Adaptive remodeling of hypoplastic hemodialysis fistulas salvaged with angioplasty.

OBJECTIVES: The aim of this study was to determine whether immature hemodialysis fistulas undergo flow-induced adaptive remodeling after successful percutaneous angioplasty. BACKGROUND: Approximately 50% of radiocephalic fistulas remain immature after surgery and cannot be used for hemodialysis. Small fistulas with anastomotic inflow stenoses may undergo salvage angioplasty, but the time course of outward remodeling after successful treatment has not been defined. METHODS: Thirty-two of 39 patients (82%) with inaccessible, hypoplastic radiocephalic fistulas underwent attempted salvage angioplasty of inflow stenoses involving the arteriovenous anastomoses. Twenty patients experienced salvage of their fistulas and successfully underwent hemodialysis (51%). RESULTS: Eleven patients had serial angiographic procedures, which allowed paired sequential quantitative angiographic measurements of the fistulas to be made during a median follow-up of 200 days (range 5-2,298 days). Fistula diameters increased from 4.5 +/- 1.3 mm to 8.0 +/- 2.5 mm (mean +/- S.D.). The mean growth of the fistulas was 1.0 +/- 0.9 mm per year. CONCLUSIONS: The mechanism of adaptive remodeling transforms nonmaturing hypoplastic autogenous fistulas into functioning accessible dialysis accesses after successful percutaneous transluminal angioplasty of inflow anastomotic stenoses.

Bayes Factor Meta-Analysis of the Mortality Claim for Peripheral Paclitaxel-Eluting Devices.

OBJECTIVES: The aim of the present study was to quantify the probability of increased mortality with paclitaxel compared with control in a dataset of 28 randomized controlled trials. BACKGROUND: Analysis of data from 28 randomized controlled trials using conventional null-hypothesis statistical testing has produced the unexpected finding of a 68% increase in mortality at 2 years and a 93% increase at 3 to 5 years after using paclitaxel-eluting balloons and stents to treat femoropopliteal arterial disease, but no biologic explanation for increased mortality has been identified. METHODS: A Bayesian sequential model was developed to quantify the probability of increased mortality 1, 2, and 3 to 5 years after treatment, and p values were replaced with meta-analytic Bayes factors (BFs), which provide decisive evidence at values >100 and very strong evidence at values of 32 to 100. RESULTS: The evidence for increased mortality at 1 year (BF = 0.02), 2 years (BF = 8.5), and 3 to 5 years (BF = 14.6) was less than conclusive. All-cause mortality at 1 year was similar between the paclitaxel and control arms at 1 year (odds ratio: 0.92; 95% Bayesian credible interval: 0.53 to 1.53) and 2 years (odds ratio: 1.23; 95% Bayesian credible interval: 0.84 to 1.71) but was increased at 3 to 5 years (odds ratio: 1.43; 95% Bayesian credible interval: 1.01 to 1.90). CONCLUSIONS: This study finds some support for increased mortality after using paclitaxel-eluting devices in femoropopliteal arterial disease, but the evidence is not unequivocal and may not sway skeptical investigators concerned about causation, unreported studies, or the post hoc analysis of trials underpowered for mortality.

Regadenoson, a selective A2A adenosine receptor agonist, causes dose-dependent increases in coronary blood flow velocity in humans.

BACKGROUND: Regadenoson is a selective A2A adenosine receptor agonist and vasodilator used to increase the heterogeneity of distribution of coronary blood flow during myocardial perfusion imaging. This study characterized the dose dependence of regadenoson-induced coronary hyperemia. METHODS AND RESULTS: An open-label, dose-escalation study of regadenoson (10-500 microg, rapid intravenous bolus) was performed in 34 subjects; in 4 additional subjects, the effect of aminophylline to reverse the response to regadenoson was determined. Intracoronary peak blood flow velocity in either the left anterior descending or left circumflex artery was measured by continuous Doppler signal recording, heart rate, central aortic blood pressure, and adverse effects were recorded. Regadenoson increased peak blood flow velocity by up to 3.4-fold in a dose-dependent manner. The mean duration of the increase in flow velocity of 2.5-fold or greater caused by 400 to 500 microg of regadenoson was 2.3 to 2.4 minutes. Regadenoson (400-500 microg) increased heart rate by up to 21 +/- 6 beats/min and decreased systolic blood pressure (-5 +/- 8 mm Hg to -24 +/- 16 mm Hg) and diastolic blood pressure (-8 +/- 4 mm Hg to -15 +/- 14 mm Hg). Aminophylline (100 mg) attenuated the increase in peak flow velocity but not tachycardia caused by 400 microg of regadenoson. CONCLUSION: The results of this study demonstrate the utility of regadenoson as a coronary vasodilator for myocardial perfusion imaging.

Phytoestrogens and coronary microvascular function in women with suspected myocardial ischemia: a report from the Women's Ischemia Syndrome Evaluation (WISE) Study.

AIMS: Soy phytoestrogens are popular, but information on their coronary effects in patients with suspected ischemic heart disease is limited. Accordingly, we investigated the relationship between blood phytoestrogen levels and coronary reactivity in women with suspected myocardial ischemia referred for coronary angiography. METHODS: Coronary flow velocity reserve (CFVR) and volumetric flow reserve (VFR) to adenosine (ADO) and nitroglycerin (NTG) (nonendothelial-dependent responses) and acetylcholine (ACH) (endothelial-dependent response) were assessed in 106 women from the Women's Ischemia Syndrome Evaluation (WISE). Blood phytoestrogen (daidzein and genistein) and estrogen (estradiol) levels were correlated with coronary reactivity measures. RESULTS: Participants were mostly postmenopausal (79%), mean age 56 years, and 24% had obstructive coronary artery disease (CAD) at angiography. Genistein blood levels were negatively correlated with nonendothelial-dependent coronary flow responses. The highest genistein tertile (>6.1 ng/mL) had a CFVR of 2.1 +/- 0.5 (mean +/- SD) and VFRADO of 1.0 +/- 0.6, and both were significantly (p= 0.0001) lower compared with the other genistein tertiles combined. Similar associations were noted for CFVR(NTG) and VFR(NTG) (p = 0.03 and p = 0.01, respectively). The highest genistein tertile was associated with lower CFVR(ACH) compared with the other tertiles (p = 0.03). In multivariable modeling, blood genistein levels were significant independent predictors of coronary flow responses to ADO. There were no significant correlations between coronary reactivity variables and daidzein or endogenous estrogen. CONCLUSIONS: In women with suspected myocardial ischemia, higher genistein blood levels are associated with impaired nonendothelial-dependent and endothelial-dependent coronary microvascular function.

Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Altered coronary reactivity is frequent in women with findings of myocardial ischemia without significant obstructive disease. This suggests a defect in coronary microvascular function. The adenosine-related component of this altered reactivity has been described in male and mixed gender populations, while the factors influencing this component of coronary reactivity in symptomatic women have received limited attention. Accordingly, the relationship between adenosine-related microvascular coronary reactivity and risk factors in symptomatic women evaluated for suspected ischemia remains uncertain. HYPOTHESIS: Abnormal coronary microvascular reactivity to adenosine is predicted by atherosclerosis risk factors in women. METHODS: As part of the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE), we investigated the relationship between risk factors and coronary microvascular reactivity as flow velocity reserve to intracoronary adenosine (CFVR(Ado)) in 210 women referred for angiography to evaluate suspected ischemia. RESULTS: Univariate analyses identified associations between CFVR(Ado) and multiple risk conditions; however, after adjusting for age, none remained significant. The best multivariable model using combinations of risk conditions to predict CFVR(Ado) yielded an R2 of only 0.18. CONCLUSIONS: Among women with suspected ischemia, risk factors account for <20% of observed variability in CFVR(Ado). Therefore, other as yet unidentified factors must primarily account for coronary microvascular reactivity to adenosine.

Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Coronary vascular dysfunction has been linked to atherosclerosis and adverse cardiovascular outcomes in men, but these relationships have not been firmly established in women. METHODS AND RESULTS: As part of the Women's Ischemia Syndrome Evaluation (WISE) sponsored by the National Heart, Lung, and Blood Institute, 163 women referred for clinically indicated coronary angiography underwent coronary reactivity assessment with quantitative coronary angiography and intracoronary Doppler flow before and after intracoronary administration of acetylcholine, adenosine, and nitroglycerin and were then followed up for clinical outcomes. History of hypertension was present in 61%, dyslipidemia in 54%, diabetes in 26%, and current tobacco use in 21% of women enrolled. Seventy-five percent had no or only mild epicardial coronary artery disease (CAD). Over a median follow-up of 48 months, events occurred in 58 women. On bivariate analysis, women with an event had significantly less change in coronary cross-sectional area (DeltaCSA) in response to acetylcholine (P=0.0006) and nitroglycerin (P=0.04). In addition, women with abnormal coronary dilator response to acetylcholine had less time free from cardiovascular events (P=0.004). In multivariable analysis, after controlling for age, hypertension, diabetes, dyslipidemia, tobacco use, and CAD severity, %DeltaCSA with acetylcholine (P=0.001) independently predicted events. When the outcome was restricted to only death, myocardial infarction, congestive heart failure, and stroke, %DeltaCSA with acetylcholine remained a significant predictor (P=0.006). CONCLUSIONS: In women in this study, impaired coronary vasomotor response to acetylcholine was independently linked to adverse cardiovascular outcomes regardless of CAD severity.

Pulse pressure and adverse outcomes in women: a report from the Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Recent data suggest that brachial pulse pressure (PP) may be a better predictor of outcome than systolic or diastolic blood pressure (SBP/DBP). We sought to investigate the relative contributions of these indices to risk for adverse outcomes in women with suspected coronary artery disease (CAD) and myocardial ischemia. METHODS: Among 857 women referred for angiography for suspected myocardial ischemia, baseline evaluations were performed, and the women were followed for clinical outcome. Relationships between baseline characteristics, blood pressure components, and outcomes were evaluated. Separate multivariate stepwise Cox regression models for PP and SBP (expressed in 10 mm Hg increments) were constructed and included covariates significantly associated with adverse outcomes. RESULTS: After 5.2 years (mean), univariate testing identified higher PP associated with higher risk for cardiovascular (CV) mortality and adverse CV outcomes than SBP, DBP, or mean arterial pressure (MAP). Multivariate modeling identified both PP and SBP associated with adverse CV outcomes, but only PP was significantly associated with higher CV mortality. When both PP and SBP were included in the model, only PP remained an independent predictor of adverse outcomes for CV events. CONCLUSIONS: In women with suspected CAD and myocardial ischemia, PP is a stronger predictor of adverse outcomes than SBP, DBP, or MAP with an 18% excess mortality risk for every 10 mm Hg increase in PP. Further investigations into pathophysiologic mechanisms and specific pharmacologic approaches to modifying this novel target are warranted.

Some thoughts on the vasculopathy of women with ischemic heart disease.

Considerable experimental and clinical data indicate that sex has an important influence on cardiovascular physiology and pathology. This report integrates selected literature with new data from the Women's Ischemia Syndrome Evaluation (WISE) on vascular findings in women with ischemic heart disease (IHD) and how these findings differ from those in men. A number of common vascular disease-related conditions are either unique to (e.g., hypertensive disorders of pregnancy, gestational diabetes, peripartum dissection, polycystic ovarian syndrome, etc.) or more frequent (e.g., migraine, coronary spasm, lupus, vasculitis, Raynaud's phenomenon, etc.) in women than men. Post-menopausal women more frequently have many traditional vascular disease risk conditions (e.g., hypertension, diabetes, obesity, inactivity, and so on), and these conditions cluster more frequently in them than men. Considerable evidence supports the notion that, with these requisite conditions, women develop a more severe or somewhat different form of vascular disease than men. Structurally, women's coronary vessels are smaller in size and appear to contain more diffuse atherosclerosis, their aortas are stiffer (fibrosis, remodeling, and so on), and their microvessels appear to be more frequently dysfunctional compared with men. Functionally, women's vessels frequently show impaired vasodilator responses. Limitations of existing data and higher risks in women with acute myocardial infarction, need for revascularization, or heart failure create uncertainty about management. A better understanding of these findings should provide direction for new algorithms to improve management of the vasculopathy underlying IHD in women.