Novel ITPA variants identified by whole genome sequencing and RNA sequencing.

Approximately 80% of rare diseases have a genetic cause, and an accurate genetic diagnosis is necessary for disease management, prognosis prediction, and genetic counseling. Whole-exome sequencing (WES) is a cost-effective approach for exploring the genetic cause, but several cases often remain undiagnosed. We combined whole genome sequencing (WGS) and RNA sequencing (RNA-seq) to identify the pathogenic variants in an unsolved case using WES. RNA-seq revealed aberrant exon 4 and exon 6 splicing of ITPA. WGS showed a previously unreported splicing donor variant, c.263+1G>A, and a novel heterozygous deletion, including exon 6. Detailed examination of the breakpoint indicated the deletion caused by recombination between Alu elements in different introns. The proband was found to have developmental and epileptic encephalopathies caused by variants in the ITPA gene. The combination of WGS and RNA-seq may be effective in diagnosing conditions in proband who could not be diagnosed using WES.

Ten-Year Clinical Observation of Immunoglobulin G4-Related Coronary Periarteritis with Aneurysms.

Coronary periarteritis with aneurysms has been reported as a cardiovascular manifestation of immunoglobulin G4 (IgG4) -related disease. We report a 10-year clinical observation of a patient with IgG4-related coronary periarteritis (IgG4-rCP) characterized by multiple thickening of periarterial tissue and coronary artery aneurysms (CAAs).A 60-year-old man with a history of IgG4-related autoimmune pancreatitis had an incidental detection of a total of 5 tumor-like lesions surrounding the right and left coronary arteries on coronary computed tomography angiography (CCTA) in 2012. Among them, 3 lesions were located at the middle to the distal portions of the right coronary artery (RCA) and the most proximal lesion was accompanied by a CAA. Although corticosteroid therapy was continued, 4-year follow-up of CCTA in 2016 showed the most proximal lesion gradually increased from 33 to 45 mm and the CAA enlarged from 9 to 22 mm. In order to avoid aneurysmal rupture, the patient underwent resection of the most proximal lesion with an enlarged aneurysm concomitant with coronary artery bypass grafting (CABG). Histopathological findings were coincident with IgG4-rCP. CCTA in 2018, however, showed the remaining distal tumor-like lesion of RCA had slightly enlarged and a new CAA developed despite the corticosteroid therapy. Follow-up CCTA in 2022 revealed the CAA increased to 13 mm, which showed rapid enlargement by 4 mm/year. A second operation through a re-median sternotomy was planned. The residual lesions with the CAA were resected followed by CABG. The other lesions at the left coronary artery remained stable without aneurysmal change, but careful follow-up has been continued.

Strategic validation of variants of uncertain significance in ECHS1 genetic testing.

BACKGROUND: Enoyl-CoA hydratase short-chain 1 (ECHS1) is an enzyme involved in the metabolism of branched chain amino acids and fatty acids. Mutations in the ECHS1 gene lead to mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, resulting in the accumulation of intermediates of valine. This is one of the most common causative genes in mitochondrial diseases. While genetic analysis studies have diagnosed numerous cases with ECHS1 variants, the increasing number of variants of uncertain significance (VUS) in genetic diagnosis is a major problem. METHODS: Here, we constructed an assay system to verify VUS function for ECHS1 gene. A high-throughput assay using ECHS1 knockout cells was performed to index these phenotypes by expressing cDNAs containing VUS. In parallel with the VUS validation system, a genetic analysis of samples from patients with mitochondrial disease was performed. The effect on gene expression in cases was verified by RNA-seq and proteome analysis. RESULTS: The functional validation of VUS identified novel variants causing loss of ECHS1 function. The VUS validation system also revealed the effect of the VUS in the compound heterozygous state and provided a new methodology for variant interpretation. Moreover, we performed multiomics analysis and identified a synonymous substitution p.P163= that results in splicing abnormality. The multiomics analysis complemented the diagnosis of some cases that could not be diagnosed by the VUS validation system. CONCLUSIONS: In summary, this study uncovered new ECHS1 cases based on VUS validation and omics analysis; these analyses are applicable to the functional evaluation of other genes associated with mitochondrial disease.

Involvement of GLCCI1 in mouse spermatogenesis.

Spermatid production is a complex regulatory process in which coordination between hormonal control and apoptosis plays a pivotal role in maintaining a balanced number of sperm cells. Apoptosis in spermatogenesis is controlled by pro-apoptotic and anti-apoptotic molecules. Hormones involved in the apoptotic process during spermatogenesis include gonadotrophins, sex hormones, and glucocorticoid (GC). GC acts broadly as an apoptosis inducer by binding to its receptor (glucocorticoid receptor: GR) during organ development processes, such as spermatogenesis. However, the downstream pathway induced in GC-GR signaling and the apoptotic process during spermatogenesis remains poorly understood. We reported previously that GC induces full-length glucocorticoid-induced transcript 1 (GLCCI1-long), which functions as an anti-apoptotic mediator in thymic T cell development. Here, we demonstrate that mature murine testis expresses a novel isoform of GLCCI1 protein (GLCCI1-short) in addition to GLCCI1-long. We demonstrate that GLCCI1-long is expressed in spermatocytes along with GR. In contrast, GLCCI1-short is primarily expressed in spermatids where GR is absent; instead, the estrogen receptor is expressed. GLCCI1-short also binds to LC8, which is a known mediator of the anti-apoptotic effect of GLCCI1-long. A luciferase reporter assay revealed that ß-estradiol treatment synergistically increased Glcci1-short promotor-driven luciferase activity in Erα-overexpressing cells. Together with the evidence that the conversion of testosterone to estrogen is preceded by aromatase expression in spermatids, we hypothesize that estrogen induces GLCCI1-short, which, in turn, may function as a novel anti-apoptotic mediator in mature murine testis.

Severe spinal cord hypoplasia due to a novel ATAD3A compound heterozygous deletion.

Biallelic deletions extending into the ATPase family AAA-domain containing protein 3A (ATAD3A) gene lead to infantile lethality with severe pontocerebellar hypoplasia (PCH). However, only 12 such cases have been reported worldwide to date, and the genotype-phenotype correlations are not well understood. We describe cases associated with the same novel biallelic deletions of the ATAD3A and ATAD3B/3A regions in Japanese siblings with severe spinal cord hypoplasia and multiple malformations, including PCH, leading to neonatal death. The ATAD3A protein is essential for normal interaction between mitochondria and endoplasmic reticulum and is important for mitochondrial biosynthesis. The cases were evaluated using whole-genome sequencing for genetic diagnosis of mitochondrial disease. Spinal cord lesions associated with biallelic compound heterozygous deletion extending into the ATAD3A gene have not been reported. In addition, the ATAD3A deletion was 19 base pairs long, which is short compared with those reported previously. This deletion introduced a frameshift, resulting in a premature termination codon, and was expected to be a null allele. The pathological findings of the atrophic spinal cord showed gliosis and tissue destruction of the gray and white matter. We describe spinal cord lesions as a new central nervous system phenotype associated with a biallelic compound heterozygous deletion extending into the ATAD3A gene. Biallelic ATAD3A deletions should be considered in cases of mitochondrial disease with spinal cord hypoplasia and PCH.

Impact of measuring heteroplasmy of a pathogenic mitochondrial DNA variant at the single-cell level in individuals with mitochondrial disease.

Pathogenic mitochondrial DNA heteroplasmy has mainly been assessed with bulk sequencing in individuals with mitochondrial disease. However, the distribution of heteroplasmy at the single-cell level in skin fibroblasts obtained from individuals, together with detailed clinical and biochemical information, remains to be investigated. We used the mitochondrial DNA single-cell assay for the transposase-accessible chromatin sequencing method. Skin fibroblasts were obtained from six individuals with mitochondrial disease and pathogenic m.3243A>G variants of differing severity. Different distributions of heteroplasmy at the single-cell level were identified in skin fibroblasts from all six individuals. Four individuals with different outcomes showed similar averaged heteroplasmy rates with normal mitochondrial respiratory chain enzyme activity, while the distribution of single-cell heteroplasmy patterns differed among the individuals. This study showed different heteroplasmy distribution patterns at the single-cell level in individuals with the m.3243A>G variant, who had a similar averaged heteroplasmy rates with normal mitochondrial respiratory chain enzyme activity. Whether such different heteroplasmy distribution patterns explain the different clinical outcomes should be assessed further in future studies. Measuring heteroplasmy of pathogenic mitochondrial DNA variants at the single-cell level could be important in individuals with mitochondrial disease.

P-Wave Terminal Force V1 Is Associated with Left Ventricular Diastolic Function in Patients with No Significant Perfusion Abnormality.

P-wave terminal force in lead V1 (PTFV1) is a marker of increased left atrial (LA) overload. Whether PTFV1 is associated with left ventricular (LV) diastolic function remains undetermined. We tested the hypothesis that PTFV1 is associated with LV diastolic parameters derived from gated myocardial perfusion single-photon emission computed tomography (SPECT) in patients with no significant perfusion abnormalities.The study population included 158 patients with preserved ejection fraction and no significant perfusion abnormalities. The amplitude and duration of the P-wave negative phase in lead V1 were measured using an electrocardiogram, and PTFV1 was calculated. The peak filling rate (PFR) and one-third mean filling rate (1/3 MFR) were obtained as LV diastolic parameters using gated SPECT.PTFV1 showed a weak correlation with the LA volume index (r = 0.31; P < 0.001). Significant associations were observed between PTFV1 and PFR (r = -0.27; P < 0.001) and 1/3 MFR (r = -0.26; P = 0.001). A multivariate linear regression analysis showed that age (ß = -0.26; P < 0.001), LV end-diastolic volume index (ß = -0.27; P = 0.001), and PTFV1 (ß = -0.15; P = 0.036) were significant factors associated with PFR. Moreover, male gender (ß = -0.16; P = 0.041), LV mass index (ß = -0.17; P = 0.046), and PTFV1 (ß = -0.17; P = 0.022) were significant factors associated with the 1/3 MFR.PTFV1 is associated with LV diastolic function, as derived from gated SPECT in patients with no significant perfusion abnormalities.

Neonatal-onset mitochondrial disease: clinical features, molecular diagnosis and prognosis.

OBJECTIVE: Neonatal-onset mitochondrial disease has not been fully characterised owing to its heterogeneity. We analysed neonatal-onset mitochondrial disease in Japan to clarify its clinical features, molecular diagnosis and prognosis. DESIGN: Retrospective observational study from January 2004 to March 2020. SETTING: Population based. PATIENTS: Patients (281) with neonatal-onset mitochondrial disease diagnosed by biochemical and genetic approaches. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Disease types, initial symptoms, biochemical findings, molecular diagnosis and prognosis. RESULTS: Of the 281 patients, multisystem mitochondrial disease was found in 194, Leigh syndrome in 26, cardiomyopathy in 38 and hepatopathy in 23 patients. Of the 321 initial symptoms, 236 occurred within 2 days of birth. Using biochemical approaches, 182 patients were diagnosed by mitochondrial respiratory chain enzyme activity rate and 89 by oxygen consumption rate. The remaining 10 patients were diagnosed using a genetic approach. Genetic analysis revealed 69 patients had nuclear DNA variants in 36 genes, 11 of 15 patients had mitochondrial DNA variants in five genes and four patients had single large deletion. The Cox proportional hazards regression analysis showed the effects of Leigh syndrome (HR=0.15, 95% CI 0.04 to 0.63, p=0.010) and molecular diagnosis (HR=1.87, 95% CI 1.18 to 2.96, p=0.008) on survival. CONCLUSIONS: Neonatal-onset mitochondrial disease has a heterogenous aetiology. The number of diagnoses can be increased, and clarity regarding prognosis can be achieved by comprehensive biochemical and molecular analyses using appropriate tissue samples.

Factors Influencing Cardiac Sympathetic Nervous Function in Patients With Severe Aortic Stenosis: Assessment by 123I-Metaiodobenzylguanidine Myocardial Scintigraphy.

BACKGROUND: Numerous studies have shown that 123I-metaiodobenzylguanidine (MIBG) scintigraphy, an index of cardiac sympathetic nervous (CSN) activity, is useful for predicting prognosis in patients with heart failure. However, the factors influencing the CSN activity of patients with severe aortic stenosis (AS) remain unclear. METHODS: We enrolled 91 patients with severe AS who underwent 123I-MIBG scintigraphy, coronary computed tomography (CCT), and transthoracic echocardiography. When CCT angiography (CCTA) showed an obstructive epicardial artery, invasive coronary angiography was performed within 1 week of CCTA. RESULTS: There were 21 male and 70 female patients with a mean age of 84±5 years. Eighty-five (85) patients (93%) had hypertension and 13 patients (14%) had diabetes. Two (2) patients (2%) had previous myocardial infarction and eight (9%) had a previous coronary intervention. All patients had severe AS: aortic valve area was 0.63±0.18 cm2 and the mean pressure gradient was 56±19 mmHg. Regarding 123I-MIBG parameters, early heart-to-mediastinum (H/M) ratio was 3.1±0.5, delayed H/M ratio was 2.8±0.6, and the washout rate (WR) was 35%±13%. Multivariable linear regression analysis showed that coronary artery disease (ß=-0.30, p=0.002) was an independent predictor of delayed H/M ratio, and that aortic valve area (ß=-0.20, p=0.048) was an independent predictor of WR. CONCLUSIONS: Our findings suggest that coronary artery disease is an independent predictor of delayed H/M ratio, and aortic valve area is an independent predictor of WR in patients with severe AS.

Development of Leigh syndrome with a high probability of cardiac manifestations in infantile-onset patients with m.14453G > A.

The m.14453G > A mutation in MT-ND6 has been described in a few patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes or Leigh syndrome.However, the clinical spectrum and molecular characteristics are unclear.Here, we present four infantile-onset patients with m.14453G > A-associated Leigh syndrome. All four patients had brainstem lesions with basal ganglia lesions, and two patients had cardiac manifestations. Decreased ND6 protein expression and immunoreactivity were observed in patient-derived samples. There was no clear correlation between heteroplasmy levels and onset age or between heteroplasmy levels and phenotype; however, infantile onset was associated with Leigh syndrome.

Genome sequencing and RNA-seq analyses of mitochondrial complex I deficiency revealed Alu insertion-mediated deletion in NDUFV2.

Isolated complex I deficiency is the most common cause of pediatric mitochondrial disease. Exome sequencing (ES) has revealed many complex I causative genes. However, there are limitations associated with identifying causative genes by ES analysis. In this study, we performed multiomics analysis to reveal the causal variants. We here report two cases with mitochondrial complex I deficiency. In both cases, ES identified a novel c.580G>A (p.Glu194Lys) variant in NDUFV2. One case additionally harbored c.427C>T (p.Arg143*), but no other variants were observed in the other case. RNA sequencing showed aberrant exon splicing of NDUFV2 in the unsolved case. Genome sequencing revealed a novel heterozygous deletion in NDUFV2, which included one exon and resulted in exon skipping. Detailed examination of the breakpoint revealed that an Alu insertion-mediated rearrangement caused the deletion. Our report reveals that combined use of transcriptome sequencing and GS was effective for diagnosing cases that were unresolved by ES.

The Monocyte to High-Density Lipoprotein Cholesterol Ratio Is Associated with Left Ventricular Diastolic Function in Patients with No Significant Perfusion Abnormality.

The monocyte to high-density lipoprotein cholesterol (HDL-C) ratio has been considered to be a prognostic marker. Whether this ratio is associated with left ventricular (LV) diastolic function remains undetermined. We tested the hypothesis that the monocyte to HDL-C ratio is associated with LV diastolic parameters derived from gated myocardial perfusion single-photon emission computed tomography (SPECT) in patients with no significant perfusion abnormality.The study population included 196 patients with no significant perfusion abnormalities and preserved ejection fraction. The peak filling rate (PFR) and one-third mean filling rate (1/3 MFR) were obtained as LV diastolic parameters using gated SPECT. Monocyte counts and plasma HDL-C levels were also examined.Significant associations were observed between the monocyte to HDL-C ratio and PFR (r = -0.20; P = 0.005) and 1/3 MFR (r = -0.19; P = 0.009). Multivariate linear regression analysis was performed to determine factors associated with LV diastolic parameters. Age (ß = -0.27; P < 0.001), LV end-diastolic volume (ß = -0.19; P = 0.034), and monocyte to HDL-C ratio (ß = -0.15; P = 0.027) were determined to be significantly associated with PFR. Moreover, age (ß = -0.13; P = 0.007), LV mass index (ß = -0.18; P = 0.037), and the monocyte to HDL-C ratio (ß = -0.13; P = 0.045) were significantly associated with 1/3 MFR.These results demonstrated that the monocyte to HDL-C ratio is associated with LV diastolic function, as derived from gated SPECT in patients with no significant perfusion abnormality.

Long-term prognosis and genetic background of cardiomyopathy in 223 pediatric mitochondrial disease patients.

BACKGROUND: Cardiomyopathy is a risk factor for poor prognosis in pediatric patients with mitochondrial disease. However, other risk factors including genetic factors related to poor prognosis in mitochondrial disease has yet to be fully elucidated. METHODS AND RESULTS: Between January 2004 and September 2019, we enrolled 223 consecutive pediatric mitochondrial disease patients aged <18 years with a confirmed genetic diagnosis, including 114 with nuclear gene mutations, 89 patients with mitochondrial DNA (mtDNA) point mutations, 11 with mtDNA single large-scale deletions and 9 with chromosomal aberrations. Cardiomyopathy at baseline was observed in 46 patients (21%). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for all-cause mortality. Over a median follow-up of 36 months (12-77), there were 85 deaths (38%). The overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p < 0.001, log-rank test). By multivariable analysis, left ventricular (LV) hypertrophy (HR = 4.6; 95% CI: 2.8-7.3), neonatal onset (HR = 2.9; 95% CI: 1.8-4.5) and chromosomal aberrations (HR = 2.9; 95% CI: 1.3-6.5) were independent predictors of all-cause mortality. Patients with LV hypertrophy with neonatal onset and/or chromosomal aberrations had higher mortality (100% in 21 patients) than those with LV hypertrophy alone (71% in 14 patients). CONCLUSION: In pediatric patients with mitochondrial disease, cardiomyopathy was common (21%) and was associated with increased mortality. LV hypertrophy, neonatal onset and chromosomal aberrations were independent predictors of all-cause mortality. Prognosis is particularly unfavorable if LV hypertrophy is combined with neonatal onset and/or chromosomal aberrations.

Clinical heterogeneity in patients with m.4412G > A MT-TM mutation and different heteroplasmy levels.

The identification of the m.4412G > A MT-TM (mt-tRNAMet) mutation was first reported in 2019. The affected individual presented with childhood-onset seizures and myopathy and bilateral basal ganglia changes, with heteroplasmy levels in muscle as high as 90%. Here, we describe another adult-onset patient with the same mutation and additional phenotypes, including hearing impairment, cerebellar ataxia, progressive dementia, and myopathy. The 10% heteroplasmy level observed in skin fibroblasts from this patient are lower than those in the previously reported patient. Our report suggests possible clinical heterogeneity in patients with mitochondrial tRNA mutations based on heteroplasmy levels.

Associations of frontal QRS-T angle with left ventricular volume and function derived from ECG-gated SPECT in patients with advanced chronic kidney disease.

BACKGROUND: The frontal QRS-T angle is one of markers of ventricular repolarization. We investigated whether or not the frontal QRS-T angle could predict left ventricular (LV) volume and function derived from ECG-gated SPECT in patients with advanced chronic kidney disease (CKD). METHODS: Two hundred and twelve patients with advanced CKD defined as estimated glomerular filtration rate of < 45 ml min-1/1.73 m2 were enrolled. Wide QRS-T angle was defined as its angle of > 90°, and was considered abnormal. Enlarged LV end-diastolic volume (LVEDV) was defined as LVEDV index of > 76 ml m-2 in men and > 57 ml m-2 in women. Reduced LV ejection fraction (LVEF) was defined as LVEF of < 40%. RESULTS: Fifty-one patients (24%) had wide QRS-T angle, and 161 patients (76%) had normal QRS-T angle. Patients with wide QRS-T angle had larger SSS [9 (5-16) vs 4 (1-9), p < 0.001], larger LVEDV index (69 ± 29 vs 50 ± 18 ml m-2, p < 0.001) and lower LVEF (47 ± 13 vs 59 ± 12%, p < 0.001) than those with normal QRS-T angle. Multivariate analysis showed that wide QRS-T angle (odds ratio 5.93; 95% CI 2.55-14.33; p < 0.001) was significantly associated with enlarged LVEDV, whereas SSS severity was not. Severely abnormal SSS (odds ratio 3.80; 95% CI 1.16-14.05; p < 0.03) and wide QRS-T angle (odds ratio 5.67; 95% CI 2.10-16.22; p < 0.001) were significantly associated with reduced LVEF. CONCLUSIONS: Our results suggest that wide QRS-T angle is associated with LV remodeling such as enlarged LVEDV or reduced LVEF in patients with advanced CKD.

Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in the ATAD3 locus.

BACKGROUND: In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosis. A contributing factor is the difficulty with repetitive regions of the genome, such as those generated by segmental duplications. The ATAD3 locus is one such region, in which recessive deletions and dominant duplications have recently been reported to cause lethal perinatal mitochondrial diseases characterized by pontocerebellar hypoplasia or cardiomyopathy, respectively. METHODS: Whole exome, whole genome and long-read DNA sequencing techniques combined with studies of RNA and quantitative proteomics were used to investigate 17 subjects from 16 unrelated families with suspected mitochondrial disease. FINDINGS: We report six different de novo duplications in the ATAD3 gene locus causing a distinctive presentation including lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently corneal clouding or cataracts and encephalopathy. The recurrent 68 Kb ATAD3 duplications are identifiable from genome and exome sequencing but usually missed by microarrays. The ATAD3 duplications result in the formation of identical chimeric ATAD3A/ATAD3C proteins, altered ATAD3 complexes and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue. CONCLUSIONS: ATAD3 duplications appear to act in a dominant-negative manner and the de novo inheritance infers a low recurrence risk for families, unlike most pediatric mitochondrial diseases. More than 350 genes underlie mitochondrial diseases. In our experience the ATAD3 locus is now one of the five most common causes of nuclear-encoded pediatric mitochondrial disease but the repetitive nature of the locus means ATAD3 diagnoses may be frequently missed by current genomic strategies. FUNDING: Australian NHMRC, US Department of Defense, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance and Australian Mito Foundation.

Aortic valve calcium is associated with left ventricular diastolic function in patients without evidence of ischaemic heart disease: assessment by gated single-photon emission computed tomography.

BACKGROUND: Several studies have shown that aortic valve calcium (AVC) is associated with cardiovascular events. Furthermore, the extent of AVC is associated with adverse prognosis even in patients without significant aortic stenosis. We investigated the relationship between AVC and left ventricular (LV) diastolic parameters determined by gated single-photon emission computed tomography (SPECT) in patients with no evidence of ischaemic heart disease. METHODS: This study included 157 patients with no evidence of ischaemic heart disease who underwent both coronary computed tomography and gated SPECT. The AVC scores were calculated by the Agatston method, and peak filling rate (PFR) and one-third mean filling rate (1/3 MFR) were determined as LV diastolic parameters. RESULTS: There were 93 (59%) and 64 (41%) patients with and without AVC, respectively, and the AVC scores ranged from 0 to 1251. There was no significant difference in LV end-diastolic volume (EDV) (60 ± 18 vs 62 ± 25 mL, p = 0.52) or LV ejection fraction (67% ± 10% vs 66% ± 8%, p = 0.60) between the two groups. Patients with AVC had lower PFR (2.2 ± 0.5 vs 2.4 ± 0.5 EDV/s, p = 0.002) and 1/3 MFR (1.3 ± 0.3 vs 1.5 ± 0.4 EDV/s, p = 0.003) than those without AVC. Multivariate linear regression analysis showed that ln(AVC score + 1) was significantly associated with PFR and 1/3 MFR. CONCLUSION: In patients without evidence of ischaemic heart disease, the extent of AVC was inversely correlated with gated SPECT-derived parameters of LV diastolic function.

Effects of Newly Developed Right Versus Left Bundle Branch Block on the QRS Axis, T-wave Axis and Frontal QRS-T Angle in Patients with a Narrow QRS.

Objective The QRS-T angle has been established as a repolarization marker. In the present study, we determined whether or not newly developed bundle branch block (BBB) affected the QRS-T angle in patients with a narrow QRS. Methods Twenty-four patients with newly developed BBB and no adverse cardiac events were retrospectively included. The frontal QRS-T angle was defined as the absolute value of the difference between the frontal plane QRS axis and the T-wave axis. These electrocardiogram parameters were serially measured in the settings of narrow QRS and BBB. Results Twelve patients had newly developed right BBB (RBBB), and 12 had newly developed left BBB (LBBB). The development of RBBB did not affect the QRS axis, T-wave axis of QRS-T angle (41° ±42° to 53° ±65°, p = 0.63). In contrast, the development of LBBB shifted the QRS axis to the left (25° ±29° to -18° ±31°, p = 0.003), resulting in an increased QRS-T angle (72° ±50° to 123° ±39°, p = 0.001). Regarding RBBB, an excellent correlation and agreement were found between the QRS-T angles in the setting of narrow QRS and RBBB (r = 0.88; p <0.001; bias, 2.9° ±20.9°). However, there was a significant bias between the QRS-T angles in the setting of narrow QRS and LBBB (51.9° ±40.4°; p = 0.001). Conclusion Our data suggested that the QRS-T angle in the setting of RBBB reflected the original QRS-T angle in the setting of narrow QRS well, whereas the QRS-T angle in the setting of LBBB did not.

Effects of upright T-wave in lead aVR on left ventricular volume and function derived from ECG-gated SPECT in patients with advanced chronic kidney disease.

BACKGROUND: Numerous studies have shown the association between chronic kidney disease (CKD) and adverse cardiac events. We investigated whether or not the upright T-wave in lead aVR (TaVR) could predict left ventricular (LV) volume and function derived from ECG-gated SPECT in patients with advanced CKD. METHODS: Two hundred and sixty-one patients with advanced CKD [estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2] were enrolled. Upright TaVR was defined as a wave with a positive deflection of > 0 mV. Enlarged LV end-diastolic volume (LVEDV) was defined as LVEDV index of > 76 ml/m2 in men and > 57 ml/m2 in women. Reduced LV ejection fraction (LVEF) was defined as LVEF of < 40%. RESULTS: Forty-six patients (18%) had upright TaVR, and 215 patients (82%) had negative TaVR. Summed redistribution score (SRS) [ 6 (1-12) vs. 2 (0-5), p < 0.001] and summed difference score (SDS) [4 (1-6) vs. 2 (0-4), p = 0.004] were significantly larger in patients with upright TaVR than those with negative TaVR. Patients with upright TaVR had larger LVEDV index (75 ± 33 ml/m2 vs. 50 ± 18 ml/m2, p < 0.001) and lower LVEF (43 ± 14% vs. 58 ± 11%, p < 0.001) compared to those with negative TaVR. After adjusted for other variables including SRS and SDS, upright TaVR remained a significant predictor of enlarged LVEDV (odds ratio 5.45; 95% CI 2.16-14.22; p < 0.001) and reduced LVEF (odds ratio 4.54; 95% CI 1.70-12.23; p = 0.003). CONCLUSIONS: Our data suggested that upright TaVR could predict LV volume and function derived from ECG-gated SPECT in patients with advanced CKD.