Ventricular Septal Myectomy for the Treatment of Left Ventricular Outflow Tract Obstruction Due to Fabry Disease.

Fabry cardiomyopathy can cause symptomatic left ventricular outflow tract obstruction. We review a case of Fabry cardiomyopathy mimicking hypertrophic cardiomyopathy on echocardiography with severe left ventricular outflow tract obstruction treated with ventricular septal myectomy.

Low frequency of Fabry disease in patients with common heart disease.

PURPOSE: To test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease. METHODS: Globotriaosylceramide in random whole urine using tandem mass spectroscopy, α-galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing. RESULTS: We tested 2,256 consecutive patients: 852 women (median age 65 years (19-95)) and 1,404 men (median age 65 years (21-92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568). Urinary globotriaosylceramide was elevated in 15% of patients and 15 males had low α-galactosidase A activity. GLA variants found included R118C (n = 2), D83N, and D313Y (n = 7); IVS6-22 C>T, IVS4-16 A>G, IVS2+990C>A, 5'UTR-10 C>T (n = 4), IVS1-581 C>T, IVS1-1238 G>A, 5'UTR-30 G>A, IVS2+590C>T, IVS0-12 G>A, IVS4+68A>G, IVS0-10 C>T, IVS2-81-77delCAGCC, IVS2-77delC. Although the pathogenicity of several of these missense mutations and complex intronic haplotypes has been controversial, none of the patients screened in this study were diagnosed definitively with Fabry disease. CONCLUSION: This population of patients with common heart disease did not contain a substantial number of patients with undiagnosed Fabry disease. GLA gene sequencing is superior to urinary globotriaosylceramide or α-galactosidase A activity in the screening for Fabry disease.

Prognostic value of urinary 11-dehydro-thromboxane B2 for mortality: A cohort study of stable coronary artery disease patients treated with aspirin.

AIM: There is a variable cardiovascular risk reduction attributable to aspirin because of individual differences in the suppression of thromboxane A2 and its downstream metabolite 11-dehydro-thromboxane B2 (11dhTxB2 ). The aim of this study is to evaluate the optimal cut point of urinary 11dhTxB2 for the risk of mortality in aspirin-treated coronary artery disease (CAD) patients. METHODS AND RESULTS: This was a prospective cohort study including stable CAD patients who visited the Baylor Heart and Vascular Hospital in Dallas or the Texas Heart Hospital Baylor Plano, TX between 2010 and 2013. The outcome of all-cause mortality was ascertained from chart review and automated sources. The 449 patients included in this analysis had a mean age of 66.1 ± 10.1 years. 67 (14.9%) patients died within 5 years; 56 (87.5%) of the 64 patients with known cause of death suffered a cardiovascular related mortality. Baseline ln(urinary 11dhTxB2 /creatinine) ranged between 5.8 and 11.1 (median = 7.2) with the higher concentrations among those who died (median: 7.6) than those who survived (median = 7.2, P < 0.001). Using baseline ln(11dhTxB2 ) to predict all-cause mortality, the area under the curve was 0.70 (95% CI: 0.64-0.76). The optimal cut point was found to be ln(7.38) = 1597.8 pg/mg, which had the following decision statistics: sensitivity = 0.67, specificity = 0.62, positive predictive value = 0.24, negative predictive value = 0.92, and accuracy = 0.63. CONCLUSION: Our data indicate the optimal cut point for urine 11dhTxB2 is 1597.8 (pg/mg) for the risk prediction of mortality over five years in stable patients with CAD patients treated with aspirin.

Urinary 11-Dehydro-Thromboxane B2 and Mortality in Patients With Stable Coronary Artery Disease.

Antiplatelet therapy with aspirin has been shown to reduce adverse outcomes in patients with coronary artery disease (CAD). Aspirin irreversibly inhibits platelet cyclooxygenase-1 and attenuates thromboxane A2 (TXA2)-mediated platelet aggregation, but there is variable suppression of cyclooxygenase-1. From a cohort of patients with stable CAD, we performed blinded, detailed chart abstraction, and measured urinary 11-dehydro-thromboxane B2 (11dhTxB2), an inactive metabolite of TxA2 from frozen samples. There were 327 men (73%) and 122 women (27%) with a mean age (±SD) of 67 ± 10 and 65 ± 10 years, respectively. A positive linear trend for age was observed among tertiles of 11dhTxB2 (p trend = 0.01). Higher proportions of women (p = 0.001), chronic obstructive pulmonary disease (p trend = 0.0003), and heart failure (p trend = 0.003) were observed in the upper tertile of 11dhTxB2. Sixty-seven patients (14.9%) died over a median follow-up of 1,149 days and 87.5% of the deaths were due to cardiovascular causes. Twenty-six nonsurvivors (38.8%) were treated with P2Y12 receptor antagonists versus 161 survivors (42.2%; p = 0.61). By stepwise Cox proportional hazards analysis, we identified that patients in the middle (hazard ratio 7.14; 95% CI 2.46 to 20.68) and upper tertiles (hazard ratio 9.91; 95% CI 3.45 to 28.50) had higher risks for mortality after adjusting for age and co-morbidities. In conclusion, urinary concentration of 11dhTxB2 was a strong independent risk factor for all-cause mortality among patients with stable CAD on aspirin therapy and may be a marker for patients with CAD who require more intensive secondary prevention measures.

Residual thromboxane activity and oxidative stress: influence on mortality in patients with stable coronary artery disease.

BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2α (8-IsoPGF2α)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2α in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2α. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2α were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2α below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2αadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2αadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2α, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin.

A prospective 10-year study of individualized, intensified enzyme replacement therapy in advanced Fabry disease.

OBJECTIVES: To test the hypothesis that more frequent enzyme replacement therapy (ERT) slows the decline in kidney function in adult patients with Fabry disease. METHODS: A single center open label 10-year prospective clinical trial of 12 patients with advanced Fabry disease who, after having experienced an ongoing decline in renal function after 2-4 years of receiving ERT at the approved dose of 0.2 mg/kg agalsidase alfa every other week (EOW), were switched to weekly (EW) ERT at the same dose. We used linear regression to fit each individual patient's longitudinal estimated glomerular filtration rate (eGFR) record in order to compare the deterioration rates between EOW and EW ERT. RESULTS: For the entire group, mean slope on agalsidase alfa every 2 weeks was -7.92 ± 2.88 ml/min/1.73 m(2)/year and 3.84 ± 4.08 ml/min/1.73 m(2)/year on weekly enzyme infusions (p = 0.01, two-tailed paired t test). Three patients (25 %) completed the entire study with relatively preserved renal function while 50 % of patients reached end-stage renal disease (ESRD) during the 10 years of this study. The estimated average delay to ESRD was 13.8 years [n = 11; 95 % CI 0.66, 27]. One patient had a positive eGFR slope on weekly infusions while the patient with the highest antibody titer had a steeper slope after switching. Mean globotriaosylceramide concentrations in urine and plasma as well as urine protein excretion remained unchanged. CONCLUSIONS: Weekly enzyme infusions slow the decline of renal function in a subgroup of more severe patients thus showing that existing ERT can be further optimized.

Risk of death in heart disease is associated with elevated urinary globotriaosylceramide.

BACKGROUND: Elevated urinary globotriaosylceramide (Gb3) has been considered a hallmark of Fabry disease, an X-linked lysosomal disorder that is a risk factor for most types of heart disease. METHODS AND RESULTS: We screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb3 in whole urine using tandem mass spectrometry, α-galactosidase A activity in dried blood spots, and we looked for GLA mutations by parallel sequencing of the whole gene (exons and introns) in pooled genomic DNA samples followed by Sanger sequencing verification. GLA variants were found in 13 patients. In the 1408 patients without GLA mutations, urinary Gb3 levels were significantly higher in heart disease patients compared to 116 apparently healthy controls (median difference=10.0 ng/mL and P<0.001). Urinary lipid profiling showed that levels of 5 other lipids significantly distinguished between urine of patients with Fabry disease (n=7) and heart disease patients with elevated urinary Gb3 (n=6). Sphingomyelin and Gb3 levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb3 were independently associated with increased risk of death in the average follow-up of 17 months (hazard ratio=1.59 for increase in Gb3 of 200, 95% CI=1.36 and 1.87, and P<0.0001). CONCLUSIONS: In heart disease patients who do not have Fabry disease or GLA gene mutations, a higher level of urinary Gb3 is positively associated with near-term mortality. The elevation of urinary Gb3 and that of other lipids suggests that heart disease is associated with multiorgan lipid abnormalities. CLINICAL TRIAL REGISTRATION URL: clinicaltrials.gov. Unique Identifier: NCT01019629.

Quantitative neuroimaging in mucolipidosis type IV.

Mucolipidosis type IV (MLIV) is an autosomal recessive disorder resulting from mutations in the MCOLN1 gene. This gene encodes the endosomal/lysosomal transient receptor potential channel protein mucolipin-1 (TRPML1). Affected patients suffer from neurodevelopmental abnormalities and progressive retinal dystrophy. In a prospective natural history study we hypothesized the presence of an additional slow cerebral neurodegenerative process. We have recruited 5 patients, tested their neurodevelopmental status, and measured cerebral regional volumes and white matter integrity using MRI yearly. Over a period of up to 3 years, MLIV patients remained neurologically stable. There was a trend for increased cortical and subcortical gray matter volumes and increased ventricular size, while white matter and cerebellar volumes decreased. Mean diffusivity (MD) was increased and fractional anisotropy (FA) values were below normal in all analyzed brain regions. There was a positive correlation between motor scores of the Vineland Scale and the FA values in the corticospinal tract (corr coef 0.39), and a negative correlation with the MD values (corr coef -0.50) in the same brain region. We conclude from these initial findings that deficiency in mucolipin-1 affects the entire brain but that there might be a selective regional cerebral neurodegenerative process in MLIV. In addition, these data suggest that diffusion-weighted imaging might be a good biomarker for following patients with MLIV. Therefore, our findings may be helpful for designing future clinical trials.

Implementing a unit-level intervention to reduce the probability of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is the second most common hospital-acquired infection and is associated with high morbidity and mortality rates for mechanically ventilated patients in the intensive care unit. Routine nursing interventions have been shown to reduce VAP rates. OBJECTIVES: The purpose of this study was to evaluate the effectiveness of a unit-specific education intervention that emphasized hand hygiene, head-of-the-bed elevation, and oral care. The goals were to improve staff compliance with hand washing, head-of-the-bed elevation, and oral care; to decrease VAP rates, and to decrease number of ventilator days. METHODS: Two-hour observations were conducted on a convenience sample of 100 ventilated patients not diagnosed with VAP and the clinical staff that interacted with them. Instrumentation included a compliance checklist, a demographic patient survey, and the Acute Physiology and Chronic Health Evaluation AEIV tool. Unit-specific educational interventions were designed and implemented on each participating unit. RESULTS: : The VAP and the ventilator day rates did not improve significantly. There were no significant changes in clinician adherence to hand hygiene, provision of oral care, or patient positioning. DISCUSSION: Despite implementation of both structured and creative education, team-based approach, and frequent staff reminders, patient outcomes and staff compliance did not improve significantly. Unit-based education interventions may not be the best strategy to facilitate change. Organizations with frequent changes in personnel and leadership may not have the unit-level infrastructure necessary to attain and sustain change.

Adoption of a ventilator-associated pneumonia clinical practice guideline.

CONCEPTUAL FRAMEWORK: The Academic Center for Evidence-based Practice (ACE) Star Model was used to implement an evidence-based clinical practice guideline (CPG) in order to decrease ventilator-associated pneumonia (VAP) incidence rates and ventilator days. The goal was to interrupt person-to-person transmission of bacteria and bacterial colonization using low-cost, evidence-based strategies to prevent VAP. DISCOVERY: Two geographically proximate medical centers, inclusive of five intensive care units located in the southwestern region of the United States had significant variations in their VAP rates. EVIDENCE SUMMARY: Using the U.S. Preventive Services Task Force grading criteria, the results of 69 studies were used to establish a clinical practice guideline to prevent ventilator-associated pneumonia. TRANSLATION: A clinical practice guideline was developed for the prevention of VAP and included five nursing activities: (a) head-of-bed elevation; (b) oral care; (c) ventilator tubing condensate removal; (d) hand hygiene; and (e) glove use. The effect of the CPG, inclusive of an educational intervention, was measured using an observational, prospective, quasi-experimental design. INTEGRATION: A multidisciplinary education team developed a self-learning packet, educational materials, and storyboards for the staff as dissemination strategies. Strategies also included e-mail, one-on-one teaching with clinicians, and feedback on guideline adoption and VAP rate reports. EVALUATION: Observation data were collected to evaluate adoption of the CPG while caring for 106 ventilated patients. VAP rates changed at both hospitals although the change was not statistically significant. Additionally, the ICU length of stay declined at both facilities, causing cost savings. DISCUSSION: These results support the idea that adoption of evidence-based practices contributes to decreased VAP rates. For a successful program, ICU leaders should emphasize strategies that routinize adoption of evidence-based CPGs.