple regression analysis showed that the parasympathetic cardiac control was inversely related to left atrial dimension and directly related to left ventricular end-systolic dimension. Therefore in hypertrophic cardiomyopathy the parasympathetic withdrawal is more evident in patients with symptoms than in those without; the reduction in left ventricular end-systolic dimension and the increase in left atrial size are the echocardiographic features that most influence the sympathovagal balance.

Comparison of verapamil versus felodipine on heart rate variability after acute myocardial infarction.

A depressed heart rate variability (HRV) is a powerful predictor of poor outcome in myocardial infarction patients. The beneficial effect of specific interventions on its recovery has been reported, but data concerning calcium antagonists are scarce. We evaluated the effect of a phenylalkylamine derivative, verapamil, and a dihydropyridine derivative, felodipine, on time- and frequency-domain measurements of HRV by 24-hour Holter monitoring in 60 patients with acute myocardial infarction (AMI). After a first Holter recording (65 +/- 8 hours from the onset of symptoms), patients were randomly assigned to continue standard treatment or to also receive verapamil retard (120 mg 3 times daily) or felodipine extended-release (10 mg/day). Holter recording was repeated after 7 days. After verapamil, mean RR interval increased from 823 +/- 92 to 907 +/- 95 ms and the SD of all normal RR (NN) intervals (SDNN) from 99 +/- 24 to 120 +/- 30 ms (p < 0.01); the root mean square successive difference (r-MSSD) and the percent of differences between adjacent NN intervals > 50 ms (pNN50) also increased (p < 0.01). After felodipine, only SDNN increased (p < 0.01). Regarding frequency-domain measurements, after receiving verapamil, very low frequency, low- and high-frequency powers increased (p < 0.01), whereas the low- to high-frequency ratio decreased (p < 0.01). After receiving felodipine, very low-frequency power increased (p < 0.01), whereas low- and high-frequency powers and the low- to high-frequency ratio remained unchanged. This study demonstrates that verapamil, but not felodipine, improves HRV in the early phase after AMI.

Heart rate variability as a measure of autonomic nervous system function in anorexia nervosa.

BACKGROUND AND HYPOTHESIS: Alteration in sympathovagal balance may be a mechanism of increased cardiovascular mortality and sudden death of patients with anorexia nervosa. This study was undertaken to characterize cardiac autonomic control in patients with anorexia nervosa by means of heart rate variability analysis. METHODS: Heart period variability by 24-h Holter recording was evaluated in 13 young women with anorexia nervosa, 10 constitutionally thin women, and 10 women of normal weight. RESULTS: High-frequency power, a measure of parasympathetic modulation of heart rate, and all-time domain measures of heart rate variability were higher in patients with anorexia nervosa than in thin women and in those of normal weight. Thin women showed lower values of total power and of most components of power spectrum. CONCLUSIONS: Our data demonstrate an increased vagal tone in young women with anorexia nervosa. The marked increase in parasympathetic activity, not in response to an increase in sympathetic activity, could be detrimental and may contribute to the higher cardiovascular mortality of these patients.