Termination-of-resuscitation rule in the emergency department for patients with refractory out-of-hospital cardiac arrest: a nationwide, population-based observational study.

BACKGROUND: In Japan, emergency medical service (EMS) providers are prohibited from field termination-of-resuscitation (TOR) in out-of-hospital cardiac arrest (OHCA) patients. In 2013, we developed a TOR rule for emergency department physicians (Goto's TOR rule) immediately after hospital arrival. However, this rule is subject to flaws, and there is a need for revision owing to its relatively low specificity for predicting mortality compared with other TOR rules in the emergency department. Therefore, this study aimed to develop and validate a modified Goto's TOR rule by considering prehospital EMS cardiopulmonary resuscitation (CPR) duration. METHODS: We analysed the records of 465,657 adult patients with OHCA from the All-Japan Utstein registry from 2016 to 2019 and divided them into two groups: development (n = 231,363) and validation (n = 234,294). The primary outcome measures were specificity, false-positive rate (FPR), and positive predictive value (PPV) of the revised TOR rule in the emergency department for predicting 1-month mortality. RESULTS: Recursive partitioning analysis for the development group in predicting 1-month mortality revealed that a modified Goto's TOR rule could be defined if patients with OHCA met the following four criteria: (1) initial asystole, (2) unwitnessed arrest by any laypersons, (3) EMS-CPR duration > 20 min, and (4) no prehospital return of spontaneous circulation (ROSC). The specificity, FPR, and PPV of the rule for predicting 1-month mortality were 99.2% (95% confidence interval [CI], 99.0-99.4%), 0.8% (0.6-1.0%), and 99.8% (99.8-99.9%), respectively. The proportion of patients who fulfilled the rule and the area under the receiver operating curve (AUC) was 27.5% (95% CI 27.3-27.7%) and 0.904 (0.902-0.905), respectively. In the validation group, the specificity, FPR, PPV, proportion of patients who met the rule, and AUC were 99.1% (95% CI 98.9-99.2%), 0.9% (0.8-1.1%), 99.8% (99.8-99.8%), 27.8% (27.6-28.0%), and 0.889 (0.887-0.891), respectively. CONCLUSION: The modified Goto's TOR rule (which includes the following four criteria: initial asystole, unwitnessed arrest, EMS-CPR duration > 20 min, and no prehospital ROSC) with a > 99% predictor of 1-month mortality is a reliable tool for physicians treating refractory OHCAs immediately after hospital arrival.

Dispatcher instructions for bystander cardiopulmonary resuscitation and neurologically intact survival after bystander-witnessed out-of-hospital cardiac arrests: a nationwide, population-based observational study.

BACKGROUND: The International Liaison Committee on Resuscitation recommends that dispatchers provide instructions to perform compression-only cardiopulmonary resuscitation (CPR) to callers responding to adults with out-of-hospital cardiac arrest (OHCA). This study aimed to determine the optimal dispatcher-assisted CPR (DA-CPR) instructions for OHCA. METHODS: We analysed the records of 24,947 adult patients (aged ≥ 18 years) who received bystander DA-CPR after bystander-witnessed OHCA. Data were obtained from a prospectively recorded Japanese nationwide Utstein-style database for a 2-year period (2016-2017). Patients were divided into compression-only DA-CPR (n = 22,778) and conventional DA-CPR (with a compression-to-ventilation ratio of 30:2, n = 2169) groups. The primary outcome measure was 1-month neurological intact survival, defined as a cerebral performance category score of 1-2 (CPC 1-2). RESULTS: The 1-month CPC 1-2 rate was significantly higher in the conventional DA-CPR group than in the compression-only DA-CPR group (before propensity score (PS) matching, 7.5% [162/2169] versus 5.8% [1309/22778], p < 0.01; after PS matching, 7.5% (162/2169) versus 5.7% (123/2169), p < 0.05). Compared with compression-only DA-CPR, conventional DA-CPR was associated with increased odds of 1-month CPC 1-2 (before PS matching, adjusted odds ratio 1.39, 95% confidence interval [CI] 1.14-1.70, p < 0.01; after PS matching, adjusted odds ratio 1.34, 95% CI 1.00-1.79, p < 0.05). CONCLUSION: Within the limitations of this retrospective observational study, conventional DA-CPR with a compression-to-ventilation ratio of 30:2 was preferable to compression-only DA-CPR as an optimal DA-CPR instruction for coaching callers to perform bystander CPR for adult patients with bystander-witnessed OHCAs.

Sex-specific differences in survival after out-of-hospital cardiac arrest: a nationwide, population-based observational study.

BACKGROUND: It remains unclear whether men have more favorable survival outcomes after out-of-hospital cardiac arrest (OHCA) than women. METHODS: We reviewed a total of 386,535 patients aged ≥ 18 years with OHCA who were included in the Japanese registry from 2013 to 2016. The study endpoints were the rates of 1-month survival and neurologically intact survival (Cerebral Performance Category Scale score = 1 or 2). Based on age, the reviewed patients were categorized into the following eight groups: < 30, 30-39, 40-49, 50-59, 60-69, 70-79, 80-89, and ≥ 90 years. The survival outcomes in men and women were compared using hierarchical propensity score matching. RESULTS: The crude survival rate was significantly higher in men than in women in five groups: 30-39, 40-49, 50-59, 60-69, and 70-79 years (all P < 0.001). Similarly, the crude neurologically intact survival rate was significantly higher in men than in women in seven groups: < 30, 30-39, 40-49, 50-59, 60-69, 70-79, and 80-89 years (all P < 0.005). However, multivariate logistic regression analysis of each group revealed no significant sex-specific differences in 1-month survival outcomes (all P > 0.02). Moreover, after hierarchical propensity score matching, the survival outcomes did not significantly differ between both sexes (all P > 0.05). CONCLUSIONS: No significant sex-specific differences were found in the rates of 1-month survival and neurologically intact survival after OHCA.

Effects of prehospital epinephrine administration on neurologically intact survival in bystander-witnessed out-of-hospital cardiac arrest patients with non-shockable rhythm depend on prehospital cardiopulmonary resuscitation duration required to hospital arrival.

The effects of prehospital epinephrine administration on post-arrest neurological outcome in out-of-hospital cardiac arrest (OHCA) patients with non-shockable rhythm remain unclear. To examine the time-dependent effectiveness of prehospital epinephrine administration, we analyzed 118,396 bystander-witnessed OHCA patients with non-shockable rhythm from the prospectively recorded all-Japan OHCA registry between 2011 and 2014. Patients who achieved prehospital return of spontaneous circulation without prehospital epinephrine administration were excluded. Patients with prehospital epinephrine administration were stratified according to the time from the initiation of cardiopulmonary resuscitation (CPR) by emergency medical service (EMS) providers to the first epinephrine administration (≤ 10, 11-19, and ≥ 20 min). Patients without prehospital epinephrine administration were stratified according to the time from CPR initiation by EMS providers to hospital arrival (≤ 10, 11-19, and ≥ 20 min). The primary outcome was 1-month neurologically intact survival (cerebral performance category 1 or 2; CPC 1-2). Multivariate logistic regression analysis demonstrated that there was no significant difference in the chance of 1-month CPC 1-2 between patients who arrived at hospital in ≤ 10 min without prehospital epinephrine administration and patients with time to epinephrine administration ≤ 19 min. However, compared to patients who arrived at hospital in ≤ 10 min without prehospital epinephrine administration, patients with time to epinephrine administration ≥ 20 min and patients who arrived at hospital in 11-19, and ≥ 20 min without prehospital epinephrine administration were significantly associated with decreased chance of 1-month CPC 1-2 (p < 0.05, < 0.05, and < 0.001, respectively). In conclusion, when prehospital CPR duration from CPR initiation by EMS providers to hospital arrival estimated to be ≥ 11 min, prehospital epinephrine administered ≤ 19 min from CPR initiation by EMS providers could improve neurologically intact survival in bystander-witnessed OHCA patients with non-shockable rhythm.

Duration of Prehospital Cardiopulmonary Resuscitation and Favorable Neurological Outcomes for Pediatric Out-of-Hospital Cardiac Arrests: A Nationwide, Population-Based Cohort Study.

BACKGROUND: The appropriate duration of cardiopulmonary resuscitation (CPR) for pediatric out-of-hospital cardiac arrests (OHCAs) remains unclear and may differ based on initial rhythm. We aimed to determine the relationship between the duration of prehospital CPR by emergency medical services (EMS) personnel and post-OHCA outcomes. METHODS: We analyzed the records of 12 877 pediatric patients who experienced OHCAs (<18 years of age). Data were recorded in a nationwide Japanese database between 2005 and 2012. Study end points were 30-day survival and 30-day survival with favorable neurological outcomes (Cerebral Performance Category [CPC] scale 1-2). Prehospital EMS-initiated CPR duration was defined as the time from CPR initiation by EMS personnel to prehospital return of spontaneous circulation (ROSC) or to hospital arrival when prehospital ROSC was not achieved during prehospital CPR efforts. RESULTS: The rates of 30-day survival and 30-day CPC 1 to 2 were 9.1% (n=1167) and 2.5% (n=325), respectively. Prehospital EMS-initiated CPR duration was significantly and inversely associated with 30-day outcomes (adjusted odds ratio for 1-minute increments: 0.94, 95% confidence interval: 0.93-0.95 for survival; adjusted odds ratio: 0.90, 95% confidence interval: 0.88-0.92 for CPC 1-2). The duration of prehospital EMS-initiated CPR, beyond which the chance for favorable outcomes diminished to <1%, was 42 minutes for each key outcome, 30-day survival, and 30-day survival with CPC 1 to 2. When categorized by initial rhythm, the prehospital EMS-initiated CPR durations beyond which the chance for 30-day survival with CPC 1 to 2 diminished to <1% were 39 minutes for shockable rhythms, 42 minutes for pulseless electric activity, and 46 minutes for asystole, respectively. In patients with bystander-initiated CPR, the prehospital CPR duration, beyond which the chance for favorable outcome diminished to <1%, was 46 minutes from call receipt. CONCLUSIONS: Prehospital EMS-initiated CPR duration for pediatric OHCAs was independently and inversely associated with 30-day favorable outcomes. The duration of prehospital EMS-initiated CPR, beyond which the chance for 30-day favorable outcomes diminished to <1%, was 42 minutes. However, the CPR duration to achieve this proportion of outcomes differed based on initial rhythm. Further research is required to elucidate appropriate CPR duration for pediatric OHCAs, including in-hospital CPR time. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02432196.

Age-Specific Differences in the Duration of Prehospital Cardiopulmonary Resuscitation Administered by Emergency Medical Service Providers Necessary to Achieve Favorable Neurological Outcome After Out-of-Hospital Cardiac Arrest.

BACKGROUND: The appropriate duration of prehospital cardiopulmonary resuscitation (CPR)administered by emergency medical service (EMS) providers for patients with out-of-hospital cardiac arrest (OHCA) necessary to achieve 1-month survival with favorable neurological outcome (Cerebral Performance Category 1 or 2, CPC 1-2) is unclear and could differ by age.Methods and Results:We analyzed the records of 35,709 adult OHCA patients with return of spontaneous circulation (ROSC) before hospital arrival in a prospectively recorded Japanese registry between 2011 and 2014. The CPR duration was defined as the time from CPR initiation by EMS providers to prehospital ROSC. The rate of 1-month CPC 1-2 was 21.4% (7,650/35,709). The CPR duration was independently and inversely associated with 1-month CPC 1-2 (adjusted odds ratio, 0.93 per 1-min increment; 95% confidence interval, 0.93-0.94). The CPR duration increased with age (P<0.001). However, the CPR duration beyond which the proportion of OHCA patients with 1-month CPC 1-2 decreased to <1% declined with age: 28 min for patients aged 18-64 years, 25 min for 65-74 years, 23 min for 75-84 years, 20 min for 85-94 years, and 18 min for ≥95 years. CONCLUSIONS: In patients who achieved prehospital ROSC after OHCA, the duration of CPR administered by EMS providers necessary to achieve 1-month CPC 1-2 varied by age.

Improved Survival With Favorable Neurological Outcome in Elderly Individuals With Out-of-Hospital Cardiac Arrest in Japan　- A Nationwide Observational Cohort Study.

BACKGROUND: There is sparse data regarding the survival and neurological outcome of elderly patients with out-of-hospital cardiac arrest (OHCA). METHODS AND RESULTS: OHCA patients (334,730) aged ≥75 years were analyzed using a nationwide, prospective, population-based Japanese OHCA database from 2008 to 2012. The overall 1-month survival with favorable neurological outcome (Cerebral Performance Category Scale, category 1 or 2; CPC 1-2) rate was 0.88%. During the study period, the annual 1-month CPC 1-2 rate in whole OHCA significantly improved (0.73% to 0.96%, P for trend <0.001). In particular, outcomes of OHCA patients aged 75 to 84 years and those aged 85 to 94 years significantly improved (0.98% to 1.28%, P for trend=0.01; 0.46% to 0.70%, P for trend <0.001, respectively). However, in OHCA patients aged ≥95 years, the outcomes did not improve. Multivariate logistic regression analysis indicated that younger age, shockable first documented rhythm, witnessed arrest, earlier emergency medical service (EMS) response time, and cardiac etiology were significantly associated with the 1-month CPC 1-2. Under these conditions, elderly OHCA patients who had cardiac etiology, shockable rhythm and had a witnessed arrest had acceptable 1-month CPC1-2 rate; 7.98% in cases where OHCA was witnessed by family, 15.2% by non-family, and 25.6% by EMS. CONCLUSIONS: The annual 1-month CPC 1-2 rate after OHCA among elderly patients significantly improved, and the resuscitation of elderly patients in a selected population is not futile. (Circ J 2016; 80: 1153-1162).

Prognostic Impact of Functional Mitral Regurgitation in Patients Admitted With Acute Decompensated Heart Failure.

BACKGROUND: Functional mitral regurgitation (FMR) is a common complication of heart failure (HF) and worsens in acute decompensation. It is unclear whether FMR on admission or discharge determines the outcome. This study aimed to elucidate the prognostic significance of FMR on admission or discharge in patients admitted with acute decompensated HF. METHODS AND RESULTS: From 2006 to 2009, 349 patients admitted with acute decompensated HF were enrolled. They were followed with the composite endpoint of all-cause death and hospitalization for HF; 74 (21%) died and 113 (32%) developed the composite endpoint during 2.1±1.3 years. Moderate/severe FMR at discharge was associated with the composite endpoint (P=0.001), whereas that on admission was not. Multivariate Cox proportional hazard analysis showed that moderate/severe FMR (hazard ratio [95% confidence interval] =1.70 [1.03-2.73] P=0.04), logBNP, and NYHA class III/IV at discharge were independent determinants of the outcome. Moderate/severe FMR at discharge with BNP ≥200 pg/ml was prognostic, but BNP <200 pg/ml was no longer prognostic. CONCLUSIONS: Residual moderate/severe FMR after medical therapy for acute decompensated HF was associated with poor outcome, suggesting a potential target for further treatment of HF.

Prognostic significance of late gadolinium enhancement quantification in cardiac magnetic resonance imaging of hypertrophic cardiomyopathy with systolic dysfunction.

Hypertrophic cardiomyopathy (HCM) with systolic dysfunction carries a poor prognosis. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance is associated with adverse cardiac events in HCM and is inversely related to left ventricular ejection fraction (LVEF), it is unknown whether LGE or LVEF more accurately predicts adverse cardiac events in HCM with systolic dysfunction. We retrospectively assessed the extent of LGE with a threshold of 6 standard deviations in 46 consecutive HCM patients with systolic dysfunction defined as LVEF <50 % (average 35 ± 12 %) who underwent cardiac magnetic resonance (35 males, mean age 59 ± 14 years). They were followed up over 1755 ± 594 days. The composite adverse cardiac events end point included cardiovascular death, lethal arrhythmia, cardioembolic stroke, and unplanned heart failure hospitalization. LGE was detected in all patients, and the mean extent was 30 ± 15 %. Twenty-nine patients developed adverse cardiac events. Multivariate Cox proportional hazard analysis revealed the extent of LGE as a good independent predictor of adverse cardiac events. Risk increased with the extent of LGE (hazard ratio = 1.62/10 % increase in LGE, 95 % confidence interval = 1.23-2.15, p < 0.001). LVEF was inversely related to the extent of LGE (r = -0.44; p = 0.002) and was also an independent predictor of adverse cardiac events. Risk decreased with LVEF (hazard ratio = 0.68/10 % increase in LVEF, 95 % confidence interval = 0.51-0.91, p = 0.010). The Akaike information criterion evaluating the fit of a model demonstrated that the extent of LGE was a better independent predictor of MACE than LVEF (Akaike information criterion = 172.20 and 178.09, respectively).The extent of LGE was a good independent predictor of adverse cardiac events and reflected mortality and morbidity more precisely than LVEF in HCM with systolic dysfunction.

The predictability of renin-angiotensin-aldosterone system factors for clinical outcome in patients with acute decompensated heart failure.

Although counter-regulation between B-type natriuretic peptide (BNP) levels and renin-angiotensin-aldosterone system (RAAS) activation in heart failure (HF) has been suggested, whether the regulation is preserved in acute decompensated heart failure (ADHF) patients remains unclear. This study aimed to determine: (1) the relationship between RAAS activation and clinical outcomes in ADHF patients, and (2) the relationships between plasma BNP levels and degrees of activation in RAAS factors. This study included ADHF patients (n = 103, NYHA3-4, plasma BNP > 200 pg/ml). We studied the predictability of RAAS factors for cardiovascular events and the relationships between plasma BNP levels and the degrees of activation in RAAS factors, which were evaluated by plasma renin activity (PRA) and aldosterone concentration (PAC). PRA was a strong predictor of cardiovascular (CV) events over 1 year, even after accounting for plasma BNP levels (hazard ratio (HR): 1.04, CI [1.02-1.06], p < 0.01) and medication such as RAAS blockers (HR: 1.03, CI [1.01-1.05], p < 0.01), whereas PAC was borderline-significant (univariate analysis, p = 0.06). Cut-off value of PRA (5.3 ng/ml/h) was determined by AUC curve. Of the enrolled patients, higher PRA was found in 40 % of them. Although no correlation between the plasma BNP levels and PRA was found (p = 0.36), after adjusting for hemodynamic parameters, eGFR and medication, a correlation was found between them (p = 0.01). Elevated RAAS factors were found in a substantial number of ADHF patients with high plasma BNP levels in the association with hemodynamic state, which predicts poor clinical outcomes. The measurements of RAAS factors help to stratify ADHF patients at risk for further CV events.

Neurological outcomes in children dead on hospital arrival.

INTRODUCTION: Obtaining favorable neurological outcomes is extremely difficult in children transported to a hospital without a prehospital return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA). However, the crucial prehospital factors affecting outcomes in this cohort remain unclear. We aimed to determine the prehospital factors for survival with favorable neurological outcomes (Cerebral Performance Category 1 or 2 (CPC 1-2)) in children without a prehospital ROSC after OHCA. METHODS: Of 9093 OHCA children, 7332 children (age <18 years) without a prehospital ROSC after attempting resuscitation were eligible for enrollment. Data were obtained from a prospectively recorded Japanese national Utstein-style database from 2008 to 2012. The primary endpoint was 1-month CPC 1-2 after OHCA. RESULTS: The 1-month survival and 1-month CPC 1-2 rates were 6.92 % (n = 508) and 0.99 % (n = 73), respectively. The proportions of the following prehospital variables were significantly higher in the 1-month CPC 1-2 cohort than in the 1-month CPC 3-5 cohort: age (median, 3 years (interquartile range (IQR), 0-14) versus 1 year (IQR, 0-11), p <0.05), bystander-witnessed arrest (52/73 (71.2 %) versus 1830/7259 (25.2 %), p <0.001), initial ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT) rhythm (28/73 (38.3 %) versus 241/7259 (3.3 %), p <0.001), presumed cardiac causes (42/73 (57.5 %) versus 2385/7259 (32.8 %), p <0.001), and actual shock delivery (25/73 (34.2 %) versus 314/7259 (4.3 %), p <0.0001). Multivariate logistic regression analysis indicated that 2 prehospital factors were associated with 1-month CPC 1-2: initial non-asystole rhythm (VF/pulseless VT: adjusted odds ratio ( aOR), 16.0; 95 % confidence interval (CI), 8.05-32.0; pulseless electrical activity (PEA): aOR, 5.19; 95 % CI, 2.77-9.82) and bystander-witnessed arrest (aOR, 3.22; 95 % CI, 1.84-5.79). The rate of 1-month CPC 1-2 in witnessed-arrest children with an initial VF/pulseless VT was significantly higher than that in those with other initial cardiac rhythms (15.6 % versus 2.3 % for PEA and 1.2 % for asystole, p for trend <0.001). CONCLUSIONS: The crucial prehospital factors for 1-month survival with favorable neurological outcomes after OHCA were initial non-asystole rhythm and bystander-witnessed arrest in children transported to hospitals without a prehospital ROSC.

Late aneurysm formation of Valsalva sinus after aortic valve replacement due to Takayasu's arteritis.

Takayasu's arteritis (TA) is an inflammatory disease of unknown etiology involving the aorta and its branches, and also causes aortic regurgitation (AR). One of the most serious but rare complications after aortic valve replacement (AVR) in TA is aneurysm formation of the sinus of Valsalva. A 64-year-old woman had undergone AVR with a prosthetic valve for AR due to TA 4 years earlier and had received an implanted permanent pacemaker for complete atrioventricular block (AVB) 2 years later. Aortography 4 years postoperatively demonstrated aneurysm formation (47 mm in diameter) at the sinus of Valsalva although preoperative aortography showed severe AR without dilatation of the sinus of Valsalva. We recommended reoperation for the aneurysm but the patient refused. The perioperative histopathological examination revealed extensive destruction of the medial elastic fibers. Both the fragility of the sinus of Valsalva and the residual inflammation could have caused the patient's aneurysm formation. Moreover, extension of TA into the ventricular septum or mechanical compression of the aneurysm against the conduction system might have caused her progressive AVB. Close and lifelong follow-up for patients with TA regarding development of aneurysm after surgical treatment is indispensable when fragility of the aortic root had been confirmed.

Pathophysiological impact of serum fibroblast growth factor 23 in patients with nonischemic cardiac disease and early chronic kidney disease.

Although the important role of fibroblast growth factor (FGF)23 on cardiac remodeling has been suggested in advanced chronic kidney disease (CKD), little is known about serum (s)FGF23 levels in patients with heart failure (HF) due to nonischemic cardiac disease (NICD) and early CKD. The present study aimed to investigate sFGF23 levels in NICD patients and identify the responsible factors for the elevation of sFGF23 levels. We prospectively measured sFGF23 levels in consecutive hospitalized NICD patients with early CKD (estimated glomerular filtration rate ≥ 40 ml·min(-1)·1.73 m(-2)) and analyzed the data of both echocardiography and right heart catheterization. Of the 156 NICD patients (estimated glomerular filtration rate range: 41-128 ml·min(-1)·1.73 m(-2)), the most severe HF symptom (New York Heart Association class III-IV, 53% vs. 33%, P = 0.015) was found in the above median sFGF23 (39.1 pg/ml) group compared with the below median sFGF23 group. sFGF23 levels were higher in patients with HF hospitalization history compared with those without HF [median: 46.8 (interquartile range: 38.8-62.7) vs. 34.7 (interquartile range: 29.6-42.4) pg/ml, P < 0.0001]. In the multivariate analysis, HF hospitalization was independently related to elevated sFGF23 levels (P = 0.022). Both systolic dysfunction and high plasma aldosterone concentration were identified as predictors of high sFGF23 levels (P < 0.05). Among the neurohormonal parameters, elevated sFGF23 levels were the only factor to predict a declining left ventricular ejection fraction (P = 0.001). These findings suggest that the progression of HF per se contributes to the elevation of sFGF23 levels even in the early stages of CKD, which leads to further myocardial dysfunction, potentially creating a vicious cycle.

Compound heterozygosity deteriorates phenotypes of hypertrophic cardiomyopathy with founder MYBPC3 mutation: evidence from patients and zebrafish models.

Although most founder mutation carriers of hypertrophic cardiomyopathy (HCM), such as the cardiac myosin-binding protein C gene (MYBPC3), arose from a common ancestor exhibit favorable clinical phenotypes, there still remain small fractions of these carriers associated with increased cardiovascular events. However, few data exist regarding the defining factors that modify phenotypes of these patients, particularly in terms of multiple gene mutations. Therefore, we assessed genotype-phenotype correlations and investigated factors that contribute to phenotypic diversities of mutation carriers from 488 unrelated HCM probands. A prevalent founder mutation (Val762Asp) in MYBPC3 was identified in 33 subjects from 19 families. Among them, 28 carriers harbored an isolated Val762Asp mutation and exhibited a late onset of overt HCM compared with other MYBPC3 mutation carriers (62.8 ± 3.0 vs 50.1 ± 2.6 yr, P < 0.05). In contrast, the remaining five carriers had additional sarcomere gene mutations (3 carriers in MYBPC3 and 2 carriers in the cardiac troponin T gene). Of these five carriers, two carriers showed early disease onset and one carrier exhibited end-stage HCM. These phenotypes were recapitulated in zebrafish models; injection of MYBPC3 Val762Asp alone did not alter ventricular size or function, but ventricular dimension was significantly increased when MYBPC3 Val762Asp mRNA was coinjected with MYBPC3 Arg820Gln mRNA. These results demonstrate that MYBPC3 Val762Asp may be associated with unfavorable HCM phenotypes in some cases when combined with another MYBPC3 mutation.

Serum blood urea nitrogen and plasma brain natriuretic Peptide and low diastolic blood pressure predict cardiovascular morbidity and mortality following discharge in acute decompensated heart failure patients.

BACKGROUND: Patients with heart failure (HF) have a high risk of cardiovascular (CV) death and re-hospitalization. The purpose of the present study was therefore to investigate predictors of CV death and re-hospitalization for acute decompensated HF (ADHF). METHODS AND RESULTS: A total of 225 patients aged 67.2±15.2 years, including 134 men (59.6%), who were hospitalized for ADHF between 2008 and 2009, were followed up. After discharge, the relationship between clinical parameters and CV events (ie, CV death or re-hospitalization for HF) was examined. Follow-up was continued until 30 April 2011. The most important predictors of re-hospitalization were serum blood urea nitrogen (BUN; adjusted hazard ratio [HR], 1.02; 95% confidence interval [CI]: 1.00-1.03, P=0.01), plasma brain natriuretic peptide (BNP; adjusted HR, 1.85; 95% CI: 1.12-3.04, P=0.02), and diastolic blood pressure (DBP; adjusted HR, 0.97; 95% CI: 0.94-1.00, P=0.049). The only predictor of CV mortality was a high BUN (adjusted HR, 1.05; 95% CI: 1.01-1.09, P=0.01). CONCLUSIONS: High serum BUN (≥22.5mg/dl), high plasma BNP (≥250pg/ml), and low DBP (<60mmHg) predict CV events in patients hospitalized for ADHF. These factors may identify high-risk patients for CV events and provide therapeutic targets for managing HF. (Circ J 2012; 76: 2372-2379).

Association of dispatcher-assisted cardiopulmonary resuscitation with initial shockable rhythm and survival after out-of-hospital cardiac arrest.

BACKGROUND AND IMPORTANCE: Bystander cardiopulmonary resuscitation (CPR) and initial shockable rhythm are crucial predictors of survival after out-of-hospital cardiac arrest (OHCA). However, the relationship between dispatcher-assisted CPR (DA-CPR) and initial shockable rhythm is not completely elucidated. OBJECTIVE: To examine the association of DA-CPR with initial shockable rhythm and outcomes. DESIGN, SETTING AND PARTICIPANTS: This nationwide population-based observational study conducted in Japan included 59 688 patients with witnessed OHCA of cardiac origin after excluding those without bystander CPR. Patients were divided into DA-CPR (n = 42 709) and CPR without dispatcher assistance (unassisted CPR, n = 16 979) groups. OUTCOME MEASURES AND ANALYSIS: The primary outcome measure was initial shockable rhythm, and secondary outcome measures were 1-month survival and neurologically intact survival. A Cox proportional hazards model adjusted for collapse-to-first-rhythm-analysis time and multivariable logistic regression models were used after propensity score (PS) matching to compare the incidence of initial shockable rhythm and outcomes, respectively. MAIN RESULTS: Among all patients (mean age 76.7 years), the rates of initial shockable rhythm, 1-month survival and neurologically intact survival were 20.8, 10.7 and 7.0%, respectively. The incidence of initial shockable rhythm in the DA-CPR group (20.4%, 3462/16 979) was significantly higher than that in the unassisted CPR group (18.5%, 3133/16 979) after PS matching (P < 0.0001). However, no significant differences were found between the two groups with respect to the incidence of initial shockable rhythm in the Cox proportional hazards model [adjusted hazard ratio of DA-CPR for initial shockable rhythm compared with unassisted CPR, 0.99; 95% confidence interval (CI), 0.97-1.02, P = 0.56]. No significant differences were observed in the survival rates in the two groups after PS matching [10.8% (1833/16 979) vs. 10.3% (1752/16 979), P = 0.16] and neurologically intact survival rates [7.3% (1233/16 979) vs. 6.8% (1161/16 979), P = 0.13]. The multivariable logistic regression model showed no significant differences between the groups with regard to survival (adjusted odds ratio of DA-CPR compared with unassisted CPR: 1.00; 95% CI, 0.89-1.13, P = 0.97) and neurologically intact survival (adjusted odds ratio: 1.12; 95% CI, 0.98-1.29, P = 0.14). CONCLUSION: DA-CPR after OHCA had the same independent association with the likelihood of initial shockable rhythm and 1-month meaningful outcome as unassisted CPR.

Dispatcher-assisted conventional cardiopulmonary resuscitation and outcomes for paediatric out-of-hospital cardiac arrests.

AIM: As asphyxial cardiac arrest is more common than cardiac arrest from a primary cardiac event in paediatric cardiac arrest, effective ventilation is important during paediatric cardiopulmonary resuscitation (CPR). We aimed to determine optimal dispatcher-assisted CPR instructions for bystanders after paediatric out-of-hospital cardiac arrest (OHCA). METHODS: We analysed the records of 8172 children who received bystander dispatcher-assisted CPR. Data were obtained from an All-Japan Utstein-style registry from 2005 to 2017. Patients were divided into conventional CPR and compression-only CPR groups. The primary study endpoint was 1-month neurologically intact survival, defined as a Cerebral Performance Category score of 1 or 2 (CPC 1-2). RESULTS: The 1-month CPC 1-2 rate was significantly higher in the dispatcher-assisted conventional CPR group than in the dispatcher-assisted compression-only CPR group (before propensity score matching, 5.7% [175/3077] vs. 3.1% [160/5095], p < 0.0001, adjusted odds ratio 2.48, 95% confidence interval 1.19-3.22; after propensity score matching, 6.0% [156/2618] vs. 2.6% [69/2618], p < 0.0001, adjusted odds ratio 2.42, 95% confidence interval 1.76-3.32). In most subgroup analyses after matching, dispatcher-assisted conventional CPR had a higher CPC 1-2 rate than dispatcher-assisted compression-only CPR; however, CPC 1-2 rates were similar between the two groups for patients with an initial shockable rhythm, those with total prehospital CPR time ≥ 20 min, those receiving public access defibrillation, advanced airway management, or adrenaline administration. CONCLUSION: Within the limitations of this retrospective observational study, dispatcher-assisted conventional CPR was preferable to dispatcher-assisted compression-only CPR as optimal CPR instructions for coaching callers to perform bystander CPR.

A KCR1 variant implicated in susceptibility to the long QT syndrome.

The acquired long QT syndrome (aLQTS) is frequently associated with extrinsic and intrinsic risk factors including therapeutic agents that inadvertently inhibit the KCNH2 K(+) channel that underlies the repolarizing I(Kr) current in the heart. Previous reports demonstrated that K(+) channel regulator 1 (KCR1) diminishes KCNH2 drug sensitivity and may protect susceptible patients from developing aLQTS. Here, we describe a novel variant of KCR1 (E33D) isolated from a patient with ventricular fibrillation and significant QT prolongation. We recorded the KCNH2 current (I(KCNH2)) from CHO-K1 cells transfected with KCNH2 plus wild type (WT) or mutant KCR1 cDNA, using whole cell patch-clamp techniques and assessed the development of I(KCNH2) inhibition in response to well-characterized KCNH2 inhibitors. Unlike KCR1 WT, the E33D variant did not protect KCNH2 from the effects of class I antiarrhythmic drugs such as quinidine or class III antiarrhythmic drugs including dofetilide and sotalol. The remaining current of the KCNH2 WT+KCR1 E33D channel after 100 pulses in the presence of each drug was similar to that of KCNH2 alone. Simulated conditions of hypokalemia (1mM [K(+)](o)) produced no significant difference in the fraction of the current that was protected from dofetilide inhibition with KCR1 WT or E33D. The previously described α-glucosyltransferase activity of KCR1 was found to be compromised in KCR1 E33D in a yeast expression system. Our findings suggest that KCR1 genetic variations that diminish the ability of KCR1 to protect KCNH2 from inhibition by commonly used therapeutic agents constitute a risk factor for the aLQTS.

Time boundaries of the three-phase time-sensitive model for ventricular fibrillation cardiac arrest.

AIM: Ventricular fibrillation (VF) cardiac arrest may consist of three time-sensitive phases: electrical, circulatory, and metabolic. However, the time boundaries of these phases are unclear. We aimed to determine the time boundaries of the three-phase model for VF cardiac arrest. METHODS: We reviewed 20,741 out-of-hospital cardiac arrest cases with initial VF and presumed cardiac origin from the All-Japan Utstein-style registry between 2013 and 2017. The study endpoint was 1-month neurologically intact survival. The collapse-to-shock interval was defined as the time from collapse to the first shock delivery by emergency medical service personnel. The patients were divided into the bystander cardiopulmonary resuscitation (CPR, n = 11,606) and non-bystander CPR (n = 9135) groups. RESULTS: In the bystander CPR group, the collapse-to-shock times that were associated with increased adjusted 1-month neurologically intact survival, compared with those in the non-bystander CPR group, ranged from 7 min (42.9% [244/4999] vs. 26.0% [119/458], adjusted odds ratio [aOR], 1.95; 95% confidence interval [CI], 1.44-2.63; P < 0.0001) to 17 min (17.1% [70/410] vs. 7.3% [21/288], aOR, 2.82; 95% CI, 1.62-4.91; P = 0.0002). However, the neurologically intact survival rate of the bystander CPR group was statistically insignificant compared with that of the non-bystander CPR group when the collapse-to-shock time was outside this range. CONCLUSIONS: The time boundaries of the three-phase time-sensitive model for VF cardiac arrest may be defined as follows: electrical phase, from collapse to <7 min; circulatory phase, from 7 to 17 min; and metabolic phase, from >17 min onward.