Jervell and Lange-Nielsen syndrome with novel KCNQ1 and additional gene mutations.

We encountered a boy with Jervell and Lange-Nielsen syndrome (JLNS) with compound heterozygous KCNQ1 mutations, maternal Trp248Phe and a novel paternal mutation, Leu347Arg. His father showed long QT (LQT) and arrhythmia. His mother was asymptomatic with no ECG abnormalities. The proband and his father had an additional mutation (SNTA1 Thr372Met), which is reportedly related to SIDS. These results suggest that multiple gene mutations influence the phenotype of KCNQ1 mutation-related arrhythmia.

New PCNT candidate missense variant in a patient with oral and maxillofacial osteodysplasia: a case report.

BACKGROUND: Osteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region. CASE PRESENTATION: A 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6 months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157 cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient. CONCLUSIONS: Protein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.

Early therapeutic effects of adaptive servo-ventilation on cardiac sympathetic nervous function in patients with heart failure evaluated using a combination of 11C-HED PET and 123I-MIBG SPECT.

RATIONALE: Adaptive servo-ventilation (ASV), a novel respiratory support therapy for sleep disorders, may improve cardiac function in heart failure (HF). However, the reasons that ASV improves cardiac function have not been fully studied especially in sympathetic nervous function (SNF). The purpose of the present study was to investigate the effects of ASV therapy on cardiac SNF in patients with HF. METHODS: We evaluated ASV therapeutic effects before and 6 months after ASV therapy in 9 HF patients [57.3 ± 17.3 years old, left ventricular ejection fraction (LVEF) 36.1 ± 16.7%]. We performed echocardiography, polysomnography, biomarkers, 11C-hydroxyephedrine (HED) PET as a presynaptic function marker and planar 123I-metaiodobenzylguanidine (MIBG) to evaluate washout rate. RESULTS: ASV therapy reduced apnea-hypopnea index (AHI) and improved plasma brain natriuretic peptide (BNP) concentration. In 123I-MIBG imaging, the early heart/mediastinum (H/M) ratio increased after ASV therapy (2.19 ± 0.58 to 2.40 ± 0.67; P = 0.045). Washout rate did not change (23.8 ± 7.3% to 23.8 ± 8.8%; P = 0.122). Global 11C-HED retention index (RI) improved from 0.068 ± 0.033/s to 0.075 ± 0.034/s (P = 0.029). CONCLUSIONS: ASV reduced AHI and improved BNP. ASV might initially improve presynaptic cardiac sympathetic nervous function in HF patients after 6 months of treatment.

Immunohistochemical identification of Propionibacterium acnes in granuloma and inflammatory cells of myocardial tissues obtained from cardiac sarcoidosis patients.

BACKGROUND: Although rare, cardiac sarcoidosis (CS) is potentially fatal. Early diagnosis and intervention are essential, but histopathologic diagnosis is limited. We aimed to detect Propionibacterium acnes, a commonly implicated etiologic agent of sarcoidosis, in myocardial tissues obtained from CS patients. METHODS AND RESULTS: We examined formalin-fixed paraffin-embedded myocardial tissues obtained by surgery or autopsy and endomyocardial biopsy from patients with CS (n = 26; CS-group), myocarditis (n = 15; M-group), or other cardiomyopathies (n = 39; CM-group) using immunohistochemistry (IHC) with a P. acnes-specific monoclonal antibody. We found granulomas in 16 (62%) CS-group samples. Massive (≥14 inflammatory cells) and minimal (<14 inflammatory cells) inflammatory foci, respectively, were detected in 16 (62%) and 11 (42%) of the CS-group samples, 10 (67%) and 10 (67%) of the M-group samples, and 1 (3%) and 18 (46%) of the CM-group samples. P. acnes-positive reactivity in granulomas, massive inflammatory foci, and minimal inflammatory foci were detected in 10 (63%), 10 (63%), and 8 (73%) of the CS-group samples, respectively, and in none of the M-group and CM-group samples. CONCLUSIONS: Frequent identification of P. acnes in sarcoid granulomas of originally aseptic myocardial tissues suggests that this indigenous bacterium causes granuloma in many CS patients. IHC detection of P. acnes in massive or minimal inflammatory foci of myocardial biopsy samples without granulomas may be useful for differentiating sarcoidosis from myocarditis or other cardiomyopathies.

Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses.

Human endogenous retroviruses (HERVs) and other long terminal repeat (LTR)-type retrotransposons (HERV/LTRs) have regulatory elements that possibly influence the transcription of host genes. We systematically identified and characterized these regulatory elements based on publicly available datasets of ChIP-Seq of 97 transcription factors (TFs) provided by ENCODE and Roadmap Epigenomics projects. We determined transcription factor-binding sites (TFBSs) using the ChIP-Seq datasets and identified TFBSs observed on HERV/LTR sequences (HERV-TFBSs). Overall, 794,972 HERV-TFBSs were identified. Subsequently, we identified "HERV/LTR-shared regulatory element (HSRE)," defined as a TF-binding motif in HERV-TFBSs, shared within a substantial fraction of a HERV/LTR type. HSREs could be an indication that the regulatory elements of HERV/LTRs are present before their insertions. We identified 2,201 HSREs, comprising specific associations of 354 HERV/LTRs and 84 TFs. Clustering analysis showed that HERV/LTRs can be grouped according to the TF binding patterns; HERV/LTR groups bounded to pluripotent TFs (e.g., SOX2, POU5F1, and NANOG), embryonic endoderm/mesendoderm TFs (e.g., GATA4/6, SOX17, and FOXA1/2), hematopoietic TFs (e.g., SPI1 (PU1), GATA1/2, and TAL1), and CTCF were identified. Regulatory elements of HERV/LTRs tended to locate nearby and/or interact three-dimensionally with the genes involved in immune responses, indicating that the regulatory elements play an important role in controlling the immune regulatory network. Further, we demonstrated subgroup-specific TF binding within LTR7, LTR5B, and LTR5_Hs, indicating that gains or losses of the regulatory elements occurred during genomic invasions of the HERV/LTRs. Finally, we constructed dbHERV-REs, an interactive database of HERV/LTR regulatory elements (http://herv-tfbs.com/). This study provides fundamental information in understanding the impact of HERV/LTRs on host transcription, and offers insights into the transcriptional modulation systems of HERV/LTRs and ancestral HERVs.

A birth of bipartite exon by intragenic deletion.

BACKGROUND: Disease-causing mutations that activate transposon-derived exons without creating a new splice-site consensus have been reported rarely, but they provided unique insights into our understanding of structural motifs required for inclusion of intronic sequences in mature transcripts. METHODS: We employ a combination of experimental and computational techniques to characterize the first de novo bipartite exon activation in genetic disease. RESULTS: The exon originated from two separate introns as a result of an in-frame COL4A5 deletion associated with a typical Alport syndrome. The deletion encompassed exons 38 through 41 and activated a cryptic 3' and 5' splice site that were derived from intron 37 and intron 41, respectively. The deletion breakpoint was in the middle of the new exon, with considerable complementarity between the two exonic parts, potentially bringing the cryptic 3' and 5' splice site into proximity. The 3' splice site, polypyrimidine tract and the branch site of the new exon were derived from an inactive, 5' truncated LINE-1 retrotransposon. This ancient LINE-1 copy sustained a series of mutations that created the highly conserved AG dinucleotide at the 3' splice site early in primate development. The exon was fully included in mature transcripts and introduced a stop codon in the shortened COL4A5 mRNA, illustrating pitfalls of inferring disease severity from DNA mutation alone. CONCLUSION: These results expand the repertoire of mutational mechanisms that alter RNA processing in genetic disease and illustrate the extraordinary versatility of transposed elements in shaping the new exon-intron structure and the phenotypic variability.

Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype.

Among more than 5,000 human monogenic disorders with known causative genes, transposable element insertion of a Long Interspersed Nuclear Element 1 (LINE1, L1) is known as the mechanistic basis in only 13 genetic conditions. Meckel-Gruber syndrome is a rare ciliopathy characterized by occipital encephalocele and cystic kidney disease. Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. A medical exome analysis detected a heterozygous frameshift mutation, c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele. The further use of a dedicated bioinformatics algorithm for detecting retrotransposon insertions led to the detection of an L1 insertion affecting exon 7 in the paternally derived allele. The complete sequencing and sequence homology analysis of the inserted L1 element showed that the L1 element was classified as L1HS (L1 human specific) and that the element had intact open reading frames in the two L1-encoded proteins. This observation ranks Meckel-Gruber syndrome as only the 14th disorder to be caused by an L1 insertion among more than 5,000 known human genetic disorders. Although a transposable element detection algorithm is not included in the current best-practice next-generation sequencing analysis, the present observation illustrates the utility of such an algorithm, which would require modest computational time and resources. Whether the seemingly infrequent recognition of L1 insertion in the pathogenesis of human genetic diseases might simply reflect a lack of appropriate detection methods remains to be seen.

Characterization of contiguous gene deletions in COL4A6 and COL4A5 in Alport syndrome-diffuse leiomyomatosis.

Alport syndrome-diffuse leiomyomatosis (AS-DL, OMIM: 308940) is a rare variant of the X-linked Alport syndrome that shows overgrowth of visceral smooth muscles in the gastrointestinal, respiratory and female reproductive tracts in addition to renal symptoms. AS-DL results from deletions that encompass the 5' ends of the COL4A5 and COL4A6 genes, but deletion breakpoints between COL4A5 and COL4A6 have been determined in only four cases. Here, we characterize deletion breakpoints in five AS-DL patients and show a contiguous COL4A6/COL4A5 deletion in each case. We also demonstrate that eight out of nine deletion alleles involved sequences homologous between COL4A5 and COL4A6. Most breakpoints took place in recognizable transposed elements, including long and short interspersed repeats, DNA transposons and long-terminal repeat retrotransposons. Because deletions involved the bidirectional promoter region in each case, we suggest that the occurrence of leiomyomatosis in AS-DL requires inactivation of both genes. Altogether, our study highlights the importance of homologous recombination involving multiple transposed elements for the development of this continuous gene syndrome and other atypical loss-of-function phenotypes.

SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

Adaptive Servo-Ventilation Has More Favorable Acute Effects on Hemodynamics Than Continuous Positive Airway Pressure in Patients With Heart Failure.

Adaptive servo-ventilation (ASV) has been attracting attention as a novel respiratory support therapy for heart failure (HF). However, the acute hemodynamic effects have not been compared between ASV and continuous positive airway pressure (CPAP) in HF patients.We studied 12 consecutive patients with stable chronic HF. Hemodynamic measurement was performed by right heart catheterization before and after CPAP 5 cmH2O, CPAP 10 cmH2O, and ASV for 15 minutes each.Heart rate, blood pressure, pulmonary capillary wedge pressure (PCWP), and stroke volume index (SVI) were not changed by any intervention. Right atrial pressure significantly increased after CPAP 10 cmH2O (3.6 ± 3.3 to 6.7 ± 1.6 mmHg, P = 0.005) and ASV (4.1 ± 2.6 to 6.8 ± 1.5 mmHg, P = 0.026). Cardiac index was significantly decreased by CPAP 10 cmH2O (2.3 ± 0.4 to 1.9 ± 0.3 L/minute/m(2), P = 0.048), but was not changed by ASV (2.3 ± 0.4 to 2.0 ± 0.3 L/ minute/m(2), P = 0.299). There was a significant positive correlation between baseline PCWP and % of baseline SVI by CPAP 10 cmH2O (r = 0.705, P < 0.001) and ASV (r = 0.750, P < 0.001). ASV and CPAP 10 cmH2O had significantly greater slopes of this correlation than CPAP 5 cmH2O, suggesting that patients with higher PCWP had a greater increase in SVI by ASV and CPAP 10 cmH2O. The relationship between baseline PCWP and % of baseline SVI by ASV was shifted upwards compared to CPAP 10 cmH2O. Furthermore, based on the results of a questionnaire, patients accepted CPAP 5 cmH2O and ASV more favorably compared to CPAP 10 cmH2O.ASV had more beneficial effects on acute hemodynamics and acceptance than CPAP in HF patients.

Identification of novel exonic mobile element insertions in epithelial ovarian cancers.

Mobile elements comprise about half of the human genome. Three active mobile element families (L1, Alu, and SVA) possibly cause diseases such as cancer. We conducted mobile element insertion (MEI) profiling of 44 epithelial ovarian cancers using exome-sequencing data. We identified a total of 106 MEIs using the Mobster program, 8 of which were novel exonic MEIs.

Cardiac magnetic resonance performs better in the detection of functionally significant coronary artery stenosis compared to single-photon emission computed tomography and dobutamine stress echocardiography.

BACKGROUND: Fractional flow reserve (FFR) measured on catheterization is now widely used for the diagnosis of functional myocardial ischemia in patients with coronary artery disease (CAD). FFR, however, is invasive and carries potential procedural complications. Therefore, the aim of this study was to compare the diagnostic capability in functionally significant stenosis identified on FFR, between cardiac magnetic resonance myocardial perfusion imaging (CMR-MPI), single-photon emission computed tomography MPI (SPECT-MPI), and dobutamine stress echocardiography (DSE) in patients with CAD. METHODS AND RESULTS: A total of 25 patients who had at least 1 angiographic stenosis ≥50% on coronary angiography was studied. CMR-MPI, SPECT-MPI and DSE were done before FFR measurement. FFR was measured in all 3 major epicardial coronary arteries. Out of 71 vascular territories excluding 4 territories due to inadequate imaging, 29 (41%) had FFR <0.80. The sensitivity of CMR-MPI was significantly higher than that of SPECT-MPI and DSE (P=0.02 and P=0.001, respectively). The area under the receiver operating characteristic curve (AUC) for CMR-MPI (AUC, 0.92) was significantly greater than for SPECT-MPI (AUC, 0.73; P=0.006) and DSE (AUC, 0.69; P<0.001). CONCLUSIONS: CMR-MPI performed well in the detection of functionally significant stenosis defined according to FFR, and had the highest diagnostic sensitivity among the 3 modalities tested in patients with CAD.

Serum choline plasmalogens-those with oleic acid in sn-2-are biomarkers for coronary artery disease.

BACKGROUND: Identifying risk factors is crucial for preventing cardiovascular events, but there are no widely accepted predictive biomarkers. In our previous study of Japanese asymptomatic cohorts, we performed global analysis of serum ether glycerophospholipids (Egp) molecular profiles, and found that choline plasmalogens (PlsCho; 1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphocholine), particularly those containing oleic acid (18:1) in the sn-2 position, were strongly associated with a wide range of risk factors for metabolic syndrome/atherosclerosis. METHODS: We determined serum concentrations of Egp molecular species of coronary artery disease patients (n=50; 31 males and 19 females) by LC/MS/MS, and plasmalogen (Pls; 1-O-alk-1'-enyl-2-acyl-sn-glycerophospholipids) contents in lipoprotein fractions by HPLC using radioactive iodine. RESULTS: We found that the serum concentrations of ether choline glycerophospholipids (EgpCho), particularly PlsCho, were not only significantly lower in males with significant coronary stenosis but also associated with atherosclerosis-related parameters, and their association was stronger than either high-density lipoprotein cholesterol or adiponectin. In addition, serum PlsCho containing 18:1 or linoleic acid (18:2) in sn-2 showed the highest correlations with a wide range of atherogenic parameters among PlsCho molecular species. CONCLUSION: These results verify our previous findings that serum PlsCho, particularly those containing 18:1 in sn-2, may serve as reliable biomarkers for atherosclerosis.

Electrocardiographically gated ¹¹C-hydroxyephedrine PET for the simultaneous assessment of cardiac sympathetic and contractile functions.

OBJECTIVE: Application of the electrocardiographically (ECG) gated positron emission tomography (PET) technique with (11)C-hydroxyephedrine (HED) would allow the simultaneous assessment of cardiac sympathetic and contractile functions. However, there are uncertainties regarding the diagnostic accuracy of left ventricular (LV) volume measurements using ECG-gated HED-PET. The purpose of this study was to clarify the minimal requirement of count statistics to measure LV volumes with ECG-gated HED-PET and to investigate the reliability of the measurements. METHODS: Five healthy volunteers and 11 patients with heart failure underwent a 40-min list-mode PET scan after an injection of HED (197 ± 35 MBq). The list-mode data were histogrammed into multiple sets of acquisition periods at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 Mcount/bin and reconstructed into corresponding gated images using an iterative algorithm. The LV end-diastolic volume (LVEDV), the LV end-systolic volume (LVESV), and the LV ejection fraction (LVEF) were calculated in each acquisition period. These values were compared with those obtained by cardiac magnetic resonance imaging (MRI). Possible effects of HED retention on the accuracy of the volume measurements were investigated. RESULTS: Collecting less than 4.0 Mcount/bin resulted in noisy cardiac images. The lower counts resulted in underestimation in the volume measurements. Reasonably accurate volume measurements required equal to or greater than 6.0 Mcount/bin. This corresponded to 7.0 ± 1.9 min (range, 4.0-10.3 min) for the acquisition period. Volumetric results using the 6.0 Mcount/bin data highly correlated with cardiac MRI (LVEDV: r = 0.85, p < 0.0001; LVESV: r = 0.89, p < 0.0001; LVEF: r = 0.77, p < 0.01). The HED retention did not affect the volumetric results compared to the MRI volumetry. CONCLUSIONS: The volumetric accuracy with ECG-gated HED-PET was affected by the count statistics rather than the HED retention. LV volume measurements were feasible with 10-min acquisition period for most of the patients. This technique allows the simultaneous assessment of cardiac sympathetic and contractile functions without the need for an additional injection or scanning time, thus reducing overall costs for diagnostic imaging.

Acute hemodynamic effects of adaptive servo-ventilation in patients with heart failure.

BACKGROUND: Adaptive servo-ventilation (ASV) improves cardiac function in patients with heart failure (HF). We compared the hemodynamics of control and HF patients, and identified the predictors for acute effects of ASV in HF. METHODS AND RESULTS: We performed baseline echocardiographic measurements and hemodynamic measurements at baseline and after 15 min of ASV during cardiac catheterization in 11 control and 34 HF patients. Heart rate and blood pressure did not change after ASV in either the control or HF group. Stroke volume index (SVI) decreased from 49.3±7.6 to 41.3±7.6 ml/m2 in controls (P<0.0001) but did not change in the HF patients (from 34.8±11.5 to 32.8±8.9 ml/m2, P=0.148). In the univariate analysis, pulmonary capillary wedge pressure (PCWP), mitral regurgitation (MR)/left atrial (LA) area, E/A, E/e', and the sphericity index defined by the ratio between the short-axis and long-axis dimensions of the left ventricle significantly correlated with % change of SVI from baseline during ASV. PCWP and MR/LA area were independent predictors by multivariate analysis. Moreover, responders (15 of 34 HF patients; 44%) categorized by an increase in SVI showed significantly higher PCWP, MR, and sphericity index. CONCLUSIONS: Left ventricular structure and MR, as well as PCWP, could predict acute favorable effects on hemodynamics by ASV therapy in HF patients.

Cardiac (18)F-FDG PET/CT with heparin detects infective vegetation in a patient with mechanical valve replacement.

We report the usefulness of F-FDG PET/CT for the detection and therapy evaluation of the infective vegetation. A 64-year-old man with history of aortic valve replacement presented with 2 months of fever without identifiable cause. Echocardiogram showed no inflammation vegetation or abnormality of mechanical valve function. FDG PET/CT with 50 IU/kg IV heparin revealed focal uptakes near the mechanical aortic valve. After antibiotics therapy, fever was ameliorated, and FDG PET/CT findings showed markedly decreased uptake of the lesions. FDG PET/CT is a powerful tool to detect endocarditis even in patients with no anatomical abnormalities.

Sleep-disordered breathing is an independent risk factor of aborted sudden cardiac arrest in patients with coronary artery spasm.

BACKGROUND: Sleep-disordered breathing (SDB) is often associated with sudden cardiac arrest (SCA) during sleep. Coronary artery spasm (CS) also occurs during sleep and is rarely associated with SCA, but the role of SDB in the risk of SCA is unknown in CS patients. This study evaluated the breathing patterns during sleep in CS patients with a prior history of aborted SCA. METHODS AND RESULTS: This study enrolled 24 patients (age 61.6 ± 11.0 years, male/female 19/5) with CS proven by an acetylcholine provocation test. They were divided into 2 groups: prior history of aborted SCA due to fatal arrhythmia (SCA group; n=9) and no such history (no-SCA group; n=15). Patients underwent overnight polysomnography with ambulatory electrocardiography. The overall prevalence of SDB (apnea hypopnea index ≥15) was 45.8% in this cohort. SDB was more frequent in the SCA group than in the no-SCA group (88.9% vs. 20.0% P=0.001) and identified as a pivotal risk factor of aborted SCA (odds ratio: 38.9, 95% CI: 2.80-1,498.2, P=0.01). Very-low-frequency was significantly correlated with the apnea hypopnea index in patients with SCA (P=0.01, r=0.78) during sleep. CONCLUSIONS: SDB is a significant risk factor for SCA in CS patients and autonomic instability during sleep might be involved in this association.

Diffuse large B-cell lymphoma diagnosed by intracardiac echocardiography-guided cardiac tumor biopsy.

A 44-year-old man presented with exertional dyspnea. Transthoracic echocardiography (TTE) revealed a large tumor protruding into the right atrium and extending into the left ventricle. Cardiac magnetic resonance imaging and contrast enhanced computed tomography also confirmed the intracardiac tumor detected by TTE. An endomyocardial biopsy was performed under the intracardiac echocardiography (ICE) guidance, and he was diagnosed to have diffuse large B-cell lymphoma following the histological analysis. ICE-guided cardiac tumor biopsy is expected to be a useful diagnostic strategy that can minimize the risk of procedural complications.

Decreased glomerular filtration rate is a significant and independent risk for in-hospital mortality in Japanese patients with acute myocardial infarction: report from the Hokkaido acute myocardial infarction registry.

Renal dysfunction is a significant risk factor in the prognosis of patients with cardiovascular diseases. We sought to determine the relationship between estimated glomerular filtration rate (eGFR) values and in-hospital mortality in Japanese acute myocardial infarction (AMI) patients. A total of 2266 consecutive AMI patients admitted to 22 hospitals in Hokkaido were registered. The eGFR values were determined using the following equation: eGFR=194 × (serum creatinine)(-1.094) × (age)(-0.287) ( × 0.739 if female). Patients were classified into four groups according to their eGFR values: ≥60 (n=1304), 30-59 (n=810), 15-29 (n=87) and <15 ml min(-1) per 1.73 m(2) (n=65). A total of 110 patients (4.9%) died during hospitalization. The in-hospital mortality rate was significantly higher in patients with reduced eGFR values at 2.3, 5.4, 24.1 and 23.1% for eGFR values of ≥60, 30-59, 15-29, and <15 ml min(-1) per 1.73 m(2), respectively. The odds ratios for in-hospital all cause death were 8.26 (95% confidence interval (CI): 2.22-30.77) for eGFR<15 ml min(-1) per 1.73 m(2) and 3.42 (95% CI: 1.01-11.61) for eGFR 15-29 ml min(-1) per 1.73 m(2) compared with eGFR ≥60 ml min(-1) per 1.73 m(2). Similarly, the odds ratios for in-hospital cardiac death were 8.43 (95% CI: 1.82-39.05) for eGFR<15 ml min(-1) per 1.73 m(2) and 5.47 (95% CI: 1.51-19.80) for eGFR 15-29 ml min(-1) per 1.73 m(2). In conclusion, the eGFR of <30 ml min(-1) per 1.73 m(2) was a significant and independent risk for in-hospital mortality in abroad cohort of Japanese patients with AMI.