David Della-Morte

RESVERATROL PRETREATMENT PROTECTS RAT BRAIN FROM CEREBRAL ISCHEMIC DAMAGE VIA A SIRTUIN 1-UNCOUPLING PROTEIN 2 PATHWAY

Resveratrol is a natural polyphenol found in grapes and wine and has been associated with protective effects against cardiovascular diseases. In vitro, both resveratrol preconditioning (RPC) and ischemic preconditioning (IPC) require activation of sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, to induce neuroprotection against cerebral ischemia. In the present study, we tested two hypotheses: (a) that neuroprotection against cerebral ischemia can be induced by RPC in vivo; and (b) that RPC neuroprotection involves alterations in mitochondrial function via the SIRT1 target mitochondrial uncoupling protein 2 (UCP2). IPC was induced by 2 min of global ischemia (temporary bilateral carotid artery occlusion with hypotension), and RPC, by i.p. injection of resveratrol at 10, 50 and 100 mg/kg dosages. Forty-eight hours later, we compared the neuroprotective efficacy of RPC and IPC in vulnerable cornu ammonis 1 hippocampal pyramidal neurons using a rat model of asphyxial cardiac arrest (ACA). SIRT1 activity was measured using a SIRT1-specific fluorescent enzyme activity assay. In hippocampal mitochondria isolated 48 h after IPC or RPC, we measured UCP2 levels, membrane potential, respiration, and the mitochondrial ATP synthesis efficiency (ADP/O ratio). Both IPC and RPC induced tolerance against brain injury induced by cardiac arrest in this in vivo model. IPC increased SIRT1 activity at 48 h, while RPC increased SIRT1 activity at 1 h but not 48 h after treatment in hippocampus. Resveratrol significantly decreased UCP2 levels by 35% compared to sham-treated rats. The SIRT1-specific inhibitor sirtinol abolished the neuroprotection afforded by RPC and the decrease in UCP2 levels. Finally, RPC significantly increased the ADP/O ratio in hippocampal mitochondria reflecting enhanced ATP synthesis efficiency. In conclusion, in vivo resveratrol pretreatment confers neuroprotection similar to IPC via the SIRT1-UCP2 pathway.

Social support and long-term mortality in the elderly: Role of comorbidity

Several studies have demonstrated a global increase in morbidity and mortality in elderly subjects with low social support or high comorbidity. However, the relationship between social support and comorbidity on long-term mortality in elderly people is not yet known. Thus, the present study was performed to evaluate the relationship between social support and comorbidity on 12-year mortality of elderly people. A random sample of 1288 subjects aged 65-95 years interviewed in 1992 was studied. Comorbidity by Charlson Comorbidity Index (CCI) score and Social Support by a scale in which total score ranges from 0 to 17, assigning to lowest social support the highest score, were evaluated. At 12-year follow-up, mortality progressively increase with low social support and comorbidity increasing (from 41.5% to 66.7% and from 41.2% to 68.3%, respectively; p<0.001). Moreover, low social support progressively increases with comorbidity increasing (and 12.4±2.5 to 14.3±2.6; p<0.001). Accordingly, multivariate analysis shows an increased mortality risk of 23% for each increase of tertile of social support scale (Hazard ratio=HR=1.23; 95% CI=1.01-1.51; p=0.045). Moreover, when the analysis was performed considering different degrees of comorbidity we found that social support level was predictive of mortality only in subjects with the highest comorbidity (HR=1.39; 95% CI=1.082-1.78; p=0.01). Thus, low social support is predictive of long-term mortality in the elderly. Moreover, the effect of social support on mortality increases in subjects with the highest comorbidity.

Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments

Stroke remains a leading cause of death worldwide and the first cause of disability in the western world. Ischemic stroke (IS) accounts for almost 80% of the total cases of strokes and is a complex and multifactorial disease caused by the combination of vascular risk factors, environment and genetic factors. Investigations of the genetics of atherosclerosis and IS has greatly enhanced our knowledge of this complex multifactorial disease. In this article we sought to review common single-gene disorders relevant to IS, summarize candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors and subclinical phenotypes, and to briefly discuss pharmacogenetics related to stroke treatments. Genetics of IS is, in fact, one of the most promising research frontiers and genetic testing may be helpful for novel drug discoveries as well as for appropriate drug and dose selection for treatment of patients with cerebrovascular disease.

Role of clinical frailty on long-term mortality of elderly subjects with and without chronic obstructive pulmonary disease

Background and aims: Elderly subjects are characterized by a high prevalence of chronic obstructive pulmonary disease (COPD) and frailty. This study examined the predictive role of frailty on long-term mortality in elderly subjects with and without COPD. Methods: The study assessed mortality after a 12-year follow-up in 489 subjects with COPD and 799 subjects without COPD, selected in 1992. Frailty was assessed according to the Frailty Staging System scores ranging from 1 to 7. Results: After 12 years’ follow-up, mortality was 48.1% in subjects without and 60.7% in subjects with COPD (p>0.001). With increasing frailty, mortality increased from 41.7% to 75.1% (p for trend >0.01) in subjects without and from 54.3% to 97.0% in subjects with COPD (p for trend >0.001). Multivariate analysis showed that both COPD [hazard ratio (HR)=1.34; 95% confidence interval (95% CI)=1.02–1.81; p=0.042] and frailty score (HR=1.69 for each unit of increase; 95% CI=1.42–2.00; p>0.001) were predictive of long-term mortality. The frailty score also increased the risk of long-term mortality by 34% in the absence of COPD (HR=1.34 for each unit of increase; 95% CI=1.02-1.81; p>0.05) and by 80% in its presence (HR=1.80 for each unit of increase; 95% CI=1.28-2.53; p>0.001). Conclusions: Long-term mortality was higher in elderly subjects with than in those without COPD. The clinical frailty score also significantly predicted mortality in subjects without and, even more, in those with COPD. Thus, clinical frailty may be considered a new prognostic factor to identify COPD subjects at high risk of mortality.

Traditional cardiovascular risk factors explain the minority of the variability in carotid plaque

Background and Purpose— Subclinical atherosclerotic plaque is an important marker of increased vascular risk. Identifying factors underlying the variability in burden of atherosclerotic carotid plaque unexplained by traditional vascular risk factors may help target novel preventive strategies. Methods— As a part of the carotid substudy of the Northern Manhattan Study (NOMAS), 1790 stroke-free individuals (mean age, 69±9; 60% women; 61% Hispanic, 19% black, 18% white) were assessed for total plaque area (TPA) burden using 2-dimensional carotid ultrasound imaging. Multiple linear regression models were constructed. Model 1 used prespecified traditional risk factors: age, sex, low-density lipoprotein cholesterol, diabetes mellitus, pack-years of smoking, blood pressure, and treatment for blood pressure; and Model 2, an addition of socioeconomic and less traditional risk factors. The contributions of the components of the Framingham heart risk score and the NOMAS Global Vascular Risk Score to the TPA were explored. Results— Prevalence of carotid plaque was 58%. Mean TPA was 13±19 mm2. Model 1 explained 19.5% of the variance in TPA burden (R2=0.195). Model 2 explained 21.9% of TPA burden. Similarly, the Framingham heart risk score explained 18.8% and NOMAS global vascular risk score 21.5% of the TPA variance. Conclusions— The variation in preclinical carotid plaque burden is largely unexplained by traditional and less traditional vascular risk factors, suggesting that other unaccounted environmental and genetic factors play an important role in the determination of atherosclerotic plaque. Identification of these factors may lead to new approaches to prevent stroke and cardiovascular disease.

Ischemic preconditioning in the aging heart: From bench to bedside

Coronary artery disease is the leading cause of death in industrialized countries for people older than 65 years of age. The reasons are still unclear. A reduction of endogenous mechanisms against ischemic insults has been proposed to explain this phenomenon. Cardiac ischemic preconditioning represents the most powerful endogenous protective mechanism against ischemia. Brief episodes of ischemia are able to protect the heart against a following more prolonged ischemic period. This protective mechanism seems to be reduced with aging both in experimental and clinical studies. Alterations of mediators release and/or intracellular pathways may be responsible for age-related ischemic preconditioning reduction. Opposite studies are questionable for the experimental model used, the timing of ischemic preconditioning, and the selection of elderly patients. Several pharmacological stimuli failed to mimic ischemic preconditioning in the aging heart but exercise training and caloric restriction separately, and more powerfully taken together, are able to completely preserve and/or restore the age-related reduction of ischemic preconditioning.

Neuroprotective properties of marrow-isolated adult multilineage-inducible cells in rat hippocampus following global cerebral ischemia are enhanced when complexed to biomimetic microcarriers

J. Neurochem. (2011) 119, 972–988.

Treatment for chronic heart failure in the elderly: current practice and problems.

Treatment for chronic heart failure (CHF) is strongly focused on evidence-based medicine. However, large trials are often far away from the “real world” of geriatric patients and their messages are poorly transferable to the clinical management of CHF elderly patients. Precipitating factors and especially non-cardiac comorbidity may decompensate CHF in the elderly. More importantly, drugs of first choice, such as angiotensin-converting enzyme inhibitors and β-blockers, are still underused and effective drugs on diastolic dysfunction are not available. Poor adherence to therapy, especially for cognitive and depression disorders, worsens the management. Electrical therapy is indicated, but attention to the older age groups with reduced life expectancy has to be paid. Physical exercise, stem cells, gene delivery, and new devices are encouraging, but definitive results are still not available. Palliative care plays a key role to the end-stage of the disease. Follow-up of CHF elderly patient is very important but tele-medicine is the future. Finally, self-care management, caregiver training, and multidimensional team represent the critical point of the treatment for CHF elderly patients.

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.

Depressive symptoms predict mortality in elderly subjects with chronic heart failure

Eur J Clin Invest 2011; 41 (12): 1310–1317