Gut microbiota, endotoxemia, inflammation, and oxidative stress in patients with heart failure, left ventricular assist device, and transplant.

BACKGROUND: Gut microbial imbalance may contribute to endotoxemia, inflammation, and oxidative stress in heart failure (HF). Changes occurring in the intestinal microbiota and inflammatory/oxidative milieu during HF progression and following left ventricular assist device (LVAD) or heart transplantation (HT) are unknown. We aimed to investigate variation in gut microbiota and circulating biomarkers of endotoxemia, inflammation, and oxidative stress in patients with HF (New York Heart Association, Class I-IV), LVAD, and HT. METHODS: We enrolled 452 patients. Biomarkers of endotoxemia (lipopolysaccharide and soluble [sCD14]), inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-α, and endothelin-1 adiponectin), and oxidative stress (isoprostane) were measured in 644 blood samples. A total of 304 stool samples were analyzed using 16S rRNA sequencing. RESULTS: Gut microbial community measures of alpha diversity were progressively lower across worsening HF class and were similarly reduced in patients with LVAD and HT (p < 0.05). Inflammation and oxidative stress were elevated in patients with Class IV HF vs all other groups (all p < 0.05). Lipopolysaccharide was elevated in patients with Class IV HF (vs Class I-III) as well as in patients with LVAD and HT (p < 0.05). sCD14 was elevated in patients with Class IV HF and LVAD (vs Class I-III, p < 0.05) but not in patients with HT. CONCLUSIONS: Reduced gut microbial diversity and increased endotoxemia, inflammation, and oxidative stress are present in patients with Class IV HF. Inflammation and oxidative stress are lower among patients with LVAD and HT relative to patients with Class IV HF, whereas reduced gut diversity and endotoxemia persist in LVAD and HT.

Michigan Stroke Transitions Trial.

BACKGROUND: To test whether access to home-based social worker-led case management (SWCM) program or SWCM program combined with a website providing stroke-related information improves patient-reported outcomes in patients with stroke, relative to usual care. METHODS AND RESULTS: The MISTT (Michigan Stroke Transitions Trial), an open (unblinded) 3-group parallel-design clinical trial, randomized 265 acute patients with stroke to 3 treatment groups: Usual Care (group-1), SWCM (group-2), and SWCM+MISTT website (group-3). Patients were discharged directly home or returned home within 4 weeks of discharge to a rehabilitation facility. The SWCM program provided in-home and phone-based case management services. The website provided patient-orientated information covering stroke education, prevention, recovery, and community resources. Both interventions were provided for up to 90 days. Outcomes data were collected by telephone at 7 and 90 days. Primary patient-reported outcomes included Patient-Reported Outcomes Measurement Information System Global-10 Quality-of-Life (Physical and Mental Health subscales) and the Patient Activation Measure. Treatment efficacy was determined by comparing the change in mean response (90 days minus 7 days) between the 3 treatment groups using a group-by-time interaction. Subjects were aged 66 years on average, 49% were female, 21% nonwhite, and 86% had ischemic stroke. There were statistically significant changes in Patient-Reported Outcomes Measurement Information System Physical Health ( P=0.003) and Patient Activation Measure ( P=0.042), but not Patient-Reported Outcomes Measurement Information System Mental Health ( P=0.56). The mean change in Patient-Reported Outcomes Measurement Information System Physical Health scores for group-3 (SWCM+MISTT Website) was significantly higher than both group-2 (SWCM; difference, +2.4; 95% CI, 0.46-4.34; P=0.02) and group-1 (usual care; difference, +3.4; 95% CI, 1.41-5.33; P<0.001). The mean change in Patient Activation Measure scores for group-3 was significantly higher than group-2 (+6.7; 95% CI, 1.26-12.08; P=0.02) and marginally higher than group-1 (+5.0; 95% CI, -0.47 to 10.52; P=0.07). CONCLUSIONS: An intervention that combined SWCM with access to online stroke-related information produced greater gains in patient-reported physical health and activation compared with usual care or case management alone. There was no intervention effect on mental health. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02653170.

Prognostic implications of serial outpatient blood pressure measurements in patients with an axial continuous-flow left ventricular assist device.

BACKGROUND: Elevated blood pressure (BP) has been linked to adverse events during left ventricular assist device support. In this study we investigated the association between outpatient BP and stroke or suspected pump thrombosis among HeartMate II (HMII) recipients. METHODS: We retrospectively studied 220 HMII patients. Serial outpatient BP measurements were averaged. Patients were categorized by: (1) mean arterial pressure (MAP), high (>90 mm Hg) vs intermediate (80 mm Hg ≤ MAP ≤ 90 mm Hg) vs low (<80 mm Hg); (2) systolic BP (SBP), high (≥101 mm Hg, median) vs low; and (3) pulse pressure (PP), high (≥22 mm Hg, median) vs low. To assess visit-to-visit BP variability, patients were divided in quartiles of standard deviation of MAP and SBP. The primary end-point was the composite of stroke or suspected pump thrombosis. RESULTS: The risk for the primary end-point was increased in the high MAP group (adjusted hazard ratio [HR] 2.75, 95% confidence interval [CI] 1.49 to 5.05, vs intermediate MAP; and 6.73, 1.9 to 23.9, vs low MAP). MAP had higher predictive value for the primary end-point compared with SBP (p = 0.05). Patients with high SBP had a higher rate of stroke (HR 2.8, 95% CI 1.09 to 7.17, vs low SBP). The combination of high SBP and low PP was associated with the highest risk for stroke. The lowest quartile of visit-to-visit MAP variability was associated with the highest risk for the primary end-point. CONCLUSIONS: Elevated outpatient BP is associated with increased risk for stroke or suspected pump thrombosis in HMII recipients. Reduced PP and low visit-to-visit BP variability may confer additional risk.

Observed long-term mortality after 18,000 person-years among survivors in a large regional drowning registry.

AIM: Long-term outcomes beyond one year after non-fatal drowning are uncharacterized. We estimated long-term mortality and identified prognostic factors in a large, population-based cohort. METHODS: Population-based prospective cohort study (1974-1996) of Western Washington Drowning Registry (WWDR) subjects surviving the index drowning through hospital discharge. Primary outcome was all-cause mortality through 2012. We tabulated Utstein-style exposure variables, estimated Kaplan-Meier curves, and identified prognostic factors with Cox proportional hazard modeling. We also compared 5-, 10-, and 15-year mortality estimates of the primary cohort to age-specific mortality estimates from United States Life Tables. RESULTS: Of 2824 WWDR cases, 776 subjects (5[IQR 2-17] years, 68% male) were included. Only 63 (8%) non-fatal drowning subjects died during 18,331 person-years of follow-up. Long-term mortality differed by Utstein variables (age, precipitating alcohol use, submersion interval, GCS, CPR, intubation, defibrillation, initial vital signs, neurologic status at hospital discharge) and inpatient markers of illness severity (mechanical ventilation, vasopressor use, seizure, pneumothorax). Survival differed by age (HR 1.04;95%CI 1.03-1.05), drowning-related cardiac arrest (HR 3.47;95%CI 1.97-6.13), and neurologic impairment at hospital discharge (HR 5.10;95% CI 2.70-9.62). In adjusted analysis, age (HR 1.05;95%CI 1.03-1.06) and severe neurologic impairment at discharge (HR 2.31;95%CI 1.01-5.28) were associated with long-term mortality. Subjects aged 5-15 years had higher mortality risks than those calculated from Life Tables. CONCLUSION: Most drownings were fatal, but survivors of non-fatal drowning had low risk of subsequent long-term mortality similar to the general population that was independently associated with age and neurologic status at hospital discharge.

The Wearable Cardioverter Defibrillator in Nonischemic Cardiomyopathy: A US National Database Analysis.

BACKGROUND: The wearable cardioverter defibrillator (WCD) is often used in patients at risk of sudden cardiac death (SCD) who are not yet candidates for an implantable cardioverter defibrillator (ICD). Newly diagnosed cardiomyopathy may be reversible, and a WCD may protect patients during the initial period of risk. We evaluate the benefit and compliance of the WCD in patients with nonischemic cardiomyopathy (NICM). METHODS: We reviewed a national database of patients with NICM who used WCDs and who self-reported a history of excess alcohol use, although other causes of cardiomyopathy could not be excluded. The database contained demographic data, initial ejection fraction (EF), reason for WCD prescription, compliance and use data, any detected arrhythmias, therapies, and reason for discontinuing WCD. Statistical analyses were performed using SAS, version 9.3 (SAS Institute, Cary, NC). RESULTS: Of the 127 patients, 88% were men with a mean age of 52.6 ± 11.0 years. The mean initial EF was 19.9% ± 7.4%. Patients wore the WCD for a median of 51 days and a median daily use of 18.0 hours per day. The most common reasons for discontinuing the WCD were improvement in EF (33%) or ICD implantation (23.6%). Seven patients (5.5%) had 9 sustained ventricular arrhythmia events, which were successfully treated with 100% conversion. There were 11 deaths (8.6%) during 100 days of follow-up. No deaths resulted from WCD shock failure or undersensing. CONCLUSIONS: NICM may have a significant risk of ventricular arrhythmias and death in the first few months. The WCD delivered appropriate therapy in 5.5% of patients. This study suggests that a WCD may be effective temporary prophylaxis for prevention of SCD in patients with newly diagnosed NICM.

Role of cholesterol crystals in atherosclerosis is unmasked by altering tissue preparation methods.

Standard tissue preparation for light and scanning electron microscopy (SEM) uses ethanol as a dehydrating agent but that can also dissolve cholesterol crystals (CC) leaving behind empty tissue imprints or "clefts". Cholesterol crystals may contribute to plaque rupture by their sharp tips that can tear membranes and trigger inflammation. Therefore, use of ethanol in tissue processing can mask the pathological role of CC. Here we evaluated the amount of cholesterol dissolved from CC with single and complete series of standard graded ethanol concentrations (25-100%) used in tissue preparation. Also, solubility of CC in ethanol at physiological levels was measured. Furthermore, we compared the effect of ethanol on CC in fresh human atherosclerotic plaques to matched segments dehydrated using vacuum (-1 atm, 12h). Tissue crystal density ranging from 0 to +3 was measured semi-quantitatively by SEM. For CC exposed to 25% and 100% ethanol for 10 min each, 0.38% and 95% of CC were dissolved respectively. Also, increase in CC solubility was significant at physiological levels of ethanol (0.16%) compared to water (43.4 ± 18.0 ng/mL vs. 30.9 ± 13.9 ng/mL; p < 0.05). We speculate that this could represent a potential mechanism of cardio-protective effects of alcohol consumption. In atherosclerotic plaques, CC density was lower in ethanol vs. saline treatment (+1.2 vs. +2.8; P < 0.01) with visible dissolving noted by SEM. Ethanol has been used for centuries in tissue preparation for microscopy. Here we demonstrate how current tissue preparation methods greatly alter histological findings with SEM by masking the potential mechanism of plaque rupture.

Clinical predictors of accurate prehospital stroke recognition.

BACKGROUND AND PURPOSE: Prehospital activation of in-hospital stroke response hastens treatment but depends on accurate emergency medical services (EMS) stroke recognition. We sought to measure EMS stroke recognition accuracy and identify clinical factors associated with correct stroke identification. METHODS: Using EMS and hospital records, we assembled a cohort of EMS-transported suspect, confirmed, or missed ischemic stroke or transient ischemic attack cases. The sensitivity and positive predictive value (PPV) for EMS stroke recognition were calculated using the hospital discharge diagnosis as the gold standard. We used multivariable logistic regression analysis to determine the association between Cincinnati Prehospital Stroke Scale use and EMS stroke recognition. RESULTS: During a 12-month period, 441 EMS-transported patients were enrolled; of which, 371 (84.1%) were EMS-suspected strokes and 70 (15.9%) were EMS-missed strokes. Overall, 264 cases (59.9%) were confirmed as either ischemic stroke (n=186) or transient ischemic attack (n=78). The sensitivity of EMS stroke recognition was 73.5% (95% confidence interval, 67.7-78.7), and PPV was 52.3% (95% confidence interval, 47.1-57.5). Sensitivity (84.7% versus 30.9%; P<0.0001) and PPV (56.2% versus 30.4%; P=0.0004) were higher among cases with Cincinnati Prehospital Stroke Scale documentation. In multivariate analysis, Cincinnati Prehospital Stroke Scale documentation was independently associated with EMS sensitivity (odds ratio, 12.0; 95% confidence interval, 5.7-25.5) and PPV (odds ratio, 2.5; 95% confidence interval, 1.3-4.7). CONCLUSIONS: EMS providers recognized 3 quarters of the patients with ischemic stroke and transient ischemic attack; however, half of EMS-suspected strokes were false positives. Documentation of a Cincinnati Prehospital Stroke Scale was associated with higher EMS stroke recognition sensitivity and PPV.

The quality of prehospital ischemic stroke care: compliance with guidelines and impact on in-hospital stroke response.

BACKGROUND: A number of emergency medical services (EMSs) performance measures for stroke have been proposed to promote early stroke recognition and rapid transportation to definitive care. This study examined performance measure compliance among EMS-transported stroke patients and the relationship between compliance and in-hospital stroke response. METHODS: Eight quality indicators were derived from American Stroke Association guidelines. A prospective cohort of consecutive, EMS-transported patients discharged from 2 large Midwestern stroke centers with a diagnosis of acute ischemic stroke was identified. Data were abstracted from hospital and EMS records. Compliance with 8 prehospital quality indicators was calculated. Univariate and multivariable logistic regression analysis were performed to measure the association between prehospital compliance and a binary outcome of door-to-computed tomography (CT) time less than or equal to 25 minutes. RESULTS: Over the 12 month study period, 186 EMS-transported ischemic stroke patients were identified. Compliance was highest for prehospital documentation of a glucose level (86.0%) and stroke screen (78.5%) and lowest for on-scene time less than or equal to 15 minutes (46.8%), hospital prenotification (56.5%), and transportation at highest priority (55.4%). After adjustment for age, time from symptom onset, and stroke severity, transportation at highest priority (odds ratio [OR], 13.45) and hospital prenotification (OR, 3.75) were both associated with significantly faster door-to-CT time. No prehospital quality metric was associated with tissue-plasminogen activator delivery. CONCLUSIONS: EMS transportation at highest priority and hospital prenotification were associated with faster in-hospital stroke response and represent logical targets for EMS quality improvement efforts.

A simple risk index and thrombolytic treatment response in acute ischemic stroke.

IMPORTANCE: The Stroke Prognostication using Age and the NIH Stroke Scale index, created by combining age in years plus a National Institutes of Health (NIH) Stroke Scale score of 100 or higher (and hereafter referred to as the SPAN-100 index), is a simple risk score for estimating clinical outcomes for patients with acute ischemic stroke (AIS). The association between this index and response to intravenous thrombolysis for AIS has not been properly evaluated. OBJECTIVE: To assess the relationship between SPAN-100 index status and outcome following treatment with intravenous thrombolysis for AIS. DESIGN, SETTING, AND PARTICIPANTS: Using the Virtual International Stroke Trials Archive (VISTA) database, an international repository of clinical trials data, we assessed the SPAN-100 index among 7093 patients with AIS who participated in 4 clinical trials from 2000 to 2006. The SPAN-100 index is considered positive if the sum of the age and the NIH Stroke Scale (a 15-item neurological examination scale with scores ranging from 0 to 42, with higher scores indicating more severe strokes) score is greater than or equal to 100. Multivariable logistic regression analyses were used to determine the independent association between SPAN-100 index status and 90-day outcomes. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of severe disability or death measured 90 days after stroke, and the secondary outcomes were death alone and a composite of no disability/modest disability. RESULTS: Of 7093 patients, 743 (10.5%) were SPAN-100 positive, and 2731 (38.5%) received intravenous thrombolysis. Compared with SPAN-100-negative patients, SPAN-100-positive patients were more likely to experience a catastrophic outcome (adjusted odds ratio [AOR], 9.03 [95% CI, 6.68-12.21]) or death alone (AOR, 5.03 [95% CI, 4.06-6.23]) and less likely to experience a favorable outcome (AOR, 0.08 [95% CI, 0.06-0.13]). However, there was an interaction between SPAN-100 index status and thrombolysis treatment (P < .001) revealing a reduction in the likelihood of severe disability/death with thrombolytic treatment for SPAN-100-positive (AOR, 0.46 [95% CI, 0.29-0.71]) but not SPAN-100-negative patients (AOR, 0.96 [95% CI, 0.85-1.07]). Similar interactions between SPAN-100 index status and thrombolysis treatment were observed for the 2 secondary outcomes. CONCLUSION AND RELEVANCE: Compared with the SPAN-100-negative patients with AIS, the SPAN-100-positive patients with AIS seem to have poorer 3-month outcomes but may derive greater benefit when treated with intravenous thrombolysis. The SPAN-100-positive patients are often excluded from AIS clinical trials but should probably not be denied thrombolysis treatment on the basis of such a profile alone.