Ryota Teramoto

Lipoprotein(a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gain-of-Function Mutations.

BACKGROUND It has been shown that serum lipoprotein(a) [Lp(a)] is elevated in familial hypercholesterolemia (FH) with mutation(s) of the LDL receptor (LDLR) gene. However, few data exist regarding Lp(a) levels in FH with gain-of-function mutations of the PCSK9 gene. METHODSANDRESULTS We evaluated 42 mutation-determined heterozygous FH patients with aPCSK9gain-of-function mutation (FH-PCSK9, mean age 52, mean LDL-C 235 mg/dl), 198 mutation-determined heterozygous FH patients with aLDLRmutation (FH-LDLR, mean age 44, mean LDL-C 217 mg/dl), and 4,015 controls (CONTROL, mean age 56, mean LDL-C 109 mg/dl). We assessed their Lp(a), total cholesterol, triglycerides, HDL-C, LDL-C, use of statins, presence of hypertension, diabetes, chronic kidney disease, smoking, body mass index (BMI) and coronary artery disease (CAD). Multiple regression analysis showed that HDL-C, use of statins, presence of hypertension, smoking, BMI, and Lp(a) were independently associated with the presence of CAD. Under these conditions, the serum levels of Lp(a) in patients with FH were significantly higher than those of the CONTROL group regardless of their causative genes, among the groups propensity score-matched (median Lp(a) 12.6 mg/dl [IQR:9.4-33.9], 21.1 mg/dl [IQR:11.7-34.9], and 5.0 mg/dl [IQR:2.7-8.1] in the FH-LDLR, FH-PCSK9, and CONTROL groups, respectively, P=0.002 for FH-LDLR vs. CONTROL, P=0.002 for FH-PCSK9 vs. CONTROL). CONCLUSIONS These data demonstrate that serum Lp(a) is elevated in patients with FH caused by PCSK9 gain-of-function mutations to the same level as that in FH caused by LDLR mutations.

Assessment of Coronary Atherosclerosis in Patients With Familial Hypercholesterolemia by Coronary Computed Tomography Angiography

The aims of this study were (1) to determine whether the accumulation of coronary plaque burden assessed with coronary computed tomography angiography (CCTA) can predict future events and (2) to estimate the onset and progression of coronary atherosclerosis in patients with familial hypercholesterolemia (FH). Consecutive 101 Japanese patients with heterozygous FH (men = 52, mean age 56 ± 16 years, mean low-density lipoprotein cholesterol 264 ± 58 mg/dl) who underwent 64-detector row CCTA without known coronary artery disease were retrospectively evaluated by assigning a score (0 to 5) to each of 17 coronary artery segments according to the Society of Cardiovascular Computed Tomography guidelines. Those scores were summed and subsequently natural log transformed. The periods to major adverse cardiac events (MACE) were estimated using multivariable Cox proportional hazards models. During the follow-up period (median 941 days), 21 MACE had occurred. Receiver operating characteristic curve analyses identified a plaque burden score of 3.35 (raw score 28.5) as the optimal cutoff for predicting a worse prognosis. Multivariate Cox regression analysis identified the presence of a plaque score ≥3.35 as a significant independent predictor of MACE (hazard ratio = 3.65; 95% confidence interval 1.32 to 25.84, p <0.05). The regression equations were Y = 0.68X - 15.6 (r = 0.54, p <0.05) in male and Y = 0.74X - 24.8 (r = 0.69, p <0.05) in female patients with heterozygous FH. In conclusion, coronary plaque burden identified in a noninvasive, quantitative manner was significantly associated with future coronary events in Japanese patients with heterozygous FH and that coronary atherosclerosis may start to develop, on average, at age 23 and 34 years in male and female patients with heterozygous FH, respectively.

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). METHODSANDRESULTS 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).

Usefulness of Electrocardiographic Voltage to Determine Myocardial Fibrosis in Hypertrophic Cardiomyopathy.

Classic electrocardiographic (ECG) voltage indexes have been applied to screen for left ventricular (LV) hypertrophy in hypertrophic cardiomyopathy (HC). However, it is unclear whether low ECG voltage reflects deteriorated electrical forces because of replacement of the myocardium by fibrotic tissues in HC. We investigated correlations between classic ECG voltage indexes (Cornell, total QRS voltage, and Sokolow-Lyon) and cardiac magnetic resonance (CMR) parameters focusing on the impact of low ECG voltage on the LV ejection fraction (LVEF) and myocardial fibrosis in HC. We studied 108 consecutive patients with HC who underwent CMR imaging with late gadolinium enhancement (LGE). Nineteen patients with complete right or left bundle branch block were excluded, leaving 89 patients for analysis (age 61.0 ± 13.9 years; 58 men). Of the 3 voltage indexes, the total QRS voltage and Sokolow-Lyon indexes were positively correlated with LVEF. For discriminating patients with end-stage HC (LVEF <50%) from patients with HC and preserved LVEF (≥ 50%), receiver-operating characteristic analysis revealed an excellent area under the curve of 0.87 for the total QRS voltage index and 0.90 for the Sokolow-Lyon index, whereas the area under the curve for the Cornell index was only 0.54 (p <0.01). Moreover, these 2 voltage indexes were negatively correlated with the extent of LGE-determined myocardial fibrosis when adjusted by the LV maximal wall thickness. In conclusion, low ECG voltage indexes may reflect increased myocardial fibrosis in patients with HC.

Age-specific differences in prognostic significance of rhythm conversion from initial non-shockable to shockable rhythm and subsequent shock delivery in out-of-hospital cardiac arrest☆

BACKGROUND Early rhythm conversion from an initial non-shockable to a shockable rhythm and subsequent shock delivery in patients with out-of-hospital cardiac arrest (OHCA) has been associated with favourable neurological outcome (Cerebral Performance Category score 1 or 2; CPC 1-2). We hypothesized that the prognostic significance of rhythm conversion and subsequent shock delivery differs by age and time from initiation of cardiopulmonary resuscitation (CPR) by emergency medical service (EMS) providers to first defibrillation (shock delivery time). METHODS We analysed 430,443 OHCA patients with an initial non-shockable rhythm using a prospective Japanese Utstein-style database from 2011 to 2014. The primary endpoint was 1-month CPC 1-2. RESULTS Multivariate logistic regression revealed that rhythm conversion and subsequent shock delivery is positively associated with 1-month CPC 1-2: the adjusted odds ratio was 6.09 (95% confidence interval: 3.65-9.75) for shock delivery time <10min and 3.34 (2.58-4.27) for 10-19min in patients aged 18-64 years, and 3.16 (1.45-6.09) for <10min and 2.17 (1.51-3.03) for 10-19min in patients aged 65-74 years. However, it is negatively associated with 1-month CPC 1-2 for shock delivery time of 20-59min in patients aged 75-84 years (0.55; 0.27-0.98) and ≥85 years (0.17; 0.03-0.53). CONCLUSIONS Early rhythm conversion from an initial non-shockable to a shockable rhythm and subsequent shock delivery is associated with increased odds of 1-month CPC 1-2 in OHCA patients aged 18-74 years but not in those aged ≥75 years.

Prehospital predictors of neurological outcomes in out-of-hospital cardiac arrest patients aged 95 years and older: A nationwide population-based observational study

BACKGROUND Population aging has rapidly progressed in Japan. However, few data exist regarding the characteristics of extremely elderly patients with out-of-hospital cardiac arrest (OHCA). We aimed to determine the prehospital predictors of one-month survival with favorable neurological outcomes (Cerebral Performance Category scale, category 1 or 2; CPC 1-2) in this population. METHODS We investigated 23,520 OHCA patients aged ≥95 years from a prospectively recorded, nationwide, Utstein-style Japanese database between 2008 and 2012. The primary study endpoint was one-month CPC 1-2 after OHCA. RESULTS The one-month CPC 1-2 rate was 0.27% (63/23,520). Only two variables were significantly associated with one-month CPC 1-2 in a multivariate logistic regression model: prehospital return of spontaneous circulation (ROSC) [adjusted odds ratio (aOR), 94.4; 95% confidential interval (CI), 50.1-191.7] and emergency medical service (EMS)-witnessed arrest (aOR, 5.1; 95% CI, 2.6-10.2). When stratified by these two predictors, the one-month CPC 1-2 rates were 20.2% (18/89) for patients who had both prehospital ROSC and EMS-witnessed arrest, 4.2% (33/783) for those who had prehospital ROSC without EMS-witnessed arrest, 0.28% (3/1065) for those who had EMS-witnessed arrest without prehospital ROSC, and 0.04% (9/21,583) for those who had neither predictor, respectively. CONCLUSIONS The crucial prehospital predictors for one-month CPC 1-2 in elderly OHCA patients aged ≥95 years in Japan were prehospital ROSC and EMS-witnessed arrest and the former was the predominant predictor.

Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy

BACKGROUND The development of candidate gene approaches to enable molecular diagnosis of hypertrophic cardiomyopathy (HCM) has required extensive and prolonged efforts. Whole exome sequencing (WES) technologies have already accelerated genetic studies of Mendelian disorders, yielding approximately 30% diagnostic success. As a result, there is great interest in extending the use of WES to any of Mendelian diseases. This study investigated the potential of WES for molecular diagnosis of HCM. METHODS WES was performed on seven relatives from a large HCM family with a clear HCM phenotype (five clinically affected and two unaffected) in the Kanazawa University Hypertrophic Cardiomyopathy Registry. Serial bioinformatics filtering methods as well as using combined annotation dependent depletion (CADD) score and high heart expression (HHE) gene data were applied to detect the causative variant. Moreover, additional carriers of the variant were investigated in the HCM registry, and clinical characteristics harboring the variant were collected and evaluated. RESULTS WES detected 60020 rare variants in the large HCM family. Of those, 3439 were missense, nonsense, splice-site, or frameshift variants. After genotype-phenotype matching, 13 putative variants remained. Using CADD score and HHE gene data, the number of candidates was reduced to one, a variant in the myosin essential light chain (MYL3, NM_000258.2:c.281G>A, p.Arg94His) that was shared by the five affected subjects. Additional screening of the HCM registry (n=600) identified two more subjects with this variant. Serial assessments of the variant carriers revealed the following phenotypic characteristics: (1) disease-penetrance of 88%; (2) all clinically affected carriers exhibited asymmetric septal hypertrophy with a substantial maximum left ventricular wall thickness of 18±3mm without any obstruction. CONCLUSIONS WES combined with CADD score and HHE gene data may be useful even in HCM. Furthermore, the MYL3 Arg94His variant was associated with high disease penetrance and substantial interventricular septal hypertrophy.

Impact of Distal Protection with Filter-Type Device on Long-term Outcome after Percutaneous Coronary Intervention for Acute Myocardial Infarction: Clinical Results with Filtrap(®).

Aim: Although distal embolization during percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) deteriorates cardiac function, whether distal protection (DP) can improve prognosis is still controversial. We investigated whether a filter-type DP device, Filtrap®, could improve long-term outcomes after PCI for AMI. Method: We studied 164 patients (130 men, mean age: 65.7 years) who underwent PCI. Patients were divided into two groups based on the use of Filtrap®. The occurrence of congestive heart failure (CHF) and major adverse cardiac events (MACE) defined as cardiac death, recurrent AMI, and target vessel revascularization were compared. Result: Between DP (n = 53, 41 men, mean age: 65.5 years) and non-DP (n = 111, 89 men, mean age: 65.8 years) groups, although there was significantly greater plaque area in the DP group than in the non-DP group, there were no significant differences in coronary reperfusion flow after PCI. Interestingly, patients with CHF in the non-DP group exhibited a higher CK level than those in the DP group. During a 2-year follow-up period, cumulative CHF was significantly lower in the DP group than in the non-DP group (log-rank p = 0.018), and there was no significant difference in the MACE rate (log-rank p = 0.238). The use of DP device could not predict MACE, but could predict CHF by multivariate analysis (odds ratio = 0.099, 95% CI: 0.02–0.42, p = 0.005). Conclusion: These results demonstrate that favorable clinical outcomes could be achieved by the filter-type DP device in AMI, particularly in patients with CHF.

A case of rhabdomyolysis related to sorafenib treatment for advanced hepatocellular carcinoma

We report on a case of rhabdomyolysis related to sorafenib treatment for advanced hepatocellular carcinoma. A 70-year-old man was admitted to our hospital with fatigue, myalgia and an elevated creatine phosphokinase level. He was diagnosed as rhabdomyolysis related to sorafenib treatment for advanced hepatocellular carcinoma. After discontinuation of sorafenib, his fatigue and myalgia resolved and his creatine phosphokinase level returned to normal. Rhabdomyolysis related to sorafenib treatment is rare adverse effect. This is the first detailed case report of rhabdomyolysis related to sorafenib treatment.

Spontaneous healing of posttraumatic focal coronary aneurysm: A case report

We report on the spontaneous healing of a posttraumatic focal coronary aneurysm in a previously healthy 61-year-old man after his involvement in a motor vehicle accident, resulting in blunt chest trauma that injured the anterior wall of his left ventricle. Left-sided cardiac catheterization and selective coronary angiography 1 month after the accident showed an aneurysm in the proximal part of the left anterior descending artery, and normal coronary arteries otherwise. Intravascular ultrasound revealed that the lesion was a pseudoaneurysm protruding toward the myocardium. Surgical removal of the aneurysm was not considered, and the patient was discharged after 2 months of uneventful hospitalization. Follow-up coronary angiography and intravascular ultrasound at 3 months and 1 year after the accident showed a total regression of the aneurysm. The patient has remained asymptomatic, with no residual ischemia 3 years after the accident. This case indicates that careful conservative treatment is a therapeutic option for posttraumatic coronary pseudoaneurysms.