Takayuki Otani

Inhibitory Cardiac Transcription Factor, SRF-N, Is Generated by Caspase 3 Cleavage in Human Heart Failure and Attenuated by Ventricular Unloading

Background—Knowledge about molecular mechanisms leading to heart failure is still limited, but reduced gene activities and modest activation of caspase 3 are hallmarks of end-stage heart failure. We postulated that serum response factor (SRF), a central cardiac transcription factor, might be a cleavage target for modest activated caspase 3, and this cleavage of SRF may play a dominant inhibitory role in propelling hearts toward failure. Methods and Results—We examined SRF protein levels from cardiac samples taken at the time of transplantation in 13 patients with end-stage heart failure and 7 normal hearts. Full-length SRF was markedly reduced and processed into 55- and 32-kDa subfragments in all failing hearts. SRF was intact in normal samples. In contrast, the hearts of 10 patients with left ventricular assist devices showed minimal SRF fragmentation. Specific antibodies to N- and C-terminal SRF sequences and site-directed mutagenesis revealed 2 alternative caspase 3 cleavage sites, so that 2 fragments were detected of each containing either the N- or C-terminal SRF. Expression of SRF-N, the 32-kDa fragment, in myogenic cells inhibited the transcriptional activity of &agr;-actin gene promoters by 50% to 60%, which suggests that truncated SRF functioned as a dominant-negative transcription factor. Conclusions—Caspase 3 activation in heart failure sequentially cleaved SRF and generated a dominant-negative transcription factor, which may explain the depression of cardiac-specific genes. Moreover, caspase 3 activation may be reversible in the failing heart with ventricular unloading.

Coronary angioscopic findings 9 months after everolimus-eluting stent implantation compared with sirolimus-eluting stents

OBJECTIVESnWe assessed angioscopic findings after everolimus-eluting stents (EES) implantation, compared with sirolimus-eluting stents (SES).nnnBACKGROUNDnCoronary angioscopy (CAS) provides an opportunity to assess neointimal coverage over stent struts, thrombus, and plaque color by direct visualization. CAS is a useful tool for evaluating stent struts after drug-eluting stent implantation. Angioscopic findings after EES implantation have not been reported before.nnnMETHODSnWe performed CAS in 23 patients who were treated with EES and 41 patients with SES. CAS was performed 8.5 months after stent implantation. We assessed neointimal coverage, thrombus, and plaque color. We classified neointimal coverage in 4 grades: grade 0=struts were completely exposed; grade 1=struts were visible with dull light reflexion; grade 2=there was no light reflexion from slightly visible struts; grade 3=struts were completely covered.nnnRESULTSnThere was no significant difference in minimum, maximum, dominant grade of neointimal coverage, and heterogeneity index between EES and SES. Thrombus was less frequently observed in EES than SES (4% vs 29%, p=0.02). When we divided study patients into acute coronary syndrome (ACS) or stable angina pectoris (SAP), there was a tendency toward less thrombus in EES than SES, in both ACS and SAP. Maximum color grade of the plaques was less advanced in EES than SES (p<0.01). Yellow plaques of grade 2 or 3 were less frequent in EES than SES (35% vs 76%, p<0.01).nnnCONCLUSIONSnThis study suggested that EES were associated with lower risk of thrombus formation than SES.

Resistance to conventional cardiopulmonary resuscitation in witnessed out-of-hospital cardiac arrest patients with shockable initial cardiac rhythm.

BACKGROUNDnShockable initial cardiac rhythm is a key predictor of survival after out-of-hospital cardiac arrest (OHCA). However, not all patients with shockable OHCA achieve return of spontaneous circulation (ROSC) via conventional cardiopulmonary resuscitation (CPR). Therefore, we retrospectively analyzed patients with witnessed OHCA and shockable initial cardiac rhythm to identify the resistance factors for conventional CPR.nnnMETHODSnWe retrospectively analyzed consecutive patients with witnessed OHCA and shockable initial cardiac rhythm who were admitted to our hospital between October 2009 and October 2014. We then compared the baseline characteristics, pre-hospital clinical course, and causes of the cardiopulmonary arrest among patients who achieved ROSC via conventional CPR and patients who did not achieve ROSC via conventional CPR and underwent extracorporeal CPR (ECPR).nnnRESULTSnA total of 85 patients achieved ROSC via conventional CPR (non-ECPR group) and 40 patients did not achieve ROSC via conventional CPR and underwent ECPR (ECPR group). Among these 125 patients, 113 had known causes for their cardiopulmonary arrest, including 66 cases (53%) of acute myocardial infarction (AMI). There were no significant differences in the causes of arrest between the non-ECPR and ECPR cases. However, among the 66 cases of AMI (43 non-ECPR and 23 ECPR), the rate of non-recanalization during the initial coronary angiography was significantly higher among the ECPR cases (non-ECPR: 58% vs. ECPR: 87%; p=0.03).nnnCONCLUSIONSnThe major cause of witnessed OHCA with shockable initial cardiac rhythm was AMI, and resistance to conventional CPR was related to continuous myocardial ischemia.

At what level of unconsciousness is mild therapeutic hypothermia indicated for out-of-hospital cardiac arrest: a retrospective, historical cohort study

BackgroundAppropriate patient selection is very important when initiating mild therapeutic hypothermia (MTH) for patients following out-of-hospital cardiac arrest, and the extent of unconsciousness at implementation must be defined in such cases. However, there are no clear standards regarding the level of unconsciousness at which MTH would be beneficial. The effects of MTH in patients with different degrees of unconsciousness according to the motor response score of the Glasgow Coma Scale (GCS) were investigated.MethodsThe subjects consisted of witnessed non-traumatic adult out-of-hospital cardiac arrest patients admitted to our institute from April 2002 to August 2011. The patients were divided into six groups according to the GCS motor response score: 1 (GCS M1), 2 (GCS M2), 3 (GCS M3), 4 (GCS M4), 5 (GCS M5), and 6 (GCS M6). The neurological outcome was evaluated at 30xa0days after hospital admission using the Cerebral Performance Category. Chi-squared Automatic Interaction Detection (CHAID) analysis was performed to estimate the threshold GCS M level where therapeutic hypothermia is indicated. Odds ratios were then calculated by multiple logistic-regression analysis using factors including GCS M5–6 and MTH.ResultsA total of 289 patients were enrolled in this study. CHAID analysis demonstrated two points of significant increase in percentage of good recovery at 30xa0days after admission, dividing the GCS M categories into three groups. Patients classified with a GCS motor response score of 5 or higher had the highest percentage of good recovery. The odds ratio for good recovery (CPC1–2) was 2.901 (95xa0% CI 1.460–5.763, Pu2009=u20090.002) for MTH, and that for GCS M5–6 was 159.835 (95xa0% CI 33.592–760.513, Pu2009<u20090.001).ConclusionsMTH may be unnecessary in patients with a GCS motor response score of 5 or higher. Consequently, because there are post cardiac arrest patients with a GCS motor response score of 4 or lower who benefit from MTH, MTH may be limited to patients with a GCS motor response score of 4 or lower.

Global Registry of Acute Coronary Events risk score predicts mortality and neurological outcome in out-of hospital cardiac arrest

Purpose: The aim of this study was to assess the usefulness of the Global Registry of Acute Coronary Events (GRACE) risk score in predicting in‐hospital mortality and neurological outcome of patients resuscitated after out‐of‐hospital cardiac arrest (OHCA). Methods: We retrospectively analyzed the data of patients admitted to our hospital between October 2009 and October 2015 with OHCA and shockable initial cardiac rhythm who were resuscitated via conventional cardiopulmonary resuscitation. We calculated the GRACE risk score on admission and assessed its usefulness in predicting in‐hospital mortality and neurological outcome. Results: Among 91 patients, 42 (46%) had acute myocardial infarction (AMI), 19 (21%) died in‐hospital, and 52 (57%) had favorable neurological outcome. Among all the study patients, GRACE risk score was lower in survivors than in non‐survivors (median 211 [interquartile range 176–240] vs. 266 [219–301], p < 0.001, respectively) and in favorable than in unfavorable neurological outcome group (202 [167–237] vs. 242 [219–275], p < 0.001, respectively). Multivariate analysis showed significant association between GRACE risk score and favorable neurological outcome (odds ratio, 0.975; 95% confidence interval, 0.961–0.990). Areas under receiver‐operating characteristic curves, that describe the accuracy of GRACE risk score in predicting in‐hospital mortality and favorable neurological outcome, were both 0.79. Conclusion: GRACE risk score may predict the in‐hospital mortality and neurological outcome associated with resuscitated patients with OHCA and shockable initial cardiac rhythm, regardless of the cause of arrest.

D-dimer predicts bleeding complication in out-of-hospital cardiac arrest resuscitated with extracorporeal membrane oxygenation

Purpose In out‐of‐hospital cardiac arrest (OHCA) patients resuscitated with veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO), known as extracorporeal cardiopulmonary resuscitation (ECPR), bleeding is a common complication. The purpose of this study was to assess the risk factors for bleeding complications in ECPR patients. Methods We retrospectively analyzed the data for OHCA patients admitted to our hospital and resuscitated with ECPR between October 2009 and December 2016. We compared patients with and without major bleeding (i.e. the Bleeding Academic Research Consortium class ≥ 3 bleeding) within 24 h of hospital admission. Patients, whose bleeding complication was not evaluated, were excluded. Results During the study period, 133 OHCA patients were resuscitated with ECPR, of whom 102 (77%) were included. In total, 71 (70%) patients experienced major bleeding. There were significant differences in age (median 65 vs. 50 years, P < 0.001), prior antiplatelet therapy (25% vs. 3%, P = 0.008), hemoglobin (median 11.6 vs. 12.6 g/dL, P = 0.003), platelet count (median 125 vs. 155 × 103/&mgr;L, P = 0.001), and D‐dimer levels on admission (median 18.8 vs. 6.7 &mgr;g/mL, P < 0.001) among patients with and those without major bleeding. Multivariate analysis showed significant associations between major bleeding and D‐dimer levels (odds ratio, 1.066; 95% confidence interval, 1.018–1.116). Area under receiver‐operating characteristic curve, which describes the accuracy of D‐dimer levels in predicting major bleeding, was 0.76 (95% confidence interval, 0.66–0.87). Conclusion D‐dimer levels may predict major bleeding in ECPR patients, suggesting that hyperfibrinolysis may be related to bleeding.

Low-flow time is associated with a favorable neurological outcome in out-of-hospital cardiac arrest patients resuscitated with extracorporeal cardiopulmonary resuscitation

Propose: The aim of this retrospective study was to investigate the prognostic factors in extracorporeal cardiopulmonary resuscitation (ECPR) patients and to assess their accuracy as predictors of a favorable neurological outcome. Materials and methods: Between October 2009 and December 2017, we retrospectively analyzed witnessed out‐of‐hospital cardiac arrest patients who were admitted to our hospital and resuscitated with ECPR. We compared the baseline characteristics, pre‐hospital clinical course, arrest causes, and blood samples on admission for the favorable and unfavorable outcome groups. Results: Among the 135 patients included, 22 (16%) had a favorable neurological outcome. Low‐flow time was shorter (median 38 vs. 48 min, p < 0.001) in the favorable neurological outcome group; in multiple logistic analyses, low‐flow time was significantly associated with a favorable neurological outcome (odds ratio, 0.88; 95% confidence interval, 0.82–0.94). The area under the receiver‐operating characteristic curve of low‐flow time was 0.80 (95% confidence interval, 0.70–0.89), and the cut‐off value of 58 min corresponded to a sensitivity of 0.25 and a specificity of 1.0. Conclusions: In ECPR patients, low‐flow time was significantly associated with a favorable neurological outcome, and ECPR should be performed within 58 min of the low‐flow time.