Domenico Bonaduce

Effects of converting enzyme inhibition on heart period variability in patients with acute myocardial infarction.

Heart period variability provides useful prognosticinformation on autonomic cardiac control, and a strong association has been demonstrated after myocardial infarction (MI) between cardiac mortality, sudden death, and reduced total power, ultralow-frequency (ULF) power, and very-lowfrequency (VLF) power. Converting enzyme inhibitors are widely used in MI patients, but their influence on heart period variability emains to be defined. Methods and ResultsTime- and frequency-domain measures of heart period variability were calculated from 24-hour Holter monitoring in 40 patients with a first uncomplicated MI. After baseline examination between 48 and 72 hours after symptom onset, patients were randomly assigned to placebo or captopril administration, and on the third day, 24- hour Holter monitoring was repeated. No changes in time and frequency domain were detectable after placebo. After captopril, the SD of all normal RR (NN) intervals (SDNN) increased from 90±29 to 105±30 milliseconds (P < .01); the SD of the average NN intervals for all 5-minute segments (SDANN index) and the mean of the SDs of all NN intervals for all 5-minute segments (SDNN index) also increased from 74±24 to 90±26 milliseconds (P < .01) and from 45±17 to 49±15 milliseconds (P < .05), respectively. The root mean square successive difference (r-MSSD) and the percent of differences between adjacent NN intervals >50 milliseconds (pNN50) remained unchanged. In regard to frequency-domain measures, after captopril, total power (ln unit) increased from 8.28±0.42 to 8.47±0.30 (P < .01); considering the frequency bands, a significant increase was observed in ULF (P < .01), VLF (P < .05), and low-frequency (LF) power (P < .05), whereas high-frequency (HF) power remained unchanged. ConclusionsThis study supports the hypothesis that the renin-angiotensin system modulates the amplitude of ULF and VLF power. Furthermore, it demonstrates that in MI patients, converting enzyme inhibition favorably modifies measures of heart period variability strongly associated with a poor prognosis.

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.

Reversal of acromegalic cardiomyopathy in young but not in middle‐aged patients after 12 months of treatment with the depot long‐acting somatostatin analogue octreotide

background Cardiovascular disease is the most frequent cause of death of patients with acromegaly.

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 </=40% underwent echocardiographic examination and 24-hour Holter recording. Heart failure was caused by coronary artery disease in 57 patients (59%) and idiopathic dilated cardiomyopathy in 40 (41%). RESULTS During follow-up (39 +/- 18 months), 32 cardiac deaths occurred. By Cox multivariate analysis, significant predictors of death were left ventricular end-systolic volume (hazard ratio 1.04), low- to high-frequency ratio (hazard ratio 0.09), percentage of differences between successive normal R-R intervals >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.

Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis

Restenosis after percutaneous transluminal coronary angioplasty is caused by neointimal hyperplasia, which involves impairment of nitric oxide (NO)-dependent pathways, and may be further exacerbated by a concomitant aging process. We compared the effects of NO-releasing-aspirin (NCX-4016) and aspirin (ASA) on experimental restenosis in both adult and elderly rats. Moreover, to ascertain the efficacy of NCX-4016 during vascular aging, we fully characterized the release of bioactive NO by the drug. Sprague–Dawley rats aged 6 and 24 months were treated with NO releasing-aspirin (55 mg/kg) or ASA (30 mg/kg) for 7 days before and 21 days after standard carotid balloon injury. Histological examination and immunohistochemical double-staining were used to evaluate restenosis. Plasma nitrite and nitrate and S-nitrosothiols were determined by a chemiluminescence-based assay. Electron spin resonance was used for determining nitrosylhemoglobin. Treatment of aged rats with NCX-4016 was associated with increased bioactive NO, compared with ASA. NO aspirin, but not ASA, reduced experimental restenosis in old rats, an effect associated with reduced vascular smooth muscle cell proliferation. NCX-4016, but not ASA, was well tolerated and virtually devoid of gastric damage in either adult or old rats. Thus, impairment of NO-dependent mechanisms may be involved in the development of restenosis in old rats. We suggest that an NCX-4016 derivative could be an effective drug in reducing restenosis, especially in the presence of aging and/or gastrointestinal damage.

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

Abstract. 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 (χ2=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 χ2 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 (χ2=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 χ2 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.

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.

Review and metaanalysis of the frequency of familial dilated cardiomyopathy.

Several studies have investigated the frequency of familial dilated cardiomyopathy (FDC). However, no systematic review and meta-analysis on this topic are available. Therefore, using the PubMed, MEDLINE, Cochrane, and the ISI Web of Science databases, relevant reports published through December 2010 were identified. For the summation of prevalence findings, prevalence point estimates and 95% confidence intervals were computed using the logit transformation formula. An aggregate estimate of clinically confirmed FDC of 23% (95% confidence interval 0.17 to 0.31) was found. However, the prevalence rates reported across these studies varied widely, ranging from 2% to 65%, and the analysis showed very high heterogeneity (Q = 295, p <0.001, I(2) = 93%). Meta-regression analysis between logit event rate and year of publication explained 23% of between-study variance (p <0.05). Cumulative meta-analysis confirmed the influence of year of publication on the reported prevalence of FDC among the different studies. However, most of the observed heterogeneity may be explained by the fact that the various studies used different preselected criteria for the diagnosis of FDC. In conclusion, data obtained from trials performed using standardized criteria are needed to better define the true prevalence of FDC.

β-adrenergic receptor responsiveness in aging heart and clinical implications.

Elderly healthy individuals have a reduced exercise tolerance and a decreased left ventricle inotropic reserve related to increased vascular afterload, arterial-ventricular load mismatching, physical deconditioning and impaired autonomic regulation (the so called “β-adrenergic desensitization”). Adrenergic responsiveness is altered with aging and the age-related changes are limited to the β-adrenergic receptor density reduction and to the β-adrenoceptor-G-protein(s)-adenylyl cyclase system abnormalities, while the type and level of abnormalities change with species and tissues. Epidemiological studies have shown an high incidence and prevalence of heart failure in the elderly and a great body of evidence correlate the changes of β-adrenergic system with heart failure pathogenesis. In particular it is well known that: (a) levels of cathecolamines are directly correlated with mortality and functional status in heart failure, (b) β1-adrenergic receptor subtype is down-regulated in heart failure, (c) heart failure-dependent cardiac adrenergic responsiveness reduction is related to changes in G proteins activity. In this review we focus on the cardiovascular β-adrenergic changes involvement in the aging process and on similarities and differences between aging heart and heart failure.

Cognitive impairment and cardiovascular diseases in the elderly. A heart–brain continuum hypothesis

The aging population is increasing and, therefore, a higher prevalence of cardiac disease is emerging; including hypertension, coronary artery disease, atrial fibrillation and chronic heart failure. Large cohort studies have revealed a relationship among increased risk for cognitive impairment and dementia in cardiovascular diseases probably due to embolic stroke or chronic cerebral hypoperfusion. Thus, the aim of the present review is to overview the studies that investigate the presence and/or the development of cognitive impairments and dementia in patients with varied types of cardiovascular disease. Finally, a continuum among hypertension, coronary artery disease, atrial fibrillation and chronic heart failure with to the development of cognitive impairment and progression to dementia has been hypothesized.