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Background Subtle reductions in cardiac output relate to lower cerebral blood flow, especially in regions where Alzheimer's disease pathology first develops. Apolipoprotein E (APOE)-ε4 is a genetic susceptibility risk factor for Alzheimer's disease that also moderates vascular damage. This study investigated whether APOE-ε4 carrier status modifies the cross-sectional association between cardiac output and cognition. Methods and Results Vanderbilt Memory & Aging Project participants free of clinical stroke and dementia (n=306, 73±7 years, 42% female) underwent echocardiography to determine cardiac output (L/min), comprehensive neuropsychological assessment, and venous blood draw to determine APOE genotype and ε4 carrier status. Linear regressions related cardiac output to neuropsychological test performance, adjusting for age, sex, education, race/ethnicity, body surface area, cognitive diagnosis, Framingham Stroke Risk Profile, and APOE-ε4 status. Main effect models were null (P>0.19). With identical covariates, models were repeated testing a cardiac output×APOE-ε4 status interaction and again stratified by ε4 carrier status. Cardiac output×APOE-ε4 status related to naming (β=0.91, P=0.0009), category fluency (β=1.2, P=0.01), information processing speed (β=-5.4, P=0.001), visuospatial skill (β=0.85, P=0.003), and executive function performances (β=0.22, P=0.002). Stratified models suggested that lower cardiac output was associated with worse neuropsychological performances among APOE-ε4 carriers. Conclusions APOE-ε4 carrier status appears to modify the cross-sectional association between cardiac output and neuropsychological performance such that lower cardiac output relates to poorer performances among carriers of the ε4 allele. These findings add to increasing evidence that APOE-ε4 carrier status has important implications for associations between vascular and brain health in aging adults.
OBJECTIVE - To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults.
METHODS - Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), ε4 status, cognitive diagnosis, and regional tissue volume.
RESULTS - Lower cardiac index corresponded to lower resting CBF in the left (β = 2.4, = 0.001) and right (β = 2.5, = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe β = 2.3, = 0.003; right temporal lobe β = 2.5, = 0.003). Cardiac index was unrelated to CBF in other regions assessed ( > 0.25) and CVR in all regions ( > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left ( < 0.0001) and right ( < 0.0001) temporal lobes.
CONCLUSIONS - Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR.
© 2017 American Academy of Neurology.
Importance - Thermodilution (Td) and estimated oxygen uptake Fick (eFick) methods are widely used to measure cardiac output (CO). They are often used interchangeably to make critical clinical decisions, yet few studies have compared these approaches as applied in medical practice.
Objectives - To assess agreement between Td and eFick CO and to compare how well these methods predict mortality.
Design, Setting, and Participants - This investigation was a retrospective cohort study with up to 1 year of follow-up. The study used data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA CART) program. The findings were corroborated in a cohort of patients cared for at Vanderbilt University, an academic referral center. Participants were more than 15 000 adults who underwent right heart catheterization, including 12 232 in the Veterans Affairs cohort between October 1, 2007, and September 30, 2013, and 3391 in the Vanderbilt cohort between January 1, 1998, and December 31, 2014.
Exposures - A single cardiac catheterization was performed on each patient with CO estimated by both Td and eFick methods. Cardiac output was indexed to body surface area (cardiac index [CI]) for all analyses.
Main Outcomes and Measures - All-cause mortality over 90 days and 1 year after catheterization.
Results - Among 12 232 VA patients (mean [SD] age, 66.4 [9.9] years; 3.3% female) who underwent right heart catheterization in this cohort study, Td and eFick CI estimates correlated modestly (r = 0.65). There was minimal mean difference (eFick minus Td = -0.02 L/min/m2, or -0.4%) but wide 95% limits of agreement between methods (-1.3 to 1.3 L/min/m2, or -50.1% to 49.4%). Estimates differed by greater than 20% for 38.1% of patients. Low Td CI (<2.2 L/min/m2 compared with normal CI of 2.2-4.0 L/min/m2) more strongly predicted mortality than low eFick CI at 90 days (Td hazard ratio [HR], 1.71; 95% CI, 1.47-1.99; χ2 = 49.5 vs eFick HR, 1.42; 95% CI, 1.22-1.64; χ2 = 20.7) and 1 year (Td HR, 1.53; 95% CI, 1.39-1.69; χ2 = 71.5 vs eFick HR, 1.35; 1.22-1.49; χ2 = 35.2). Patients with a normal CI by both methods had 12.3% 1-year mortality. There was no significant additional risk for patients with a normal Td CI but a low eFick CI (12.9%, P = .51), whereas a low Td CI but normal eFick CI was associated with higher mortality (15.4%, P = .001). The results from the Vanderbilt cohort were similar in the context of a more balanced sex distribution (46.6% female).
Conclusions and Relevance - There is only modest agreement between Td and eFick CI estimates. Thermodilution CI better predicts mortality and should be favored over eFick in clinical practice.
BACKGROUND - Endotoxin (i.e. LPS) administration induces a robust inflammatory response with accompanying cardiovascular dysfunction and insulin resistance. Overabundance of nitric oxide (NO) contributes to the vascular dysfunction. However, inflammation itself also induces insulin resistance in skeletal muscle. We sought to investigate whether the cardiovascular dysfunction induced by increased NO availability without inflammatory stress can promote insulin resistance. Additionally, we examined the role of inducible nitric oxide synthase (iNOS or NOS2), the source of the increase in NO availability, in modulating LPS-induced decrease in insulin-stimulated muscle glucose uptake (MGU).
METHODS - The impact of NO donor infusion on insulin-stimulated whole-body and muscle glucose uptake (hyperinsulinemic-euglycemic clamps), and the cardiovascular system was assessed in chronically catheterized, conscious mice wild-type (WT) mice. The impact of LPS on insulin action and the cardiovascular system were assessed in WT and global iNOS knockout (KO) mice. Tissue blood flow and cardiac function were assessed using microspheres and echocardiography, respectively. Insulin signaling activity, and gene expression of pro-inflammatory markers were also measured.
RESULTS - NO donor infusion decreased mean arterial blood pressure, whole-body glucose requirements, and MGU in the absence of changes in skeletal muscle blood flow. LPS lowered mean arterial blood pressure and glucose requirements in WT mice, but not in iNOS KO mice. Lastly, despite an intact inflammatory response, iNOS KO mice were protected from LPS-mediated deficits in cardiac output. LPS impaired MGU in vivo, regardless of the presence of iNOS. However, ex vivo, insulin action in muscle obtained from LPS treated iNOS KO animals was protected.
CONCLUSION - Nitric oxide excess and LPS impairs glycemic control by diminishing MGU. LPS impairs MGU by both the direct effect of inflammation on the myocyte, as well as by the indirect NO-driven cardiovascular dysfunction.
BACKGROUND - Cross-sectional epidemiological and clinical research suggests that lower cardiac index is associated with abnormal brain aging, including smaller brain volumes, increased white matter hyperintensities, and worse cognitive performances. Lower systemic blood flow may have implications for dementia among older adults.
METHODS AND RESULTS - A total of 1039 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, and dementia formed our sample (age, 69±6 years; 53% women). Multivariable-adjusted proportional hazard models adjusting for Framingham Stroke Risk Profile score (age, sex, systolic blood pressure, antihypertensive medication, diabetes mellitus, cigarette smoking, cardiovascular disease history, atrial fibrillation), education, and apolipoprotein E4 status related cardiac magnetic resonance imaging-assessed cardiac index (cardiac output divided by body surface area) to incident all-cause dementia and Alzheimer disease (AD). Over the median 7.7-year follow-up period, 32 participants developed dementia, including 26 cases of AD. Each 1-SD unit decrease in cardiac index increased the relative risk of both dementia (hazard ratio [HR]=1.66; 95% confidence interval [CI], 1.11-2.47; P=0.013) and AD (HR=1.65; 95% CI, 1.07-2.54; P=0.022). Compared with individuals with normal cardiac index, individuals with clinically low cardiac index had a higher relative risk of dementia (HR=2.07; 95% CI, 1.02-4.19; P=0.044). If participants with clinically prevalent cardiovascular disease and atrial fibrillation were excluded (n=184), individuals with clinically low cardiac index had a higher relative risk of both dementia (HR=2.92; 95% CI, 1.34-6.36; P=0.007) and AD (HR=2.87; 95% CI, 1.21-6.80; P=0.016) compared with individuals with normal cardiac index.
CONCLUSION - Lower cardiac index is associated with an increased risk for the development of dementia and AD.
© 2015 American Heart Association, Inc.
Pulmonary arterial hypertension (PAH) has been associated with a number of different but interrelated pathogenic mechanisms. Metabolic and oxidative stresses have been shown to play important pathogenic roles in a variety of model systems. However, many of these relationships remain at the level of association. We sought to establish a direct role for metabolic stress and oxidant injury in the pathogenesis of PAH. Mice that universally express a disease-causing mutation in bone morphogenic protein receptor 2 (Bmpr2) were exposed to room air or to brief daily hyperoxia (95% oxygen for 3 h) for 6 weeks, and were compared with wild-type animals undergoing identical exposures. In both murine tissues and cultured endothelial cells, the expression of mutant Bmpr2 was sufficient to cause oxidant injury that was particularly pronounced in mitochondrial membranes. With the enhancement of mitochondrial generation of reactive oxygen species by hyperoxia, oxidant injury was substantially enhanced in mitochondrial membranes, even in tissues distant from the lung. Hyperoxia, despite its vasodilatory actions in the pulmonary circulation, significantly worsened the PAH phenotype (elevated right ventricular systolic pressure, decreased cardiac output, and increased pulmonary vascular occlusion) in Bmpr2 mutant animals. These experiments demonstrate that oxidant injury and metabolic stress contribute directly to disease development, and provide further evidence for PAH as a systemic disease with life-limiting cardiopulmonary manifestations.
Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca(2+)/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction.
Cell-free hemoglobin (Hb) exposure may be a pathogenic mediator in the development of pulmonary arterial hypertension (PAH), and when combined with chronic hypoxia the potential for exacerbation of PAH and vascular remodeling is likely more pronounced. We hypothesized that Hb may contribute to hypoxia-driven PAH collectively as a prooxidant, inflammatory, and nitric oxide (NO) scavenger. Using programmable micropump technology, we exposed male Sprague-Dawley rats housed under room air or hypoxia to 12 or 30 mg per day Hb for 3, 5, and 7 wk. Blood pressure, cardiac output, right ventricular hypertrophy, and indexes of pulmonary vascular remodeling were evaluated. Additionally, markers of oxidative stress, NO bioavailability and inflammation were determined. Hb increased pulmonary arterial (PA) pressure, pulmonary vessel wall stiffening, and right heart hypertrophy with temporal and dose dependence in both room air and hypoxic cohorts. Hb induced a modest increase in plasma oxidative stress markers (malondialdehyde and 4-hydroxynonenal), no change in NO bioavailability, and increased lung ICAM protein expression. Treatment with the antioxidant Tempol attenuated Hb-induced pulmonary arterial wall thickening, but not PA pressures or ICAM expression. Chronic exposure to low plasma Hb concentrations (range = 3-10 μM) lasting up to 7 wk in rodents induces pulmonary vascular disease via inflammation and to a lesser extent by Hb-mediated oxidation. Tempol demonstrated a modest effect on the attenuation of Hb-induced pulmonary vascular disease. NO bioavailability was found to be of minimal importance in this model.
Heart failure has served as a clinically useful model for understanding how cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to clinical brain injury. This review summarizes more recent data suggesting that subtle cardiac dysfunction or low normal levels of cardiac function, as quantified by cardiac output, are related to cognitive and neuroimaging markers of abnormal brain aging in the absence of heart failure or severe cardiomyopathy. Additional work is required, but such associations suggest that reduced cardiac output may be a risk factor for Alzheimer's disease (AD) and abnormal brain aging through the propagation or exacerbation of neurovascular processes, microembolism due to thrombosis, and AD neuropathological processes. Such mechanistic pathways are discussed in the context of a theoretical model that posits a direct pathway of injury between cardiac output and abnormal brain aging (i.e., reduced systemic blood flow disrupts cerebral blood flow homeostasis), contributing to clinical brain injury, independent of shared risk factors for both cardiac dysfunction and abnormal brain aging.