A diet supplemented with ALA-rich flaxseed prevents cardiomyocyte apoptosis by regulating caveolin-3 expression.

AIMS: n-3 polyunsaturated fatty acids (PUFAs) induce beneficial effects on the heart, but the mechanisms through which these effects are operated are not completely clarified yet. Among others, cardiac diseases are often associated with increased levels of cytokines, such as tumour necrosis factor-α (TNF), that cause degeneration and death of cardiomyocytes. The present study has been carried out to investigate (i) the potential anti-apoptotic effects induced by the n-3 polyunsaturated α-linolenic acid (ALA) in experimental models of cardiac diseases characterized by high levels of TNF, and (ii) the potential role of caveolin-3 (Cav-3) in the mechanisms involved in this process. METHODS AND RESULTS: An ALA-rich flaxseed diet, administered from weaning to hereditary cardiomyopathic hamsters, prevented the onset of myocardial apoptosis associated with high plasma and tissue levels of TNF preserving caveolin-3 expression. To confirm these findings, isolated neonatal mouse cardiomyocytes were exposed to TNF to induce apoptosis. ALA pre-treatment greatly enhanced Cav-3 expression hampering the internalization of the caveolar TNF receptor and, thus, determining the abortion of the apoptotic vs. survival cascade. CONCLUSION: This study unveiled the Cav-3 pivotal role in defending cardiomyocytes against the TNF pro-apoptotic action and the ALA capacity to regulate this mechanism preventing cardiac degenerative diseases.

Criticality of the biological and physical stimuli array inducing resident cardiac stem cell determination.

The replacement of injured cardiac contractile cells with stem cell-derived functionally efficient cardiomyocytes has been envisaged as the resolutive treatment for degenerative heart diseases. Nevertheless, many technical issues concerning the optimal procedures to differentiate and engraft stem cells remain to be answered before heart cell therapy could be routinely used in clinical practice. So far, most studies have been focused on evaluating the differentiative potential of different growth factors without considering that only the synergistic cooperation of biochemical, topographic, chemical, and physical factors could induce stem cells to adopt the desired phenotype. The present study demonstrates that the differentiation of cardiac progenitor cells to cardiomyocytes does not occur when cells are challenged with soluble growth factors alone, but requires strictly controlled procedures for the isolation of a progenitor cell population and the artifactual recreation of a microenvironment critically featured by a fine-tuned combination of specific biological and physical factors. Indeed, the scaffold geometry and stiffness are crucial in enhancing growth factor differentiative effects on progenitor cells. The exploitation of this concept could be essential in setting up suitable procedures to fabricate functionally efficient engineered tissues. Disclosure of potential conflicts of interest is found at the end of this article.

Alpha-linolenic acid-enriched diet prevents myocardial damage and expands longevity in cardiomyopathic hamsters.

Randomized clinical trials have demonstrated that the increased intake of omega-3 polyunsaturated fatty acids significantly reduces the risk of ischemic cardiovascular disease, but no investigations have been performed in hereditary cardiomyopathies with diffusely damaged myocardium. In the present study, delta-sarcoglycan-null cardiomyopathic hamsters were fed from weaning to death with an alpha-linolenic acid (ALA)-enriched versus standard diet. Results demonstrated a great accumulation of ALA and eicosapentaenoic acid and an increased eicosapentaenoic/arachidonic acid ratio in cardiomyopathic hamster hearts, correlating with the preservation of myocardial structure and function. In fact, ALA administration preserved plasmalemma and mitochondrial membrane integrity, thus maintaining proper cell/extracellular matrix contacts and signaling, as well as a normal gene expression profile (myosin heavy chain isoforms, atrial natriuretic peptide, transforming growth factor-beta1) and a limited extension of fibrotic areas within ALA-fed cardiomyopathic hearts. Consequently, hemodynamic indexes were safeguarded, and more than 60% of ALA-fed animals were still alive (mean survival time, 293+/-141.8 days) when all those fed with standard diet were deceased (mean survival time, 175.9+/-56 days). Therefore, the clinically evident beneficial effects of omega-3 polyunsaturated fatty acids are mainly related to preservation of myocardium structure and function and the attenuation of myocardial fibrosis.

Health status in older hospitalized patients with cancer or non-neoplastic chronic diseases.

BACKGROUND: Whether cancer is more disabling than other highly prevalent chronic diseases in the elderly is not well understood, and represents the objective of the present study. METHODS: We used data from the Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA) study, a large collaborative observational study based in community and university hospitals located throughout Italy. Our series consisted of three groups of patients with non-neoplastic chronic disease (congestive heart failure, CHF, N = 832; diabetes mellitus, N = 939; chronic obstructive pulmonary disease, COPD, N = 399), and three groups of patients with cancer (solid tumors without metastasis, N = 813; solid tumors with metastasis, N = 259; leukemia/lymphoma, N = 326). Functional capabilities were ascertained using the activities of daily living (ADL) scale, and categorical variables for dependency in at least 1 ADL or dependency in 3 or more ADLs were considered in the analysis. Cognitive status was evaluated by the 10-items Hodgkinson Abbreviated Mental Test (AMT). RESULTS: Cognitive impairment was more prevalent in patients with CHF (28.0%) or COPD (25.8%) than in those with cancer (solid tumors = 22.9%; leukemia/lymphoma = 19.6%; metastatic cancer = 22.8%). Dependency in at least 1 ADL was highly prevalent in patients with metastatic cancer (31.3% vs. 24% for patients with CHF and 22.4% for those with non-metastatic solid tumors, p < 0.001). In people aged 80 years or more, metastatic cancer was not associated with increased prevalence of physical disability. In multivariable analysis, metastatic cancer was associated with a greater prevalence of physical (OR 2.09, 95%CI 1.51-2.90) but not cognitive impairment (OR 1.34, 95%CI 0.94-1.91) with respect to CHF patients. Finally, diabetes was significantly associated with cognitive impairment (OR 1.40, 95%CI 1.11-1.78). CONCLUSION: Cancer should not be considered as an ineluctable cause of severe cognitive and physical impairment, at least not more than other chronic conditions highly prevalent in older people, such as CHF and diabetes mellitus.

Stem cell activation sustains hereditary hypertrophy in hamster cardiomyopathy.

Recent studies have documented the presence of stem cells within the myocardium and their role in the repair of ischaemic injury. Nevertheless, the pathogenic role of stem cells in non-ischaemic myocardial diseases, as well as the factors potentially responsible for their activation, is still under debate. The present study demonstrates the presence of an increased number of c-kit positive, MDR-positive, and Sca-1-positive stem cells within the myocardium of hereditary delta-SG null hamsters, a spontaneously occurring model of hypertrophic cardiomyopathy. When hamsters are 80 days old, ie at the 'hypertrophic' stage of the disease, but without haemodynamic overload, these cells associate with a multitude of cells co-expressing c-kit, cMet, GATA4, or MEF-2, and proliferating myocytes co-expressing myosin heavy chain, telomerase, ki67 and cyclin B. Furthermore, at the same animal age, the number of myocardial cells co-expressing c-kit and Flk-1, and the number of capillary vessels, is also amplified. In order to identify factors potentially responsible for stem cell activation, the myocardial expression of HGF and cMet and HGF plasma levels were evaluated, demonstrating their increase in 80-day-old delta-SG null hamsters. To demonstrate the possible ability of HGF to induce stem cell differentiation, bone-marrow-derived mesenchymal stem cells were challenged with HGF at the same plasma concentration observed in vivo. HGF induced cMet phosphorylation, and caused loss of stem cell features and overexpression of MEF-2, TEF1, and MHC. Our results demonstrate that stem cell activation occurs within the cardiomyopathic myocardium, very likely to maintain an efficient cardiac architecture. In this context, elevated levels of HGF might play a role in induction of stem cell commitment to the cardiomyocyte lineage and in cardioprotection through its anti-apoptotic action. Consistently, when cytokine levels declined to physiological concentrations, as in 150-day-old cardiomyopathic animals, myocardial apoptosis prevailed, prejudicing cardiac function.

Comparison of digitalis-related adverse events in hospitalized men and women in Italy: an observational study.

BACKGROUND: A higher mortality rate in women than in men treated with digitalis has been described. We hypothesized that this result could be due in part to an increased susceptibility of women to adverse events (AEs) from digitalis. OBJECTIVE: The aim of this study was to compare the incidence of AEs related to digitalis in women and men. METHODS: This was an observational study conducted in geriatrics and internal medicine acute-care wards located throughout Italy. We used the data of the Gruppo Italiano di Farmacoepidemiologia nell'Anziano (Italian Group of Pharmacoepidemiology in the Elderly), a collaborative study group on drug use and adverse drug reactions in hospitalized adults that performed 6 different surveys between 1988 and 1998. Adults who were taking digitalis at the time of admission or during the hospital stay were studied, with no other inclusion or exclusion criteria. The proportion of AEs to digitalis diagnosed at the time of admission or during the hospital stay was compared in men and women. Information on AEs was collected using a structured questionnaire at admission and during the hospital stay. A logistic regression model was used to evaluate the association between sex and AE(s) to digitalis, corrected for potential confounding variables. RESULTS: The total sample size was 9626 patients. Women received a higher weight-adjusted dose of digitalis compared with men (0.0027 mg/kg per day vs 0.0025 mg/kg per day; P < 0.001). Overall, 199 AEs to digitalis were diagnosed. Women were more likely than men to suffer from an AE to digitalis (odds ratio, 1.51; 95% CI, 1.12-2.02). This finding was confirmed after correction for dose of digitalis, age, physical and cognitive impairment, atrial fibrillation, chronic obstructive pulmonary disease, glomerular filtration rate, and use of amiodarone, beta-blockers, nondihydropyridine calcium channel blockers, and potassium-sparing diuretics (odds ratio, 1.58; 95% CI, 1.01-2.48). CONCLUSIONS: In this sample of hospitalized adults in Italy, we found a higher incidence of AEs to digitalis in women than in men.

Does aspirin attenuate the beneficial effect of ACE inhibitors in elderly people with heart failure?

BACKGROUND: Several studies have raised concerns over a possible reduction in the beneficial effects of ACE inhibitors on mortality in people also taking aspirin (acetylsalicylic acid). OBJECTIVE: We performed this study to determine whether there is a reduction in the beneficial effects of ACE inhibitors on mortality in elderly people with heart failure also taking aspirin. PARTICIPANTS: 822 patients discharged from hospital wards with a diagnosis of heart failure participated in the GIFA (Italian Group of Pharmacoepidemiology in the Elderly) study. MEASUREMENTS: We analysed the characteristics of the participants according to the type of therapy prescribed (no ACE inhibitor/no aspirin, ACE inhibitor/no aspirin, no ACE inhibitor/aspirin and ACE inhibitor/aspirin). We calculated the hazard ratios (HRs) for dying associated with each of these treatments, and calculated the synergy index to identify any negative interaction between ACE inhibitor and aspirin. RESULTS: The mean age of study participants was 79 +/- 7.3 (SD) years. Of the 629 (76.5%) patients discharged on ACE inhibitor and/or aspirin therapy, 31.0% were taking both drugs. Compared with no therapy with ACE inhibitor or aspirin, the HR for death was 0.65 (95% CI 0.31, 1.36) for aspirin users, 0.45 (95% CI 0.27, 0.74) for ACE inhibitor users and 0.37 (95% CI 0.19, 0.70) for ACE inhibitor/aspirin users. The synergy index was 0.98 (95% CI 0.34, 2.80), suggesting no interaction between the drugs. CONCLUSIONS: Our data do not support the existence of a negative interaction between ACE inhibitors and aspirin in elderly patients with heart failure.

Use of angiotensin-converting enzyme inhibitors in elderly people with heart failure: prevalence and outcomes.

BACKGROUND: There is a lack of information on the effects of angiotensin-converting enzyme (ACE) inhibitors in very old people with heart failure (HF). The objective of this study is to estimate the prevalence of prescriptions of ACE inhibitors in elderly people with HF discharged from acute care hospitals, and to evaluate the effect of these drugs on 1-year mortality rates. METHODS: We used data from the Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA). In 1998, we undertook a 1-year longitudinal study on elderly people (aged 65+ years) discharged with a diagnosis of HF. We compared the demographic and clinical characteristics associated with a prescription at discharge of ACE inhibitors, and used a Cox proportional hazard regression model to calculate the relative hazard of dying associated with the use of ACE inhibitors. RESULTS: We enrolled 818 patients in the study with a mean age of 79 years (range: 65-101 years). One fourth of the participants were aged 85 years or older. ACE inhibitors were prescribed to 550 patients (67.2%) at discharge. Older age and physical disability were negatively correlated with the use of ACE inhibitors. People using ACE inhibitors had a 40% reduction of mortality (HR [hazard ratio]: 0.60; 95% CI [confidence intervals]: 0.42-0.88). The reduction in mortality was much stronger among disabled people (HR: 0.35; 95% CI: 0.19-0.64). CONCLUSION: ACE inhibitors are still underprescribed among elderly people with HF discharged from acute care hospitals. Even in this frail, elderly population, we found a beneficial effect of ACE inhibitors. There is room to further improve the quality of care for elderly people with HF.

Seasonal hypertension: a clue to explain the high prevalence of unrecognized hypertension in the elderly? Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA).

BACKGROUND AND AIMS: Blood pressure is known to be influenced by the season, particularly in the elderly. The association between cold weather and unrecognized hypertension has not been previously studied. The present study aimed at assessing whether recognition of hypertension in the elderly follows a seasonal pattern. METHODS: All patients over 64 with either first-listed or secondary diagnosis of hypertension at discharge (N = 4487) out of 24585 consecutively admitted to 69 wards of Geriatrics or Internal Medicine during ten bi-monthly observation periods (May-June and September-October) were enrolled. The main outcome of the study was the prevalence of unrecognized hypertension, defined as no mention of hypertension and/or antihypertensive drugs in clinical histories collected on admission, and a first-listed or secondary discharge diagnosis of hypertension. RESULTS: We found a total of 928 patients with unrecognized hypertension. Being admitted in the September-October period was independently associated with the outcome unrecognized hypertension (OR 1.25, 95% CI 1.08-1.46), as were smoking addiction (OR 1.57, 95% CI 1.23-2.0) and allocation to a medical ward (OR 1.21, 95% CI 1.04-1.41). Negative correlates of the outcome were multiple pathologies (OR 0.85, 95% CI 0.73-0.99), discharge diagnosis of coronary artery disease (OR 0.77, 95% CI 0.64-0.92) or diabetes mellitus (OR 0.81, 95% CI 0.67-0.97). CONCLUSIONS: Hypertension in the elderly may at least partly follow a seasonal pattern, and this finding may be relevant for screening and therapeutic decisions.

Beta-catenin accumulates in intercalated disks of hypertrophic cardiomyopathic hearts.

OBJECTIVE: To evaluate whether cardiomyocyte membrane structure and cell/extracellular matrix adhesion alterations perturb the cadherin/catenin complex in the hypertrophic cardiomyopathy (HCM). METHODS: Hypertrophic cardiomyopathic hamster (UM-X7.1 strain) and human hearts were studied by light and electron microscopy, Northern and Western blot analyses and immunohistochemistry. RESULTS: Intercalated disks are disorganized in both hamster and human cardiomyopathic hearts; beta-catenin is increased and accumulated in intercalated disks depriving cardiomyocyte nuclei of fundamental signals. The accumulation of beta-catenin is post-translationally regulated by an increased Wnt expression, a simultaneous decrease in glycogen synthase kinase 3beta (GSK3beta) expression and a different expression pattern of adenomatous polyposis coli (APC) isoforms. CONCLUSION: The reorganization of cell/cell adhesion in cardiomyopathic hearts is mainly contributed by the cadherin/catenin system, which is differently regulated to sustain cell structural rather than signalling needs causing considerable consequences in the determination of cardiomyocyte phenotype and clinical outcome. The accumulation of beta-catenin in intercalated disks could concur to increase myocardial wall stiffness and left ventricular end-diastolic pressure (LVEDP) in hypertrophic cardiomyopathic hamster and human hearts.

Identifying older diabetic patients at risk of poor glycemic control.

BACKGROUND: Optimal glycemic control prevents the onset of diabetes complications. Identifying diabetic patients at risk of poor glycemic control could help promoting dedicated interventions. The purpose of this study was to identify predictors of poor short-term and long-term glycemic control in older diabetic in-patients. METHODS: A total of 1354 older diabetic in-patients consecutively enrolled in a multicenter study formed the training population (retrospective arm); 264 patients consecutively admitted to a ward of general medicine formed the testing population (prospective arm). Glycated hemoglobin (HbA1c) was measured on admission and one year after the discharge in the testing population. Independent correlates of a discharge glycemia > or = 140 mg/dl in the training population were assessed by logistic regression analysis and a clinical prediction rule was developed. The ability of the prediction rule and that of admission HbA1c to predict discharge glycemia > or = 140 mg/dl and HbA1c > 7% one year after discharge was assessed in the testing population. RESULTS: Selected admission variables (diastolic arterial pressure < 80 mmHg, glycemia = 143-218 mg/dl, glycemia > 218 mg/dl, history of insulinic or combined hypoglycemic therapy, Charlson's index > 2) were combined to obtain a score predicting a discharge fasting glycemia > or = 140 mg/dl in the training population. A modified score was obtained by adding 1 if admission HbA1c exceeded 7.8%. The modified score was the best predictor of both discharge glycemia > or = 140 mg/dl (sensitivity = 79%, specificity = 63%) and 1 year HbA1c > 7% (sensitivity = 72%, specificity = 71%) in the testing population. CONCLUSION: A simple clinical prediction rule might help identify older diabetic in-patients at risk of both short and long term poor glycemic control.

Predictors of rehabilitation outcomes in frail patients treated in a geriatric hospital.

OBJECTIVES: To evaluate the effect of medical indicators of health status on functional gain during rehabilitation of frail older patients. DESIGN: Observational study. SETTING: A hospital geriatric rehabilitation department (Catholic University of Rome). PARTICIPANTS: Two hundred forty-four older patients admitted consecutively for rehabilitation after acute illnesses between March 1999 and June 2000. MEASUREMENTS: Patients were evaluated with the Minimum Data Set for Post-Acute Care (MDS-PAC) assessment form soon after the admission and every 2 weeks thereafter. Two summary scales based on MDS-PAC items are designed to describe the performance in personal activities of daily living (ADLs) and the level of cognitive function (Cognitive Performance Scale). To identify predictors of functional recovery, we constructed a multiple logistic regression model having as a dependent variable the improvement of one or more points in the ADL scale. RESULTS: Patients aged 85 and older with cognitive or sensory impairment were less likely to significantly improve physical functioning after an intensive rehabilitation program. However, the cognitive impairment was the only "negative" factor that remained significant in a multivariable model (odds ratio = 0.36, 95% confidence interval = 0.14-0.92) after adjusting for several potential negative predictors. CONCLUSIONS: The results of the present study document that severe cognitive impairment may be considered a negative predictor of functional recovery after a period of intensive rehabilitation. However, the effectiveness of such a rehabilitation program in patients with dementia is controversial. Additional studies are necessary to better clarify the effect of cognitive impairment on the potential recovery of the older subjects after a period of rehabilitation and whether this is influenced by different pathologies.