Physical activity attenuates the effect of increased left ventricular mass on the risk of ischemic stroke: The Northern Manhattan Stroke Study

OBJECTIVES: The goal of this study was to determine whether the risk of ischemic stroke associated with increased left ventricular mass (LVM) is modified by physical activity (PA). BACKGROUND: Increased LVM is associated with an increased risk for stroke. Physical activity can decrease the risk of stroke and may have variable effects on LVM. METHODS: We used a case-control study design in a multiethnic population in northern Manhattan, New York, to study 394 case subjects who had a first ischemic stroke and 413 stroke-free control subjects. All subjects were interviewed and two-dimensional echocardiograms obtained to determine LVM. RESULTS: A sharp increase in risk of ischemic stroke was seen in the highest quartile of LVM (odds ratio [OR]: 6.14 [95% confidence interval [CI]: 3.04 to 12.38]). Thus, increased LVM was defined by the highest quartile of LVM. In multivariate analysis, the effect of increased LVM on the risk of stroke was significantly decreased by the presence of any level of PA versus no PA (OR: 1.59 [95% CI: 0.99 to 2.57] p < 0.07 vs. 3.53 [95% CI: 1.94 to 6.42] p < 0.0001). Although PA decreased the risk of stroke in all patients, the effect was stronger in subjects with increased LVM than among those without increased LVM (p = 0.033). CONCLUSIONS: Increased LVM is associated with an increased risk of stroke, especially among sedentary patients. Physical activity decreases the risk of stroke among patients with increased LVM to a level comparable to that of patients without increased LVM. Recommending PA may be a nonpharmacologic tool to reduce the stroke risk, especially among patients with increased LVM.     

Clinical impact of direct referral to primary percutaneous coronary intervention following pre-hospital diagnosis of ST-elevation myocardial infarction.

AIMS: Treatment delay is a powerful predictor of survival in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). We investigated effectiveness of pre-hospital diagnosis of STEMI with direct referral to PCI, alongside more conventional referral strategies. METHODS AND RESULTS: From January 2003 to December 2004, 658 STEMI patients were referred for primary PCI at our intervention laboratory. Three predefined referral routes were compared: (1) for patients within 90 min drive of the PCI centre, pre-hospital diagnosis and direct transportation (n=166), (2) diagnosis at the interventional hospital emergency department (n=316), (3) diagnosis at local hospitals before transportation (n = 176). Pre-hospital diagnosis was associated with more than 45 min reduction in treatment delay (P = 0.001). No significant difference in in-hospital mortality was apparent in the overall study population. In the cardiogenic shock subgroup (n = 80), pre-hospital diagnosis was associated with a two-thirds reduction in in-hospital mortality (P = 0.019); mortality was only 6.2% in shock patients who underwent PCI in < 2 h. CONCLUSION: This study shows that pre-hospital diagnosis can provide a reduction in primary PCI treatment delay, and suggests the hypothesis that this referral strategy might provide survival benefits to patients with cardiogenic shock.     

Stop-flow in mediastinum and thorax for resistant lymphoma

BACKGROUND/AIMS: Management of patients with heavily pretreated malignant lymphoma failing frontline treatment and salvage high-dose chemotherapy and autologous peripheral stem cell rescue, is problematic. A pilot study was conducted to evaluate isolated thoracic perfusion of drugs by means of stopflow technique. METHODOLOGY: Six patients were enrolled in the study; diagnoses included 4 advanced Hodgkin's disease, 1 primary mediastinal B-cell lymphoma, and 1 anaplastic large cell lymphoma. Patients were aged 18-37 years; 4 presented with bulky mediastinum. They had never achieved a complete response since all had progressed from front-line treatment, and 3 had even failed salvage high-dose chemotherapy with autologous peripheral stem cell rescue. Cisplatin (100 mg/m2) and melphalan (35 mg/m2) were used. Carmustine (100 mg/m2) were added to these 2 drugs and cytarabine (2000 mg/m2) in patients not previously treated by carmustine, etoposide, cytarabine, and melphalan. Epidoxorubicin (70 mg/m2) was added in patients who previously received a suboptimal dosage of antracycline. Drugs were delivered monthly via aortic perfusion performed by means of Aigner's stop-flow technique. RESULTS: Overall 13 cycles of perfusional chemotherapy were administered with a median number of 2 cycles. During the procedures there were no technical, hemodynamic, or vascular complications, and no deaths occurred during surgery. After 1 month, 6 (100%) objective responses after isolated thoracic perfusion were recorded, 3 (50%) of which were complete. Tolerance to therapy was excellent. Hematological toxicity was mild and transfusional support was needed only in one course. At the last follow-up, 2 patients are alive (1 complete response and 1 very good partial response, maintained). CONCLUSIONS: This new therapeutical approach seems very active in recurrent/refractory malignant lymphoma and may play an important role in this setting.     

The Perugia hospital-based Stroke Registry: report of the 2nd year

This study reports the characteristics of stroke patients admitted to our hospital in the period Jan 1st, 1998-Dec 31st 1999. Seven hundred and ninety seven consecutive subjects (412 males; mean age 71 +/- 13 years) with a first-ever stroke were registered. Two-thirds of patients (65%) were admitted to the Stroke Unit (SU). The remaining part was managed in six general medicine wards (GM) or other services [neurosurgery and intensive care units (ICU+ NS)]. Ischemic stroke occurred in 534 subjects (67%). The high prevalence (30.1%) of haemorrhages can be partly explained by the presence of specialized neurosurgical services. Athero-thrombotic infarctions occurred in 21.7% of patients, lacunar in 24.7%, cardioembolic in 18.1%, other determined in 6.1%, and other undetermined in 27.5%. Overall hospital mortality was 10%. In cerebral hemorrhage mortality was 18% (44/240) vs. 6.3% (32/534) in ischemic stroke (p < 0.05). The distribution of stroke types and mortality was similar to other previous reports.     

Early Detection of Anthracycline-Induced Cardiotoxicity in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Low Cumulative Dose

We investigated the left ventricular (LV) function, using for the first time strain (S) and strain rate (SR) imaging, in long-term survivors affected by acute lymphoblastic leukemia treated with a low cumulative dose of anthracyclines, and in presence of a normal global LV systolic and diastolic function. A total of 21 were enrolled in the study. The mean cumulative dose of anthracylines was 180 mg/m² (range: 120-210 mg/m²). As control group 21 age-sex matched healthy subjects were included. Radial S (17 ± 3% vs. 55 ± 6%, P < 0.0001) and SR (2.1 ± 0.3 vs. 3.0 ± 0.8 1\s, P < 0.0001), assessed on the midsegment of the posterior wall from the parasternal views were significantly reduced when compared with controls. Conversely, myocardial performance index was not able to discriminate between patients and controls. In this preliminary study, the myocardial deformation indices appear to be a more sensitive noninvasive technique for detecting subclinical LV dysfunction than other echocardiographic measurements.     

PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine

The mucosa of the small intestine is renewed completely every 3–5 d throughout the entire lifetime by small populations of adult stem cells that are believed to reside in the bottom of the crypts and to migrate and differentiate into all the different populations of intestinal cells. When the cells reach the apex of the villi and are fully differentiated, they undergo cell death and are shed into the lumen. Reactive oxygen species (ROS) production is proportional to the electron transfer activity of the mitochondrial respiration chain. ROS homeostasis is maintained to control cell death and is finely tuned by an inducible antioxidant program. Here we show that peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β) is highly expressed in the intestinal epithelium and possesses dual activity, stimulating mitochondrial biogenesis and oxygen consumption while inducing antioxidant enzymes. To study the role of PGC-1β gain and loss of function in the gut, we generated both intestinal-specific PGC-1β transgenic and PGC-1β knockout mice. Mice overexpressing PGC-1β present a peculiar intestinal morphology with very long villi resulting from increased enterocyte lifespan and also demonstrate greater tumor susceptibility, with increased tumor number and size when exposed to carcinogens. PGC-1β knockout mice are protected from carcinogenesis. We show that PGC-1β triggers mitochondrial respiration while protecting enterocytes from ROS-driven macromolecule damage and consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1β in the gut acts as an adaptive self-point regulator, capable of providing a balance between enhanced mitochondrial activity and protection from increased ROS production.The intestine represents the interface between the organism and its luminal environment and is constantly challenged by mechanical stress, diet-derived toxins and oxidants, and endogenously generated reactive oxygen species (ROS), which can induce serious damage to all biological molecules and cell structures (1). To preserve cellular integrity and tissue homeostasis, the intestine possesses self-renewing capacity via the continuous migration of new enterocytes that undergo differentiation from the crypt to the apical compartment of the villus, where they become competent to apoptosis and are shed into the lumen. ROS accumulation within intestinal epithelial cells promotes apoptotic cell death in the differentiated compartment (2). The mitochondrial electron transport chain is a major site of ROS production in the cells. Under physiological conditions, the balance between ROS generation and detoxification is controlled by a set of cellular enzymes including superoxide dismutase and catalase. Important components of the ROS-scavenging pathways are linked to mitochondrial oxidative metabolism via the peroxisome proliferator-activated receptor-γ coactivators 1α and 1β (PGC-1α and PGC-1β), apparently enabling cells to maintain normal redox status in response to changing oxidative capacity (3). PGC-1α and PGC-1β are master regulators of mitochondrial biogenesis and oxidative metabolism as well as antioxidant defense. Both PGC-1α and PGC-1β are preferentially expressed in tissues with high oxidative capacity where they participate, through mitochondrial biogenesis, in the metabolic response to high energy demand (4), such as cold-adapted thermogenesis in brown adipose tissue (5), fiber-type switching in striated muscle (6), and fatty acid β oxidation and gluconeogenesis in liver during a fasting state (7, 8). The increase in mitochondrial biogenesis and activity stimulated by PGC-1 proteins may cause an increase in the production of ROS. However, PGC-1α also has been shown to increase the expression of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2) (3, 9). Therefore, PGC-1α is able to upgrade aerobic energy metabolism while preserving ROS homeostasis, by simultaneously promoting ROS formation and detoxification. Recently, it has been shown in Drosophila that the PGC-1α homolog spargel is able to induce mitochondrial function and oxygen consumption, which is coupled to the induction of scavenger systems and ROS reduction, finally leading to increased longevity (10). On the other hand, in the differentiated intestinal epithelium of mice, PGC-1α induces mitochondrial biogenesis and oxygen consumption, but it is not able to induce the ROS-scavenging apparatus, thus promoting ROS-dependent apoptotic cell death (2).PGC-1β is highly similar to PGC-1α, both in amino acid sequence and ability to regulate several metabolic pathways (8, 11). Therefore, in the present study we focus on the function of PGC-1β in the intestinal epithelium, giving special attention to the effect of this coactivator in enterocyte homeostasis. We first show that PGC-1β is highly expressed in intestinal epithelium with an almost ubiquitous pattern of localization along the entire crypt–villus axis. To study its activation, we generated mice overexpressing PGC-1β selectively in the enterocytes. We show that in these cells PGC-1β enhances mitochondrial biogenesis and respiration and induces a parallel increase in antioxidant enzymes, such as Sod2 and glutathione peroxidase 4 (Gpx4), as well as peroxiredoxins. As a result, the intestinal morphology is severely affected, with significant increases in enterocyte longevity and mucosal villi length. Concomitantly, PGC-1β overexpression leads to a significant increase in tumor number and size in two distinct models of intestinal carcinogenesis. Moreover, to confirm the role of PGC-1β activity in the intestine, we also generated intestinal-specific PGC-1β (iPGC-1β) knockout mice that, in line with the evidence from transgenic mice, show reduced expression of several metabolic pathways and mitochondrial antioxidant systems as well as decreased susceptibility to tumors. Indeed, tumors may use adaptive mechanisms to keep their ROS burden within a range that permits their growth and survival. In such contest, PGC-1β acts as a gatekeeper of redox status, allowing enterocyte survival and, in cancer-promoting conditions, tumor progression.