Kidney dysfunction, cardiorespiratory fitness, and the risk of death in women.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased risk of cardiovascular (CV) events and death. However, the effect of cardiorespiratory fitness on the CKD-mortality relationship remains unknown, particularly in women. METHODS: We used Cox regression to estimate hazard ratios (HR) for the effect of kidney function and fitness on all-cause mortality in a prospective cohort of 5716 women free of CKD and CV disease symptoms. Serum creatinine (Cr) was used to estimate glomerular filtration rate (eGFR), and spot urine protein and maximal stress tests were performed at baseline. RESULTS: Mean age at baseline was 52.5±10.8 years, and 86% of the sample was Caucasian. Mean Cr was 1.11±0.14 mg/dL, and mean eGFR was 53.7±8.3 mL/min/1.73 m(2) at baseline. The mean follow-up was 15.9±2.2 years, with 589 deaths identified. Cr <1.4 was associated with an HR of death of 1.59 (p=0.03). After adjustment for traditional CV risk factors and fitness, the risk of death decreased by 3% (p<0.001) for every mL/min/1.73 m(2) increase in eGFR. Compared to women with an eGFR <45 mL/min/1.73 m(2), the risk of death was reduced by 36% and 47%, for eGFR 45-59.9 mL/min/1.73 m(2) and eGFR ≥60 mL/min/1.73 m(2), respectively (p<0.001). At every level of eGFR, fitness remained an independent predictor of mortality, with the lowest level of fitness (<5 metabolic equivalents [METs]) at the highest risk of mortality regardless of eGFR level. CONCLUSIONS: Fitness remains an independent predictor of mortality regardless of eGFR. eGFR was a stronger predictor of mortality compared to Cr or the presence of proteinuria. These findings have important implications for clinical practice and health policy, as the level of cardiorespiratory fitness predicts risk of death in the presence of asymptomatic CKD.

Mutant SOD1 forms ion channel: implications for ALS pathophysiology.

Point mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) impart a gain-of-function to this protein that underlies 20-25% of all familial amyotrophic lateral sclerosis (FALS) cases. However, the specific mechanism of mutant SOD1 toxicity has remained elusive. Using the complementary techniques of atomic force microscopy (AFM), electrophysiology, and cell and molecular biology, here we examine the structure and activity of A4VSOD1, a mutant SOD1. AFM of A4VSOD1 reconstituted in lipid membrane shows discrete tetrameric pore-like structure with outer and inner diameters 12.2 and 3.0nm respectively. Electrophysiological recordings show distinct ionic conductances across bilayer for A4VSOD1 and none for wildtype SOD1. Mouse neuroblastoma cells exposed to A4VSOD1 undergo membrane depolarization and increases in intracellular calcium. These results provide compelling new evidence that a mutant SOD1 is capable of disrupting cellular homeostasis via an unregulated ion channel mechanism. Such a "toxic channel" mechanism presents a new therapeutic direction for ALS research.

Multidimensional atomic force microscopy: a versatile novel technology for nanopharmacology research.

Nanotechnology is giving us a glimpse into a nascent field of nanopharmacology that deals with pharmacological phenomena at molecular scale. This review presents our perspective on the use of scanning probe microscopy techniques with special emphasis to multidimensional atomic force microscopy (m-AFM) to explore this new field with a particular emphasis to define targets, design therapeutics, and track outcomes of molecular-scale pharmacological interactions. The approach will be to first discuss operating principles of m-AFM and provide representative examples of studies to understand human health and disease at the molecular level and then to address different strategies in defining target macromolecules, screening potential drug candidates, developing and characterizing of drug delivery systems, and monitoring target-drug interactions. Finally, we will discuss some future directions including AFM tip-based parallel sensors integrated with other high-throughput technologies which could be a powerful platform for drug discovery.

Predictors of hypertension control in a diverse general cardiology practice.

Factors influencing hypertension (HTN) control in the United States are not well understood. The authors utilized a newly designed survey instrument to interview patients presenting to a diverse, general cardiology practice at a tertiary care center in order to identify factors associated with HTN control. The study was completed in 154 participants, and 121 (78.6%) had HTN. Of those, 111 (91.7%) had awareness of HTN, and 72 (59.5%) had HTN control, defined as <140/90 mm Hg. In a multivariate analysis, race/ethnicity was not associated with HTN control, but private insurance (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.25-9.28), nonsmoker status (OR 4.36, CI 1.22-15.51), and number of medications used (OR 1.32, CI 1.12-1.56) were associated with HTN control. Correct recognition of systolic blood pressure goal and knowledge of one's current state of HTN control were also associated with control. In conclusion, in a general cardiology practice where patients had a high degree of healthcare access, race/ethnicity was not associated with HTN control, while type of insurance, nonsmoker status, and increased number of medications used were associated. In addition, 2 novel predictors of HTN control, recognition of systolic blood pressure goal and knowledge of HTN control, were identified that can be utilized in creating new HTN treatment interventions.

Heart rate response to exercise stress testing in asymptomatic women: the st. James women take heart project.

BACKGROUND: The definition of a normal heart rate (HR) response to exercise stress testing in women is poorly understood, given that most studies describing a normative response were predominately based on male data. Measures of an attenuated HR response (chronotropic incompetence) and age-predicted HR have not been validated in asymptomatic women. We investigated the association between HR response to exercise testing and age with prognosis in 5437 asymptomatic women. METHODS AND RESULTS: Participants underwent a symptom-limited maximal stress test in 1992. HR reserve (change in HR from rest to peak), chronotropic index, and age-predicted peak HR were calculated. Deaths were identified to December 31, 2008. Mean age at baseline was 52+/-11 years, with 549 deaths (10%) over 15.9+/-2.2 years. Mean peak HR was inversely associated with age; mean peak HR=206-0.88(age). After adjusting for exercise capacity and traditional cardiac risk factors, risk of death was reduced by 3% for every 1-beat-per-minute increase in peak HR, and by 2% for every 1-beat-per-minute increase in HR reserve (P<0.001). Inability to achieve 85% age-predicted HR was not an independent predictor of mortality, but being >/=1 SD below the mean predicted HR or a chronotropic index <0.80 based on the prediction model established by this cohort were independent predictors of mortality (P<0.001 and P=0.023, respectively). CONCLUSIONS: Chronotropic incompetence is associated with an increased risk of death in asymptomatic women; however, the traditional male-based calculation overestimates the maximum HR for age in women. Sex-specific parameters of physiological HR response to exercise should be incorporated into clinical practice.

Multidimensional atomic force microscopy for drug discovery: a versatile tool for defining targets, designing therapeutics and monitoring their efficacy.

Current therapeutic design involves combinatorial chemistry and system biology-based molecular synthesis and bulk pharmacological assays. Therapeutics delivery is usually non-specific to disease targets and requires excessive dosage. Efficient therapeutic discovery and delivery would require molecular level understanding of the therapeutics-effectors (e.g., channels and receptors) interactions and their cell and tissue responses. This review summarizes the application of multidimensional scanning probe techniques, especially atomic force microscopy (AFM), for drug discovery. Important features of AFM include its capability of atomic scale structural and physical properties study of live biological systems, its open architecture that allows its integration with other techniques, tools and operating environments, and its application for creating and characterizing nanocarriers and implantable vehicles for controlled delivery. Specific areas covered include: 1) the operating principle and examples of AFM integrated with electrical recording, fluorescence imaging and microfluidics, (2) examples of AFM nanoscale imaging that has provided new paradigms in pathogenesis, including protein misfolding diseases (e.g., Alzheimer's disease, cancer, diabetes) and diseases arising from environmental and life choices and thus identifies potential therapeutic targets, (3) high-throughput parallel sensors, comprising integrated cantilevered microarrays, TIRF, microfluidics and nanoelectronics, for potential rapid diagnosis of pathogens, allergens and biomarkers as well as for therapeutics design, (4) the definition target macromolecules and structures, using intermolecular interaction assays, (5) the definition of abnormal vs normal tissues and the assessment of therapeutic efficacy by monitoring biomechanics, and (6) the development and characterization of nanocarrier-based drug delivery (e.g., nanoliposomes and nanoparticles) systems that allow high efficiency in vivo or the topical administration of a small dosage of therapeutics.

Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project.

BACKGROUND: Women with clinical findings suggestive of ischemia but without findings of obstructive coronary artery disease (CAD) on angiography represent a frequent clinical problem; predicting prognosis is challenging. METHODS: The Women's Ischemia Syndrome Evaluation (WISE) study examined symptomatic women referred for clinically indicated coronary angiography and followed up for a mean 5.2 years. The St James Women Take Heart (WTH) Project enrolled asymptomatic, community-based women with no history of heart disease who were followed up for 10 years. We compared cardiovascular events (ie, myocardial infarction, stroke, and hospitalization for heart failure) and death in 540 WISE women with suspected ischemia but no angiographic evidence of obstructive CAD with those from a cohort of 1000 age- and race-matched WTH women. RESULTS: Compared with the WISE women, asymptomatic WTH women had a lower prevalence of obesity, family history of CAD, hypertension, and diabetes mellitus (P < .001). Five-year annualized event rates for cardiovascular events were 16.0% in WISE women with nonobstructive CAD (stenosis in any coronary artery of 1%-49%), 7.9% in WISE women with normal coronary arteries (stenosis of 0% in all coronary arteries), and 2.4% in asymptomatic WTH women (P < or = .002), after adjusting for baseline CAD risk factors. The cardiovascular events were most frequent in women with 4 or more cardiac risk factors, with the 5-year annualized cardiovascular event rate being 25.3% in women with nonobstructive CAD, 13.9% in WISE women with normal coronary arteries, and 6.5% in asymptomatic women (P = .003). CONCLUSION: Women with symptoms and signs suggestive of ischemia but without obstructive CAD are at elevated risk for cardiovascular events compared with asymptomatic community-based women.

Regulation of the micromechanical properties of pulmonary endothelium by S1P and thrombin: role of cortactin.

Disruption of pulmonary endothelial cell (EC) barrier function is a critical pathophysiologic event in highly morbid inflammatory conditions such as sepsis and acute respiratory disease stress syndrome. Actin cytoskeleton, an essential regulator of endothelial permeability, is a dynamic structure whose stimuli-induced rearrangement is linked to barrier modulation. Here, we used atomic force microscopy to characterize structural and mechanical changes in the F-actin cytoskeleton of cultured human pulmonary artery EC in response to both barrier-enhancing (induced by sphingosine 1-phosphate (S1P)) and barrier-disrupting (induced by thrombin) conditions. Atomic force microscopy elasticity measurements show differential effects: for the barrier protecting molecule S1P, the elastic modulus was elevated significantly on the periphery; for the barrier-disrupting molecule thrombin, on the other hand, it was elevated significantly in the central region of the cell. The force and elasticity maps correlate with F-actin rearrangements as identified by immunofluorescence analysis. Significantly, reduced expression (via siRNA) of cortactin, an actin-binding protein essential to EC barrier regulation, resulted in a shift in the S1P-mediated elasticity pattern to more closely resemble control, unstimulated endothelium.

Advance directives in the cardiac care unit.

BACKGROUND: Despite effective therapies, mortality for many cardiovascular diseases remains higher than for many cancers and is difficult to predict. Guidelines recommend discussing advance directives (AD), including living wills and durable powers of attorney, with heart failure patients. The Patient Self-Determination Act mandates such discussions with all hospitalized patients. Little data are available on AD prevalence in patients with serious cardiac disease. METHODS: Patients admitted to a cardiac care unit (CCU) were surveyed regarding demographics, medical history, prevalence of AD, and interest in obtaining more information about AD. Histories of life-threatening cardiac diagnoses were tabulated. Prevalence of AD and interest in obtaining more information about AD were obtained via chart review from patients on an oncology (ONC) floor at the same hospital. RESULTS: One hundred twelve CCU (average age 58 +/- 16 years, 47 women) and 105 ONC (average age 58 +/- 14 years, 32 women) patients were enrolled. Prevalence of AD was not different between CCU and ONC patients (26% vs 31%, P = .37). Among CCU patients with prior hospitalizations but no AD, 21 of 64 did not recall being asked about AD. Cardiac care unit patients with heart failure and pulmonary hypertension were more likely to report being asked about AD in the past (39 of 54, P = .03 and 7 of 9, P = .008, respectively), but only heart failure patients were more likely to want more information about AD (P = .005). Of patients without AD, 83% from CCU and 18% from ONC wanted more information on AD (P < .001). CONCLUSIONS: Prevalence of AD in the CCU was low, and many patients did not recall prior AD discussions. The CCU patients without AD were more likely to want information about AD than the ONC patients. A renewed emphasis on AD discussions with cardiovascular patients is needed and would be welcomed. Advance directives should be emphasized in cardiovascular training programs.

The prognostic value of a nomogram for exercise capacity in women.

BACKGROUND: Recent studies have demonstrated that exercise capacity is an independent predictor of mortality in women. Normative values of exercise capacity for age in women have not been well established. Our objectives were to construct a nomogram to permit determination of predicted exercise capacity for age in women and to assess the predictive value of the nomogram with respect to survival. METHODS: A total of 5721 asymptomatic women underwent a symptom-limited, maximal stress test. Exercise capacity was measured in metabolic equivalents (MET). Linear regression was used to estimate the mean MET achieved for age. A nomogram was established to allow the percentage of predicted exercise capacity to be estimated on the basis of age and the exercise capacity achieved. The nomogram was then used to determine the percentage of predicted exercise capacity for both the original cohort and a referral population of 4471 women with cardiovascular symptoms who underwent a symptom-limited stress test. Survival data were obtained for both cohorts, and Cox survival analysis was used to estimate the rates of death from any cause and from cardiac causes in each group. RESULTS: The linear regression equation for predicted exercise capacity (in MET) on the basis of age in the cohort of asymptomatic women was as follows: predicted MET = 14.7 - (0.13 x age). The risk of death among asymptomatic women whose exercise capacity was less than 85 percent of the predicted value for age was twice that among women whose exercise capacity was at least 85 percent of the age-predicted value (P<0.001). Results were similar in the cohort of symptomatic women. CONCLUSIONS: We have established a nomogram for predicted exercise capacity on the basis of age that is predictive of survival among both asymptomatic and symptomatic women. These findings could be incorporated into the interpretation of exercise stress tests, providing additional prognostic information for risk stratification.

Prognostic value of the duke treadmill score in asymptomatic women.

The Duke Treadmill Score (DTS) has been shown to predict mortality in women who have symptomatic heart disease, but its ability to do so in asymptomatic women is unknown, as is its comparative advantage to exercise capacity. We investigated whether a decreased DTS is associated with increased mortality in a prospective cohort of 5,636 asymptomatic women. A symptom-limited exercise treadmill test using Bruce's protocol was performed at baseline. DTS was calculated using exercise time, exercise-induced angina, and ST-segment depression. Exercise capacity was measured in METs. Deaths and cause of death were identified from 1992 to 2000. After adjusting for the Framingham Risk Score, the risk of death decreased by 9% for each unit increase in DTS and by 17% for every 1-MET increase (p <0.001). Those who had a DTS <5 (moderate or high risk) had hazard ratios for death and cardiac death that were 2.2 and 2.5 times greater, respectively, than did those who had a DTS > or =5 (low risk), after adjusting for Framingham Risk Score (p <0.001). Receiver-operating characteristic curves for the DTS model and the exercise capacity model were not significantly different. In conclusion, we have demonstrated that, although the DTS is an independent predictor of mortality and cardiac mortality in asymptomatic women, it does not appear to be a better predictor than exercise capacity alone. The role of ST-segment changes and symptoms with stress testing in asymptomatic women does not provide additional prognostic information.

Exercise capacity and the risk of death in women: the St James Women Take Heart Project.

BACKGROUND: Cardiovascular disease is the leading cause of death among women and accounts for more than half of their deaths. Women have been underrepresented in most studies of cardiovascular disease. Reduced physical fitness has been shown to increase the risk of death in men. Exercise capacity measured by exercise stress test is an objective measure of physical fitness. The hypothesis that reduced exercise capacity is associated with an increased risk of death was investigated in a cohort of 5721 asymptomatic women who underwent baseline examinations in 1992. METHODS AND RESULTS: Information collected at baseline included medical and family history, demographic characteristics, physical examination, and symptom-limited stress ECG, using the Bruce protocol. Exercise capacity was measured in metabolic equivalents (MET). Nonfasting blood was analyzed at baseline. A National Death Index search was performed to identify all-cause death and date of death up to the end of 2000. The mean age of participants at baseline was 52+/-11 years. Framingham Risk Score-adjusted hazards ratios (with 95% CI) of death associated with MET levels of <5, 5 to 8, and >8 were 3.1 (2.0 to 4.7), 1.9 (1.3 to 2.9), and 1.00, respectively. The Framingham Risk Score-adjusted mortality risk decreased by 17% for every 1-MET increase. CONCLUSIONS: This is the largest cohort of asymptomatic women studied in this context over the longest period of follow-up. This study confirms that exercise capacity is an independent predictor of death in asymptomatic women, greater than what has been previously established among men. The implications for clinical practice and health care policy are far reaching.