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Aims: We assessed for an association between improvements in left ventricular ejection fraction (LVEF) and future outcomes, including health status, in routine clinical practice. Methods and results: CHAMP‐HF was a registry of outpatients with heart failure (HF) and LVEF ≤40%. Enrolled participants completed the Kansas City Cardiomyopathy Questionnaire‐12 (KCCQ‐12) at regular intervals and were followed as part of routine care. We assessed for associations between improvements in LVEF (≥10%) over time and concurrent changes in KCCQ‐12, as well as the subsequent risk of poor outcomes. We included 2092 participants in the study. They had the following characteristics: median age 67 years (25th–75th percentile 58–75), 29% female, median duration of HF 2.7 years (0.6–6.8), and median baseline LVEF 30% (23–35). Of the study participants, 689 (33%) had a ≥10% absolute improvement in LVEF. Participants with an LVEF improvement also had an improvement in KCCQ‐12 overall summary score compared with participants without an LVEF improvement (+7.6 vs. +3.5, adjusted effect estimate +4.01 [95% confidence interval CI 2.3–5.7]). Similarly, subsequent all‐cause death or HF hospitalization occurred in 12% in the LVEF improvement group versus 25% in the group without an LVEF improvement (adjusted hazard ratio 0.50, 95% confidence interval 0.41–0.61). Conclusion: In a large cohort of outpatients with chronic HF, improvements in LVEF were associated with improved health status and a reduced risk for future clinical events. These data underscore the importance of improvement in LVEF as a treatment target for medical interventions for patients with chronic HF. [ABSTRACT FROM AUTHOR]

Aims: The aim of our study was to investigate heterogeneity of health status treatment response of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF). Methods and results: We leveraged data from CHAMP‐HF, an observational registry of 140 US clinics and 5026 outpatients with chronic HFrEF, where health status was serially assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ)‐12 Overall Summary Scale (range from 0 to 100; ≥20‐point improvement is a very large improvement). In 334 patients newly initiated on sacubitril/valsartan, we used hierarchical multivariable logistic regression (13 patient‐level characteristics as well as baseline KCCQ‐12 score) to calculate the odds ratio (OR) of any characteristic being associated with a very large health status improvement. A total of 104/334 (31.1%) of patients achieved the primary endpoint, where only worse baseline health status [KCCQ‐12 score of 0–60 points had an OR = 0.86/5‐point higher score (CI 0.79, 0.93)], and those with a KCCQ‐12 score of 60–80 points had an OR = 0.61/5‐point higher score (0.45–0.82), which was associated with a very large benefit. No other patient characteristic was associated with a very large health status improvement (P > 0.05). Conclusions: We found that, after initiation of sacubitril/valsartan, only worse baseline health status was associated with very large health status improvement. Accordingly, a trial of therapy—particularly in those with worse symptoms, function, and quality of life—and assessing treatment response are likely to be the best prospective strategy. [ABSTRACT FROM AUTHOR]

Background: Leadless pacemakers (LPs) provide ventricular pacing without the risks associated with transvenous leads and device pockets. LPs are appealing for patients who need pacing, but do not need defibrillator or cardiac resynchronization therapy. Most implanted LPs provide right ventricular pacing without atrioventricular synchrony (VVIR mode). The Mode Selection Trial in Sinus Node Dysfunction (MOST) showed similar outcomes in patients randomized to dual‐chamber (DDDR) versus ventricular pacing (VVIR). We compared outcomes by pacing mode in LP‐eligible patients from MOST. Methods: Patients enrolled in the MOST study with an left ventricular ejection fraction (LVEF) >35%, QRS duration (QRSd) <120 ms and no history of ventricular arrhythmias or prior implantable cardioverter defibrillators were included (LP‐eligible population). Cox proportional hazards models were used to test the association between pacing mode and death, stroke or heart failure (HF) hospitalization and atrial fibrillation (AF). Results: Of the 2010 patients enrolled in MOST, 1284 patients (64%) met inclusion criteria. Baseline characteristics were well balanced across included patients randomized to DDDR (N = 630) and VVIR (N = 654). Over 4 years of follow‐up, there was no association between pacing mode and death, stroke or HF hospitalization (VVIR HR 1.28 [0.92‐1.75]). VVIR pacing was associated with higher risk of AF (HR 1.32 [1.08‐1.61], P =.007), particularly in patients with no history of AF (HR 2.38 [1.52‐3.85], P <.001). Conclusion: In patients without reduced LVEF or prolonged QRSd who would be eligible for LP, DDDR, and VVIR pacing demonstrated similar rates of death, stroke or HF hospitalization; however, VVIR pacing significantly increased the risk of AF development. [ABSTRACT FROM AUTHOR]

Objective: To compare predictive analytic approaches to characterize medication nonadherence and determine under which circumstances each method may be best applied.Data Sources/study Setting: Medicare Parts A, B, and D claims from 2007 to 2013.Study Design: We evaluated three statistical techniques to predict statin adherence (proportion of days covered [PDC ≥ 80 percent]) in the year following discharge: standard logistic regression with backward selection of covariates, least absolute shrinkage and selection operator (LASSO), and random forest. We used the C-index to assess model discrimination and decile plots comparing predicted values to observed event rates to evaluate model performance.Data Extraction: We identified 11 969 beneficiaries with an acute myocardial infarction (MI)-related admission from 2007 to 2012, who filled a statin prescription at, or shortly after, discharge.Principal Findings: In all models, prior statin use was the most important predictor of future adherence (OR = 3.65, 95% CI: 3.34-3.98; OR = 3.55). Although the LASSO regression model selected nearly 90 percent of all candidate predictors, all three analytic approaches had moderate discrimination (C-index ranging from 0.664 to 0.673).Conclusions: Although none of the models emerged as clearly superior, predictive analytics could proactively determine which patients are at risk of nonadherence, thus allowing for timely engagement in adherence-improving interventions. [ABSTRACT FROM AUTHOR]

Background: Patients with a pacing indication and first-degree atrioventricular (AV)-block pose a clinical challenge. The prognostic impact of first-degree AV-block in patients with sinus node dysfunction and the impact of pacing in this setting are not known. Methods: In the Mode Selection Trial (MOST), 2,010 patients with sinus node dysfunction were randomized to either dual-chamber (DDD-R) or ventricular (VVI-R) pacing and followed for a median of 33 months. We report on clinical outcomes in patients with first-degree AV-block (PR interval > 200 ms) compared with patients who had a normal PR interval at baseline. Results: Patients with first-degree AV-block (n = 378) were older (median [Ql, Q3]; 76 [70, 82] years vs 73 [66, 79]years, P< 0.0001), more often male (57% vs 49%, P= 0.0049), andhadmore comorbidity, such as hypertension (66% vs 60%, P= 0.034) and heart failure (24% vs 17%, P= 0.0050) than patients with normal AV-conduction (n = 1,159). In multivariable analyses, patients with first-degree AV-block were at greater risk of death, stroke, or heart failure hospitalization (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.06-1.61, P = 0.013). A trend towards a higher incidence of atrial fibrillation was seen (HR 1.24, 95% CI 0.98-1.55, P= 0.069). No significant interactions between pacing arm and prolonged versus normal PR were found for any endpoint, and hazard ratios were consistent across subgroups. Conclusions: First-degree AV-block is associated with more advanced disease but is still an independent predictor of poor clinical outcome. Neither DDD-R nor VVI-R pacing, as employed in MOST, eliminate the negative effects associated with first-degree AV-block. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to describe the incidence and predictors of sudden cardiac death (SCD) and heart failure (HF) death, and coexisting indications for ICDs and CRT, in patients with sinus node disease (SND) treated with pacemakers. Methods and Results: Baseline variables were used to predict SCD and HF death among 1,135 patients in the Mode Selection Trial, a 6-year trial of pacing mode in SND. There were 73 deaths among 177 patients with EF ≤ 35% (41.2%), 46/156 (29.5%) with EF 36–49%, and 147/802(18.3%) with EF ≥ 50%. SCD accounted for 21.9%, 23.9%, and 14.3% of deaths with EF ≤ 35%, 36–49%, and ≥ 50%. HF deaths accounted for 23.3%, 19.6%, and 3.4% of deaths with EF ≤ 35%, 36-49%, and ≥ 50%. EF ≤ 35% predicted SCD (hazard ratio [HR] 3.68, 95% confidence interval [CI] 1.72-7.89, P = 0.002) and HF death (HR 10.17, 95% CI 3.35, 30.82, P = 0.001). Four-year SCD rate with EF ≤ 35% was 15.5% (3.9% annually). Nearly one-fifth of patients qualified for ICDs (EF ≤ 35%) and half of these had QRS ≥ 120 ms. However, >40% died within 33 months (4-year noncardiac death rate ∼22%). Conclusions: Reduced EF predicts SCD and HF death in SND treated with pacemakers. SCD rates among patients with EF ≤ 35% are similar to control arms of primary prevention ICD trials, but mortality rates are significantly higher. Whether ICDs or CRT to provide bradycardia support would prolong life in elderly patients with EF ≤ 35% and SND merits prospective investigation. [ABSTRACT FROM AUTHOR]

ICD Therapy and Prior Coronary Revascularization. Introduction:We conducted this study to examine the effect of the ICD on the outcomes of patients with prior coronary revascularization enrolled in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and to assess the association of time from coronary revascularization to enrollment with death and sudden cardiac death (SCD).Methods and Results:We included in this analysis patients with ischemic heart disease not randomized to the amiodarone arm. Cox proportional hazards models were used to examine the association of priorCABG and of prior PCI with each outcome. Interactions between randomized treatment and each revascularization type and time were tested in each model. Of the 882 patients who met these inclusion criteria, 255 (29%) had no prior revascularization, 178 (20%) had prior PCI only, 284 (32%) had prior CABG only, and 165 (19%)had prior PCI and CABG. There was no significant difference in ICD benefit across the revascularization subgroups (all P>0.1). There was a trend toward improved survival with an ICD in patients who had their CABG>2 years before randomization (HR [CI]=0.71 [0.49, 1.04]) that was not observed in patients who had their CABG > 2 years before randomization (HR [CI] = 1.40 [0.61, 3.24]).Conclusion: In SCD-HeFT, there was no significant difference in ICD benefit across the revascularization subgroups. Patients who had their CABG>2 years before randomization showed a trend toward improved survival with an ICD that was not observed in patients who had their CABG < or equal to 2 years before randomization. [ABSTRACT FROM AUTHOR]

Introduction: The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter defibrillator (ICD) therapy reduced overall mortality in patients with class II or III heart failure and left ventricular ejection fraction (LVEF) ≤ 35%, while amiodarone had no effect on survival. There are limited data regarding the influence of gender on outcome of patients receiving ICDs for primary prevention. Methods: We examined gender differences in response to treatment and outcome in this cohort. Results: Women comprised 23% of the SCD-HeFT cohort, with similar percentages in the amiodarone, ICD, and placebo groups. Compared with men, women were more likely to be non-Caucasian, to have class III heart failure, and nonischemic heart disease. After adjustment for baseline differences, overall mortality risk was lower in women than in men. The gender difference in overall mortality was seen in the placebo group, while no gender difference in overall mortality was seen in the ICD group. There was a significantly lower absolute risk of death in the placebo arm women, compared with the placebo arm men (annual mortality rate approximately 4% vs. 6%). Conclusions: The impact of ICD therapy appears to differ between men and women in this trial, with a smaller ICD benefit among women. However, the test for an interaction between gender and therapy was not significant. The lower overall mortality risk in women in the placebo group and the smaller number of women enrolled may help to explain why treatment differences in women were much smaller and difficult to detect. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Permanent pacemakers are capable of increasing heart rate in response to physical activity by a variety of sensors including accelerometers, piezoelectric crystals, or blended sensors. The impact of these different physiologic sensors on cardiovascular events and quality of life is not known. METHODS: Of 2,010 patients randomized in the Mode Selection Trial, 1,245 patients were selected with the most commonly used pacemakers with these three sensors. Clinical characteristics and quality of life were compared between groups at baseline, 3 months, and then yearly. RESULTS: There were 449 patients with an accelerometer sensor device, 682 with a piezoelectric sensor, and 114 with a blended sensor. The groups were similar in terms of age (mean 74 years), gender, and cardiac risk factors but differences existed in weight, heart rate, mitral regurgitation, revascularization history, and drug therapy. The median ventricular pacing frequency was 80% (25th, 75th percentiles 42, 97). After a median follow-up of 33.1 months, the risk of death, heart failure hospitalization, atrial fibrillation, and the combined endpoint of mortality and stroke was not significantly different between the sensor types, after adjustment for baseline differences. Quality of life analyses demonstrated that patients with blended sensors had significantly worse (P < 0.01) physical function than did patients with the other two sensor systems. Moreover, patients receiving blended sensors had the poorest absolute scores, without reaching statistical significance, on 9 of 13 quality of life measures after adjusting for differences in the groups. CONCLUSION: We found no significant differences among the three most utilized sensors in clinical endpoints. Those patients who received blended sensors had worse physical function quality of life scores. However, clinical selection of the most sophisticated sensor for the most ill patients cannot be excluded as an explanation of these results. [ABSTRACT FROM AUTHOR]

SHUKLA, H.H., et al.: Clinical and Quality of Life Comparison of Accelerometer, Piezoelectric Crystal, and Blended Sensors in DDDR-Paced Patients with Sinus Node Dysfunction in the Mode Selection Trial (MOST). Introduction: Permanent pacemakers are capable of increasing heart rate in response to physical activity by a variety of sensors including accelerometers, piezoelectric crystals, or blended sensors. The impact of these different physiologic sensors on cardiovascular events and quality of life is not known. Methods: Of 2,010 patients randomized in the Mode Selection Trial, 1,245 patients were selected with the most commonly used pacemakers with these three sensors. Clinical characteristics and quality of life were compared between groups at baseline, 3 months, and then yearly. Results: There were 449 patients with an accelerometer sensor device, 682 with a piezoelectric sensor, and 114 with a blended sensor. The groups were similar in terms of age (mean 74 years), gender, and cardiac risk factors but differences existed in weight, heart rate, mitral regurgitation, revascularization history, and drug therapy. The median ventricular pacing frequency was 80% (25th, 75th percentiles 42, 97). After a median follow-up of 33.1 months, the risk of death, heart failure hospitalization, atrial fibrillation, and the combined endpoint of mortality and stroke was not significantly different between the sensor types, after adjustment for baseline differences. Quality of life analyses demonstrated that patients with blended sensors had significantly worse (P < 0.01) physical function than did patients with the other two sensor systems. Moreover, patients receiving blended sensors had the poorest absolute scores, without reaching statistical significance, on 9 of 13 quality of life measures after adjusting for differences in the groups. Conclusion: We found no significant differences among the three most utilized sensors in clinical endpoints. Those patients who received blended sensors had worse physical function quality of life scores. However, clinical selection of the most sophisticated sensor for the most ill patients cannot be excluded as an explanation of these results. (PACE 2005; 28:762–770) [ABSTRACT FROM AUTHOR]

Pacemaker Mode Switching in Sinus Node Dysfunction. Introduction: Atrial fibrillation (AF) is common in pacemaker patients with sinus node dysfunction (SND) and may result in rapid ventricular pacing (RVP) in the DDDR mode. Mode switching (MS) reduces RVP, but its clinical benefit in patients with SND is unknown. Methods and Results: Two hundred two patients in the Mode Selection Trial (MOST; 2,010-patient, 6-year trial of DDDR vs VVIR pacing in SND) randomized to DDDR pacemakers with atrial high-rate episode (AHRE) storage capabilities were subrandomized to MS ON (N = 96) or MS OFF (N = 106). Cardiovascular symptoms, quality of life (QOL), reprogramming due to RVP, death, stroke, and heart failure hospitalization (HFH) were compared between groups. The treatment groups were similar with regard to AF history (59% MS ON vs 57% MS OFF). AHREs occurred in 49% patients during median follow-up of 2.2 years. Median AHRE duration (in min; MS ON 116 vs MS OFF 58, P = 0.29), frequency AHREs/week (MS ON 3.5 vs MS OFF 6.4, P = 0.23), and time spent in AHRE (min/week) (MS ON 450, MS OFF 268) were similar. Reprogramming due to any RVP during AHREs occurred more in MS OFF vs MS ON (13.2% vs 3.1%, P = 0.011) and marginally more for symptomatic RVP (8.5% vs 2.1%, P = 0.062). Cardiovascular symptoms occurred in 93.6% MS ON vs 90.2% MS OFF (P = 0.38). Median number of symptoms reported per visit was similar (MS ON 1.3 vs MS OFF 1.5, P = 0.62). Median symptom frequency/severity, summed and averaged over visits, was similar (MS ON 4.3 vs MS OFF 4.5, P = 0.74). QOL was not different between groups. Death, stroke, and HFH were not different between groups. Conclusion: MS reduces pacemaker reprogramming due to RVP during AHREs in a small number of patients but does not improve QOL or cardiovascular symptoms overall among patients with SND. (J Cardiovasc Electrophysiol, Vol. 15, pp. 153-160, February 2004) [ABSTRACT FROM AUTHOR]

This article focuses on differentiation of organics from functional psychiatric patients across various intelligence quotient (IQ) ranges using the Bender-Gestalt and Hutt scoring system. In this study, subjects were 180 patients selected retrospectively from the patient files of a private psychiatric hospital, a local state hospital, and a hospital in order to compose a heterogeneous sample of psychiatric and neurological patients. From the pool of patients who had been administered both a Wechsler Adult Intelligence Scale (WAIS) and Bender-Gestalt test as a part of admission procedures, subjects for the present investigation were selected. The WAIS was utilized to gain an IQ estimate.

In liver phosphoenolpyruvate carboxykinase (PCK) activity, protein and mRNA are localized predominantly in the periportal zone. The activation of the PCK gene by glucagon was studied in primary rat hepatocyte cultures under physiological arterial and venous oxygen tensions [16% and 8% (by vol.)]. PCK gene expression was monitored on the level of transcription, mRNA abundance and enzyme activity as well as enzyme synthesis and degradation. 1. Transcription of the PCK gene was increased by 10 nM glucagon maximally after 0.5 h; it reached nearly basal levels again after 2 h. The increase in transcription was 45% lower under 8% oxygen than under 16% oxygen. 2. PCK mRNA was maximally increased after 2 h under 16% oxygen and after 4 h under 8% oxygen; it subsequently declined to twice the basal values after 8 h. The maximal increase after 2 h was 50% lower under 8% oxygen than under 16% oxygen. 3. PCK enzyme activity was maximally increased after 4–6 h. The maximal enhancement after 4 h was 50% lower under 8% oxygen than under 16% oxygen. 4. The increase in PCK enzyme activity was due to an enhanced synthesis rate of PCK protein. The rate increase after 3 h was 35% lower under 8% oxygen than under 16% oxygen. 5. The degradation of PCK protein was equal under both oxygen tensions. The results show that in cultured rat hepatocytes the induction of PCK gene expression is modulated by physiological concentrations of oxygen. The modulation occurred at the level of gene transcription, mRNA abundance, enzyme protein synthesis and enzyme activity. The periportal to perivenous oxygen gradient could be the major factor responsible for the predominant expression of the PCK gene in the periportal zone. [ABSTRACT FROM AUTHOR]

The article presents a study to investigate the effectiveness of the Hutt-Briskin scoring system for the Bender-Gestalt test in differentiating normal from organic subjects for various IQ ranges. Twenty organic and 20 nonorganic subjects were assigned to each of the following groups: IQ 60-69; 1Q70 -79; 1Q80- 89; IQ 90-99; IQ 100-109; IQ 110 and above. The Bender-Gestalt of each subject was then scored using the Hutt-Briskin scoring system. The results indicated that this scoring system is relatively effective in indicating organicity or absence of organicity only when used with patients in the borderline or dull normal IQ range.

Background The WATCH-DM (weight [body mass index], age, hypertension, creatinine, high-density lipoprotein cholesterol, diabetes control [fasting plasma glucose], ECG QRS duration, myocardial infarction, and coronary artery bypass grafting) and TRS-HF DM (Thrombolysis in Myocardial Infarction [TIMI] risk score for heart failure in diabetes) risk scores were developed to predict risk of heart failure (HF) among individuals with type 2 diabetes. WATCH-DM was developed to predict incident HF, whereas TRS-HF DM predicts HF hospitalization among patients with and without a prior HF history. We evaluated the model performance of both scores to predict incident HF events among patients with type 2 diabetes and no history of HF hospitalization across different cohorts and clinical settings with varying baseline risk. Methods and Results Incident HF risk was estimated by the integer-based WATCH-DM and TRS-HF DM scores in participants with type 2 diabetes free of baseline HF from 2 randomized clinical trials (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin], N=12 028; and Look AHEAD [Look Action for Health in Diabetes] trial, N=4867). The integer-based WATCH-DM score was also validated in electronic health record data from a single large health care system (N=7475). Model discrimination was assessed by the Harrell concordance index and calibration by the Greenwood-Nam-D'Agostino statistic. HF incidence rate was 7.5, 3.9, and 4.1 per 1000 person-years in the TECOS, Look AHEAD trial, and electronic health record cohorts, respectively. Integer-based WATCH-DM and TRS-HF DM scores had similar discrimination and calibration for predicting 5-year HF risk in the Look AHEAD trial cohort (concordance indexes=0.70; Greenwood-Nam-D'Agostino P >0.30 for both). Both scores had lower discrimination and underpredicted HF risk in the TECOS cohort (concordance indexes=0.65 and 0.66, respectively; Greenwood-Nam-D'Agostino P <0.001 for both). In the electronic health record cohort, the integer-based WATCH-DM score demonstrated a concordance index of 0.73 with adequate calibration (Greenwood-Nam-D'Agostino P =0.96). TRS-HF DM score could not be validated in the electronic health record because of unavailability of data on urine albumin/creatinine ratio in most patients in the contemporary clinical practice. Conclusions The WATCH-DM and TRS-HF DM risk scores can discriminate risk of HF among intermediate-risk populations with type 2 diabetes.

Background: Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial., Methods and Results: TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i-TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i-TTR was 55.2% (SD 21.3%) and the median i-TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i-TTR, dominant determinants were previous warfarin use (mean i-TTR of 61.1% for warfarin-experienced versus 47.4% in VKA-naïve patients) and geographic region where patients were managed (mean i-TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i-TTRs had INR distributions shifted toward lower INR values and had longer inter-INR test intervals., Conclusions: Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i-TTR in global studies of warfarin. Regional differences in mean i-TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing., Clinical Trial Registration: URL: ClinicalTrials.gov. Unique identifier: NCT00403767.