Acute Effects of Implantable Cardioverter-Defibrillator Shocks on Biomarkers of Myocardial Injury, Apoptosis, Heart Failure, and Systemic Inflammation.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) shocks are potentially associated with myocardial injury, altered hemodynamics, apoptosis, and inflammatory signaling. Their precise cellular impact can be explored after defibrillation testing (DFT) via biomarkers. We evaluated changes in biomarkers after ICD shocks during DFT. METHODS: We prospectively enrolled outpatients presenting for first implantation of a cardiac device. Biomarkers indicative of myocardial injury, inflammation, and apoptosis were measured before and after implantation, and compared between patients receiving DFT (DFT+) to those not (DFT-). RESULTS: Sixty-three patients were enrolled, 40 in the DFT+ group and 23 in the DFT- group. Average levels of troponin I, hsCRP, Calprotectin, N-terminal pro B-type natriuretic peptide (NTproBNP), and sFas increased by >50% after cardiac device implantation compared to baseline. Increase in troponin never exceeded the 50-fold upper limit of normal (2 ng/mL). Troponin trended higher in the DFT+ group at 8 hours (median 0.18 ng/mL, interquartile range [IQR] 0.11-0.48) versus the DFT- group (0.10 ng/mL, IQR 0.06-0.28, P = 0.0501); NTproBNP had a similar trend (P = 0.0581). sFas significantly increased in the DFT+ group from baseline (median 4663 pg/mL, IQR 2908-5679) to 24 hours (5039 pg/mL, IQR 3274-6261; P = 0.0338) but not in the DFT- group (P = 0.4705). CONCLUSION: DFT testing is associated with acutely increased plasma levels of troponin and sFas, a biomarker of apoptosis, along with a trend toward higher NTproBNP.

Diurnal variability in orthostatic tachycardia: implications for the postural tachycardia syndrome.

Patients with POTS (postural tachycardia syndrome) have excessive orthostatic tachycardia (>30 beats/min) when standing from a supine position. HR (heart rate) and BP (blood pressure) are known to exhibit diurnal variability, but the role of diurnal variability in orthostatic changes of HR and BP is not known. In the present study, we tested the hypothesis that there is diurnal variation of orthostatic HR and BP in patients with POTS and healthy controls. Patients with POTS (n=54) and healthy volunteers (n=26) were admitted to the Clinical Research Center. Supine and standing (5 min) HR and BP were obtained in the evening on the day of admission and in the following morning. Overall, standing HR was significantly higher in the morning (102±3 beats/min) than in the evening (93±2 beats/min; P<0.001). Standing HR was higher in the morning in both POTS patients (108±4 beats/min in the morning compared with 100±3 beats/min in the evening; P=0.012) and controls (89±3 beats/min in the morning compared with 80±2 beats/min in the evening; P=0.005) when analysed separately. There was no diurnal variability in orthostatic BP in POTS. A greater number of subjects met the POTS HR criterion in the morning compared with the evening (P=0.008). There was significant diurnal variability in orthostatic tachycardia, with a great orthostatic tachycardia in the morning compared with the evening in both patients with POTS and healthy subjects. Given the importance of orthostatic tachycardia in diagnosing POTS, this diurnal variability should be considered in the clinic as it may affect the diagnosis of POTS.

Increased 12/15-lipoxygenase enhances cell growth, fibronectin deposition, and neointimal formation in response to carotid injury.

OBJECTIVE: To determine whether increased 12/15-lipoxygenase (12/15LO) expression in vivo enhances neointimal formation in response to injury. METHODS AND RESULTS: 12/15LO expression in the vessel wall is increased in animal models of metabolic syndrome and diabetes mellitus. Increased expression of 12/15LO enhances cultured vascular smooth muscle cell (VSMC) proliferation, an effect mediated by the helix-loop-helix factor inhibitor of differentiation 3 (Id3). Carotid endothelial denudation was performed on apolipoprotein (Apo) E(-/-), ApoE(-/-)/12/15LO(-/-), C57BL/6, and 12/15LO-overexpressing transgenic mice. ApoE(-/-)/12/15LO(-/-) mice had attenuated and 12/15LO-overexpressing transgenic mice had enhanced neointimal formation compared with control mice. 12/15LO-overexpressing transgenic mice had greater postinjury carotid Id3 and Ki-67 expression, cell number, and fibronectin deposition compared with C57BL/6 mice. Loss of 12/15LO attenuated proliferation of cultured ApoE(-/-) VSMCs, whereas 12/15LO overexpression induced VSMC proliferation. Loss of Id3 enhanced immunoglobulin trascription factor (ITF)-2b binding to and activation of the p21(cip1) promoter and abrogated 12/15LO-induced VSMC proliferation. CONCLUSIONS: To our knowledge, these data are the first demonstration that increased expression of 12/15LO in the vessel wall enhances Id3-dependent cell proliferation, fibronectin deposition, and neointimal formation in response to injury. Results identify p21(cip1) as a potential target of the 12/15LO-Id3 pathway and suggest that modulation of this pathway may have therapeutic implications for targeting the increased risk of restenosis in patients with diabetes.

The psychometric validation of the OAB family impact measure (OAB-FIM).

AIMS: Although overactive bladder (OAB) impacts patient health-related quality of life, the impact of OAB on family members is not known. Presently, no validated instruments exist to assess family impact, thus we examined the psychometric properties of a new instrument, the overactive bladder family impact measure (OAB-FIM). METHODS: Dyads of OAB patient-family members and control patient-family members were recruited from clinics. Family members (spouses, significant others, or daughters) completed the 32-item draft OAB-FIM. Patients completed the overactive bladder questionnaire (OAB-q) and the patient perception of bladder condition (PPBC). Both patients and family members completed two validated relationship measures. Item and exploratory factor analyses were performed to determine subscale structure; reliability and validity were assessed. RESULTS: One hundred ninety-three patient-family member dyads (163 OAB, 30 control) participated. OAB patients were mostly women (82%); the control group was younger with fewer women (53%). Family members were predominantly men (OAB, 58%; control, 52%), and control family members were younger than OAB family members. Thirteen items were deleted from the draft OAB-FIM based on item performance and factor structure based on exploratory factor analyses, leaving 19-items in the final OAB-FIM. Four subscales (Irritation, Activities, Travel, Concern) were derived for use among all family members; two additional subscales (Sleep, Sex) were derived for use with spouses/significant others. The OAB-FIM discriminated between OAB and control family members with OAB family members demonstrating significant impact (all P < 0.0001). Internal consistency reliability (Cronbach's alpha >0.70) and 2-week test-retest reliability (intraclass correlation coefficients >0.73) were high for all subscales. Concurrent validity of the OAB-FIM was demonstrated through statistically significant (P < 0.001) Spearman correlations with the OAB-q (0.35-0.58) and the PPBC (0.31-0.56). The OAB-FIM also demonstrated known-groups validity, distinguishing between family members of OAB patients and family members of control patients. CONCLUSIONS: This study supports the reliability and validity of a new measure to assess the impact of OAB on family members and demonstrates that family members are affected by another's medical condition.

"We have to stop again?!": The impact of overactive bladder on family members.

AIMS: Overactive bladder (OAB), characterized by urinary urgency, with or without incontinence, and urinary frequency and nocturia, has a significant impact on patients' lives. Given the social context inherent in OAB, the purpose of this study was to identify issues faced by OAB family members. METHODS: Incontinent OAB patients and their family members were recruited from a urology clinic. Continent OAB family members were recruited via newspaper advertisements. Focus groups were conducted to evaluate family impact; content analysis was used to analyze data. RESULTS: Participants included 14 dyads consisting of incontinent OAB patients and their family members (partners or daughters) and 17 continent OAB family members. Urinary frequency was the most bothersome symptom for family members as family members reported that their partners' urinary frequency significantly altered their lives by limiting activities (e.g., travel, social activities) and impacting time because of persistent, and urgent, need to find a toilet. Nocturia caused sleep disruption and fatigue for both patients and their partners. Family members indicated that their partner's OAB fostered significant emotions including embarrassment, anxiety, anger, worry, frustration, and sympathy. Several spouses reported that OAB limited their sexual interactions and intimacy. CONCLUSIONS: OAB has a significant impact on OAB patients' family members, regardless of whether the patient and family member live together. Consequently, it is important to assess the family impact of symptomatic conditions such as OAB to fully understand the outcomes of disease and treatment.

Regulation of secretory protein expression in mature cells by DIMM, a basic helix-loop-helix neuroendocrine differentiation factor.

During differentiation, neuroendocrine cells acquire highly amplified capacities to synthesize neuropeptides to overcome dilution of these signals in the general circulation. Once mature, the normal functioning of integrated physiological systems requires that neuroendocrine cells remain plastic to dramatically alter neuropeptide expression for long periods in response to hormonal and electrical cues. The mechanisms underlying the long-term regulation of neuroendocrine systems are poorly understood. Here we show that the Drosophila basic helix-loop-helix protein DIMM, a critical regulator of neuroendocrine cell differentiation, controls secretory capacity in mature neurons. DIMM expression began embryonically but persisted in adults. Through spatial and temporal manipulation of transgene expression in vivo, we defined two phases of prosecretory DIMM activity. During an embryonic critical window, DIMM controlled the differentiation of amplified expression of the neuropeptide leucokinin. At the onset of metamorphosis, levels of DIMM decreased in the insulin-producing cells (IPCs) in parallel with a marked reduction in levels of Drosophila insulin-like peptide 2 and a key neuropeptide biosynthetic enzyme peptidylglycine alpha-monooxygenase (PHM). Overexpression of DIMM in the IPCs prevented the decrease in PHM levels at this stage. In addition, transient overexpression of DIMM in adults produced a dramatic increase in PHM levels in numerous neurons located throughout the brain. These findings provide insights into the mechanisms controlling the maintenance of differentiated cell states, and they suggest an effective means for dynamically adjusting the strength of hormonal signals in diverse homeostatic systems.

Clinical Benefit of Ablating Localized Sources for Human Atrial Fibrillation: The Indiana University FIRM Registry.

BACKGROUND: Mounting evidence shows that localized sources maintain atrial fibrillation (AF). However, it is unclear in unselected "real-world" patients if sources drive persistent atrial fibrillation (PeAF), long-standing persistent atrial fibrillation (LPeAF), or paroxysmal atrial fibrillation (PAF); if right atrial sites are important; and what the long-term success of source ablation is. OBJECTIVES: The aim of this study was to analyze the role of rotors and focal sources in a large academic registry of consecutive patients undergoing source mapping for AF. METHODS: One hundred seventy consecutive patients (mean age 59 ± 12 years, 79% men) with PAF (37%), PeAF (31%), or LPeAF (32%). Of these, 73 (43%) had undergone at least 1 prior ablation attempt (mean 1.9 ± 0.8; range: 1 to 4). Focal impulse and rotor modulation (FIRM) with an endocardial basket catheter was used in all cases. RESULTS: FIRM analysis revealed sources in the right atrium in 85% of patients (1.8 ± 1.3) and in the left atrium in 90% of patients (2.0 ± 1.3). FIRM ablation terminated AF to sinus rhythm or atrial flutter or tachycardia in 59% (PAF), 37% (PeAF), and 19% (LPeAF) of patients, with 15 of 67 terminations due to right atrial ablation. On follow-up, freedom from AF after a single FIRM procedure for the entire series was 95% (PAF), 83% (PeAF), and 82% (LPeAF) at 1 year and freedom from all atrial arrhythmias was 77% (PAF), 75% (PeAF), and 57% (LPeAF). CONCLUSIONS: In the Indiana University FIRM registry, FIRM-guided ablation produced high single-procedure success, mostly in patients with nonparoxysmal AF. Data from mapping, acute terminations, and outcomes strongly support the mechanistic role of biatrial rotors and focal sources in maintaining AF in diverse populations. Randomized trials of FIRM-guided ablation and mechanistic studies to determine how rotors form, progress, and regress are needed.

Measuring changes in functional status among patients with schizophrenia: the link with cognitive impairment.

Cognitive impairment associated with schizophrenia (CIAS) includes neuropsychological deficits in attention, working memory, verbal learning, and problem solving. These deficits have been shown to be linked to impairment in functional status (eg, social behavior, work performance, and activities of daily living) among patients with schizophrenia in cross-sectional studies. Less is known about the relationship between cognitive and functional change over time, such as potential functional implications of treatment-related improvement in CIAS. The purpose of this review is to summarize research on the association between change in CIAS and change in functional status, to discuss responsiveness of functional outcomes measures, and to provide recommendations for future research and measure development. Nine longitudinal studies were located on the link between CIAS and functional status, and 8 functional outcomes measures were used across these studies. The 9 studies offer initial support for a link between change in cognitive function and change in functional status. However, inconsistent findings across studies indicate that available research is preliminary, and substantial questions remain unanswered. Shortcomings of functional status measures are noted: most instruments were not developed for the target population, and none have demonstrated responsiveness to cognitive change among schizophrenic patients. It is recommended that new functional outcome measures be developed that are specifically designed to be responsive to change in cognition, with domains previously shown to be related to cognitive ability. When creating new functional outcomes measures for assessment of patients with schizophrenia, responsiveness to change in CIAS should be evaluated as part of the development and validation process.

Willingness to pay for sensory attributes of intranasal corticosteroids among patients with allergic rhinitis.

OBJECTIVE: Sensory attributes of intranasal corticosteroids (INSs) differ by product based on chemical composition. We previously reported that patients are able to demonstrate preferences for certain INS sensory attributes, which may affect their willingness to adhere to therapy. As part of the same study, we also sought to determine if these same patients are willing to pay for products not containing certain sensory attributes. METHODS: We conducted a 2-part cross-sectional study of 120 patients with allergic rhinitis at 4 allergy and immunology clinics in the United States in November and December 2003. In the first part of the study, the patients chose between pairs of hypothetical INS products that differed in the intensity of 6 sensory attributes (smell, taste, aftertaste, throat rundown, nose runout, and feel of spray in nose/throat; results were reported in the Annals of Allergy, Asthma & Immunology [2004;93:345-50]). In the second part of the study, reported here, discrete choice experiment methodology was used in which the patients chose among hypothetical INS products that differed in the intensity of the 6 sensory attributes and monthly copayments of dollar 15, dollar 30, and dollar 50. Each sensory attribute was characterized by 3 intensity levels, e.g., no aftertaste (mild intensity), weak aftertaste (moderate intensity), or strong aftertaste (severe intensity). The strength of preferences, shown as marginal willingness to pay to avoid certain sensory attributes, was measured in U.S. dollars per month. We also evaluated the effect of annual household income on willingness to pay. RESULTS: Demographic results indicated that 86.7% of participants had prior experience with at least 2 INS products. Seven patients (5.8%) were excluded from the willingness-to-pay analysis due to inconsistent responses to the logic checks used to confirm patient engagement in the study instrument. On average, the 113 remaining patients were willing to pay $11 (95% confidence interval [CI], dollar 9-dollar 13) per month in 2003 dollars to get an INS with no smell instead of strong smell, dollar 12 (95% CI, dollar 10-dollar 14) for no taste instead of strong taste, dollar 20 (95% CI, dollar 18-dollar 22) for no aftertaste instead of strong aftertaste, dollar 10 (95% CI, dollar 9-dollar 12) for no throat rundown instead of a lot of throat rundown, dollar 11 (95% CI, dollar 9-dollar 13) for no nose runout instead of a lot of nose runout, and dollar 6 (95% CI, dolalr 4-dollar 8) for a spray with a wet feel instead of a dry feel. Comparing moderate intensity levels of each sensory attribute with the mildest, only 3 attributes had statistically significant willingness to pay: aftertaste, throat rundown, and nose runout. Patients with a higher income were willing to pay more to avoid a lot of throat rundown and nose runout than those with a low income (P <0.01), but this relationship did not hold for the other sensory attributes. CONCLUSION: Patients demonstrated significant willingness to pay to avoid certain sensory attributes of INSs. Sensory attributes of INS products appear to be potentially important considerations when evaluating alternative INS products for drug therapy selection or formulary placement.

Relation of the severity of obstructive sleep apnea in response to anti-arrhythmic drugs in patients with atrial fibrillation or atrial flutter.

Atrial fibrillation (AF) is more common in those with obstructive sleep apnea (OSA) than in unaffected subjects and recurs more frequently in the presence of severe OSA after electrical cardioversion and AF ablation. However, it is unknown whether the severity of OSA influences the efficacy of antiarrhythmic drug (AAD) therapy in patients with OSA and AF. The aim of this study was to examine the impact of OSA severity on the treatment of patients with symptomatic AF using AADs. Sixty-one patients (mean age 62 ± 15 years, 21 women) treated with AADs for symptomatic AF who underwent overnight polysomnography were studied. Rhythm control was prospectively defined as successful if a patient remained on the same AAD therapy for ≥6 months with ≥75% reduction in symptomatic AF burden. Twenty-four patients (40%) had severe OSA. Thirty patients (49%) were rhythm controlled with AADs. Nonresponders to AADs were more likely to have severe OSA than milder disease (52% vs 23%, p <0.05); those with severe OSA were less likely to respond to AADs than participants with nonsevere OSA (39% vs 70%, p = 0.02). Nonresponders had higher apnea-hypopnea indexes than responders (34 ± 25 vs 22 ± 18 events/hour, p = 0.05), but there were no differences between these groups in minimum oxygen saturation or percentage of time spent in rapid eye movement sleep. In conclusion, patients with severe OSA are less likely to respond to AAD therapy for AF than those with milder forms of OSA.

Evaluating the impact of overactive bladder on sexual health in women: what is relevant?

INTRODUCTION: To assess sexual health, relevant, valid, and reliable questionnaires need to be used. AIM: To assess the relevance and content validity of three sexual health questionnaires in women with overactive bladder (OAB) and urinary incontinence. MAIN OUTCOME MEASURES: Sexual Quality of Life Questionnaire--Female (SQoL-F), Sexual Function Questionnaire (SFQ), and Pelvic Organ Prolapse-Incontinence Sexual Function Questionnaire (PISQ). METHODS: Women with OAB and urinary incontinence were recruited from five urology clinics in the United States; those who were interested in participating were mailed questionnaire packets with instructions. Each questionnaire item was followed by three questions regarding the understandability, relevance, and impact of bladder condition when responding to the question. Patients returned the completed questionnaires by mail; clinical information was obtained from chart review. RESULTS: A total of 129 patients (74% response) returned the questionnaires. The mean age was 56 years; 78% were white; 64% were married. In this sample, 64% had urge incontinence; 32% had mixed incontinence; and 4% had stress incontinence. Participants experienced bladder symptoms for a mean of 12.2 years with the following treatments: surgery (43%), bladder training (26%), exercise/biofeedback (42%), and medications (67%). SQoL-F items were understood by more than 97% of the respondents, more than 89% for SFQ, and more than 82% for PISQ. There were two SQoL-F items, one SFQ item, and 11 PISQ items that less than 60% of the respondents deemed relevant to their bladder condition. Correlations among questionnaire items and relevance to bladder condition ranged from 0.04 to 0.64 for the SQoL-F, 0.04 to 0.47 for the SFQ, and 0.01 to 0.58 for the PISQ. CONCLUSION: Women with OAB found the majority of items on all three questionnaires to be relevant to their bladder condition. Of these questionnaires, the SQoL-F had the highest understandability, fewest questions considered irrelevant, and correlated well with OAB symptoms.

Utilities and disutilities for type 2 diabetes treatment-related attributes.

INTRODUCTION: Although cost-utility analyses are frequently used to estimate treatment outcomes for type 2 diabetes, utilities are not available for key medication-related attributes. The purpose of this study was to identify the utility or disutility of diabetes medication-related attributes (weight change, gastrointestinal side effects, fear of hypoglycemia) that may influence patient preference. METHODS: Patients with type 2 diabetes in Scotland and England completed standard gamble (SG) interviews to assess utility of hypothetical health states and their own current health state. The EQ-5D, PGWB, and Appraisal of Diabetes Symptoms were administered. Construct validity and differences among health states were examined with correlations, t-tests, and ANOVAs. RESULTS: A total of 129 patients (51 Scotland; 78 England) completed interviews. Mean utility of diabetes without complications was 0.89. Greater body weight was associated with disutility, and lower body weight with added utility (e.g., 3% higher = -0.04; 3% lower = +0.02). Gastrointestinal side effects and fear of hypoglycemia were associated with significant disutility (p < 0.001). SG utility of current health (mean = 0.87) demonstrated construct validity through correlations with patient-reported outcome measures (r = 0.08-0.31). DISCUSSION: The vignette-based approach was feasible and useful for assessing added utility or disutility of medication-related attributes.

Test-retest reliability of four questionnaires for patients with overactive bladder: the overactive bladder questionnaire (OAB-q), patient perception of bladder condition (PPBC), urgency questionnaire (UQ), and the primary OAB symptom questionnaire (POSQ).

AIMS: This study examined test-retest reliability of four patient-reported outcome measures for patients with overactive bladder (OAB): Overactive Bladder Questionnaire (OAB-q), Patient Perception of Bladder Condition (PPBC), Urgency Questionnaire (UQ), and Primary OAB Symptom Questionnaire (POSQ). METHODS: Patients recruited from urology clinics were scheduled for two visits 2 weeks apart and completed all questionnaires at both visits. A demographic form was completed at Visit 1; and a treatment effect scale was completed at Visit 2. Test-retest reliability was examined among stable patients using intraclass correlations (ICC), Spearman's correlations, paired t-tests, Feldt's statistic, and kappas. RESULTS: A total of 47 patients enrolled (mean age = 66.0 years, 74.5% female), with 46 completing both visits; 35 were classified stable. Statistically significant correlations were present between Visits 1 and 2 (P < 0.05) for all subscales of the OAB-q, UQ, and POSQ. Subscale ICCs were moderate to high (OAB-q > or = 0.83, UQ > or = 0.46, POSQ continuous items > or = 0.68). No significant differences between Visit 1 and 2 were noted, except for the OAB-q symptom bother scale (change of 5.8 points on a 100-point scale). The multi-item subscales of the OAB-q and the UQ demonstrated good internal consistency (Cronbach's alpha > or = 0.83 for all subscales) across both visits. Test-retest reliability of the PPBC was somewhat weaker than the other three measures, but still acceptable for use as a global, single-item outcome measure. CONCLUSIONS: The OAB-q, POSQ, and UQ demonstrated good test-retest reliability, with ICCs roughly equivalent or superior to those previously reported for 7-day micturition diaries. Findings suggest that the four measures examined in this study demonstrate the necessary reproducibility for use as outcome measures for OAB treatments.