Pasquale Abete

Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells.

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical‐producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO‐LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl‐2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF‐2, ELK‐1, CREB, AP‐1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL‐induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical‐sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.—Napoli, C., Quehenberger, O., de Nigris, F., Abete, P., Glass, C. K., Palinski, W. Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells. FASEB J. 14, 1996–2007 (2000)

Quality of Life Determinants and Hearing Function in an Elderly Population: Osservatorio Geriatrico Campano Study Group

Background: Hearing impairment (HI) is a very common condition in elderly people and the epidemiology together with hearing-related problems is still poorly investigated. Moreover, the cognitive status may be impaired in relation to hearing function. Objective: The goal of the study was to evaluate: (a) the prevalence of HI in a random sample of elderly people aged 65 and over (n = 1,750) living in Campania, a region of southern Italy; (b) the cross-sectional relationship between hearing function and cognitive status and also depressive symptomatology and disability, and (c) to assess the role of hearing aids on depressive symptomatology. Methods: Cross-sectional study on a random sample of elderly population. Results: The overall participation rate in the study was 74.8% (n = 1,332, mean age was 74.2 ± 6.4 years). The prevalence rate of HI (evaluated by questionnaire) was 27.2%, cognitive impairment prevalence (evaluated by the Mini-Mental State Examination (MMSE)) was 27.9%, mean depressive symptomatology score (evaluated by Geriatric Depression Scale (GDS)) was 11.4 ± 6.6, while disability assessed by Activity of Daily Living (ADL) was present in 7.0% of the whole population. A strong relationship was found between both decreasing hearing function and MMSE decline, independently by the effect of age and education (r = 0.97; p < 0.01). A positive relationship (r = 0.85; p < 0.01) between GDS score and hearing function was also found. Moreover, at an increased level of hearing loss, a lower ADL score was recorded (r = 0.98; p < 0.01). Finally, the use of hearing aids reduced GDS score. In logistic regression analysis, gender, age and educational level indicate that hearing loss risk increased with age (odds ratio 1.60; 95% confidence interval 1.53–1.71), whereas education plays a protective role (odds ratio 0.75; 95% confidence interval 0.72–0.80). Conclusion: HI is very prevalent among elderly people and is associated with either cognitive impairment and/or depression and reduction of functional status. This study suggests that hearing aids may protect against cognitive impairment and disability, improving quality of life of aged people.

Congestive Heart Failure and Cognitive Impairment in an Older Population

OBJECTIVE: Congestive heart failure (CHF) is potentially preventable, and the identification of modifiable risk factors for cognitive impairment (CI) for older persons is a very important issue. We examined the cross‐sectional relationship between CHF and CI in an older population.

Frailty predicts long-term mortality in elderly subjects with chronic heart failure.

Background  The elderly are characterized by a high prevalence of chronic heart failure (CHF) and frailty, which is a complex interaction of physical, psychological and social impairment. This study aimed to examine the predictive role of frailty on long‐term mortality in elderly subjects with CHF.

Angina-induced protection against myocardial infarction in adult and elderly patients : A loss of preconditioning mechanism in the aging heart?

OBJECTIVES The present study examined whether angina 48 h before myocardial infarction provides protection in adult and elderly patients. BACKGROUND The mortality rate for coronary artery disease is greater in elderly than in young patients. In experimental studies, ischemic preconditioning affords an endogenous form of protection against ischemia-reperfusion injury in adult but not in senescent hearts. Angina before myocardial infarction, a clinical equivalent of experimental ischemic preconditioning, has a protective effect in adult patients. It is not known whether angina before myocardial infarction is also protective in aged patients. METHODS We retrospectively verified whether antecedent angina within 48 h of myocardial infarction exerts a beneficial effect on in-hospital outcomes in adult (< 65 years old, n = 293) and elderly (> or = 65 years old, n = 210) patients. RESULTS In-hospital death was more frequent in adult patients without than in those with previous angina (10% vs. 2.6%, p < 0.01), as were congestive heart failure or shock (10.7% vs. 3.3%, p < 0.02) and the combined end points (in-hospital death and congestive heart failure or shock) (20.7% vs. 5.9%, p < 0.0003). In contrast, the presence or absence of previous angina before acute myocardial infarction in elderly patients seems not to influence the incidence of in-hospital death (14.4% vs. 15.2%, p = 0.97), congestive heart failure or shock (11.0% vs. 11.9%, p = 0.99) and the combined end points (25.4% vs. 27.1%, p = 0.89). Logistic regression analysis models for in-hospital end points show that previous angina is a positive predictor in adult but not in elderly patients. CONCLUSIONS The presence of angina before acute myocardial infarction seems to confer protection against in-hospital outcomes in adults; this effect seemed to be less obvious in elderly patients. This study suggests that the protection afforded by angina in adult patients may involve the occurrence of ischemic preconditioning, which seems to be lost in senescent patients.

Preconditioning does not prevent postischemic dysfunction in aging heart

OBJECTIVES This study was performed to investigate the effect of single or multiple brief periods of ischemia and the administration of exogenous norepinephrine before a more prolonged ischemic period and after reperfusion in adult and senescent isolated and perfused rat hearts. BACKGROUND The mortality rate for coronary artery disease is greater in the elderly. Ischemic preconditioning has been proposed as an endogenous form of protection against ischemia-reperfusion injury. However, the role of preconditioning in aging heart is unknown. METHODS We compared the protective effect of preconditioning transient ischemic and norepinephrine stimuli against 20 min of global normothermic ischemia and 40 min of reperfusion in isolated perfused hearts of adult (6 months old) and senescent (24 months old) rats. Norepinephrine release in coronary effluent was determined by high performance liquid chromatography. RESULTS Final recovery of percent developed pressure was improved after single preconditioning transient ischemic and norepinephrine stimuli in adult hearts (87.7 +/- 9% and 82.3 +/- 8.7%) versus unconditioned control hearts (50.6 +/- 4.8%, p < 0.01 [mean +/-SD]). The effect of preconditioning on developed pressure recovery was not present in senescent hearts after transient ischemic stimulus (39.8 +/- 4.9% vs. 41.6 +/- 5.8%, p = NS) but was present after norepinephrine stimulus (74.3 +/- 10.5, p < 0.01). Norepinephrine release significantly increased after preconditioning transient ischemic stimulus in adult but not in senescent hearts (p < 0.01 vs. adult). Transient ischemic- and norepinephrine-induced preconditioning was blocked by alpha-adrenergic receptor antagonists in both adult and senescent hearts. Multiple transient ischemic stimuli were able to reduce postischemic dysfunction in adult but not in senescent hearts. CONCLUSIONS Preconditioning transient ischemic stimulus significantly reduces postischemic dysfunction in adult but not in senescent hearts, whereas exogenous norepinephrine is able to mimic preconditioning in both adult and senescent hearts. Ischemic preconditioning induces an increase in norepinephrine release in adult but not in senescent hearts. Preconditioning induced by transient ischemic stimulus and norepinephrine was abolished by alpha-adrenergic receptor blockade in both adult and senescent hearts. Thus, our data demonstrate that preconditioning is absent in aging heart and is probably related to the reduction of norepinephrine release and alpha-adrenergic receptor stimulation in response to ischemic preconditioning.

The role of blood pressure in cognitive impairment in an elderly population

Objective The aim of this study was to investigate the cross-sectional relationship between arterial blood pressure and cognitive impairment in a group of elderly subjects, controlling for such confounding variables as age, education, depression, drug use and antihypertensive treatment. Design and setting A cross-sectional survey in Campania, a region in southern Italy. Subjects and methods A random sample of 1339 elderly subjects aged 65–95 years (mean 73.9 ± 6.2 years) selected from the electoral rolls was interviewed by trained physicians. Sociodemographic characteristics, results of Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), blood pressure and whether antihypertensive treatment was being administered were recorded. When subjects with neurological diseases and those under psychotropic therapy were excluded from the analyses, the population numbered 1106. Results The MMSE score was less than 24 for 27.9% of the subjects and the mean GDS score was 10.8 ± 6.3. The mean systolic blood pressure (SBP) was 145.3 ± 19.0 mmHg and the mean diastolic blood pressure (DBP) was 82.0 ± 9.2 mmHg. Logistic regression analysis showed that female sex, age, GDS score and DBP but not SBP were predictive of cognitive impairment. Educational level and antihypertensive treatment, on the contrary, play a protective role. DBP was associated with cognitive impairment in subjects aged 75 years (odds ratio 1.62, 95% confidence interval 1.16–2.25) and over (odds ratio 5.16, 95% confidence interval 1.50–17.71) but not in those aged 65–74 years. Conclusion DBP but not SBP is predictive of cognitive impairment in subjects aged 75 years and over without neurological disorders independently from sex, age, education, GDS and antihypertensive treatment.

High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients.

OBJECTIVES The study investigated the effects of physical activity on preinfarction angina, a clinical equivalent of ischemic preconditioning (PC), in adult and elderly patients with acute myocardial infarction (AMI). BACKGROUND Preinfarction angina seems to confer protection against in-hospital mortality in adult but not in elderly patients. However, it has been experimentally demonstrated that exercise training restores the protective effect of PC in the aging heart. METHODS We retrospectively verified whether physical activity preserved the protective effect of preinfarction angina against in-hospital mortality in 557 elderly patients with AMI. Physical activity was quantified according to the Physical Activity Scale for the Elderly (PASE). RESULTS In-hospital mortality was 22.2% in elderly patients with preinfarction angina and 27.2% in those without (p = 0.20). When the PASE score was stratified in quartiles (0 to 40, 41 to 56, 57 to 90, >90), a high score was strongly associated with reduced in-hospital mortality (30.8%, 32.2%, 17.2% and 15.3%, respectively, p < 0.001 for trend). Interestingly, a high level of physical activity reduced in-hospital mortality in elderly patients with preinfarction angina (35.7%, 35.4%, 12.3% and 4.23%, respectively, p < 0.001 for trend) but not in those without (23.0%, 27.2%, 26.0% and 35.0%, respectively, p = 0.35 for trend). Accordingly, the protective role of preinfarction angina on in-hospital mortality was present only in elderly patients showing a high level of physical activity (adjusted odds ratio, 0.09; 95% confidence interval, 0.01 to 0.57; p < 0.05). CONCLUSIONS Physical activity and not preinfarction angina protects against in-hospital mortality in elderly patients with myocardial infarction. Nevertheless, the protective effect of preinfarction angina is preserved in elderly patients with a high level of physical activity.

Exercise training restores ischemic preconditioning in the aging heart

OBJECTIVES To investigate the effects of ischemic preconditioning in hearts from adult and both sedentary and trained senescent rats. BACKGROUND Ischemic preconditioning does not prevent postischemic dysfunction in the aging heart, probably because of reduction of cardiac norepinephrine release. Exercise training can reverse the age-related decrease of norepinephrine production. METHODS We investigated the effects on mechanical parameters of ischemic preconditioning against 20 min of global ischemia followed by 40 min of reperfusion in isolated perfused hearts from adult (six months) and sedentary or trained (six weeks of graduated swim training) senescent (24 months) rats. Norepinephrine release in coronary effluent was determined by high-performance liquid chromatography. RESULTS Final recovery of percent-developed pressure was significantly improved after preconditioning in adult hearts (91.6+/-9.6%) versus unconditioned controls (54.2+/-5.1%, p<0.01). The effect of preconditioning on developed pressure recovery was absent in sedentary but present in trained senescent hearts (39.6+/-4.1% vs. 64.3+/-7.1%, p<0.05). Norepinephrine release significantly increased after preconditioning in adult and in trained but not in sedentary senescent hearts. The depletion of myocardial norepinephrine stores by reserpine abolished preconditioning effects in adult and trained senescent hearts. CONCLUSIONS In adult and trained but not in sedentary senescent hearts, preconditioning reduces postischemic dysfunction and is associated with an increase in norepinephrine release. Preconditioning was blocked by reserpine in both adult and trained senescent hearts. Thus, exercise training may restore preconditioning in the senescent heart through an increase of norepinephrine release.

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.