DNA-binding specificities of human transcription factors.

Although the proteins that read the gene regulatory code, transcription factors (TFs), have been largely identified, it is not well known which sequences TFs can recognize. We have analyzed the sequence-specific binding of human TFs using high-throughput SELEX and ChIP sequencing. A total of 830 binding profiles were obtained, describing 239 distinctly different binding specificities. The models represent the majority of human TFs, approximately doubling the coverage compared to existing systematic studies. Our results reveal additional specificity determinants for a large number of factors for which a partial specificity was known, including a commonly observed A- or T-rich stretch that flanks the core motifs. Global analysis of the data revealed that homodimer orientation and spacing preferences, and base-stacking interactions, have a larger role in TF-DNA binding than previously appreciated. We further describe a binding model incorporating these features that is required to understand binding of TFs to DNA.

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.

The interaction landscape between transcription factors and the nucleosome.

Nucleosomes cover most of the genome and are thought to be displaced by transcription factors in regions that direct gene expression. However, the modes of interaction between transcription factors and nucleosomal DNA remain largely unknown. Here we systematically explore interactions between the nucleosome and 220 transcription factors representing diverse structural families. Consistent with earlier observations, we find that the majority of the studied transcription factors have less access to nucleosomal DNA than to free DNA. The motifs recovered from transcription factors bound to nucleosomal and free DNA are generally similar. However, steric hindrance and scaffolding by the nucleosome result in specific positioning and orientation of the motifs. Many transcription factors preferentially bind close to the end of nucleosomal DNA, or to periodic positions on the solvent-exposed side of the DNA. In addition, several transcription factors usually bind to nucleosomal DNA in a particular orientation. Some transcription factors specifically interact with DNA located at the dyad position at which only one DNA gyre is wound, whereas other transcription factors prefer sites spanning two DNA gyres and bind specifically to each of them. Our work reveals notable differences in the binding of transcription factors to free and nucleosomal DNA, and uncovers a diverse interaction landscape between transcription factors and the nucleosome.

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.

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.

Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates.

Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.

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.

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.

ANISEED 2019: 4D exploration of genetic data for an extended range of tunicates.

ANISEED (https://www.aniseed.cnrs.fr) is the main model organism database for the worldwide community of scientists working on tunicates, the vertebrate sister-group. Information provided for each species includes functionally-annotated gene and transcript models with orthology relationships within tunicates, and with echinoderms, cephalochordates and vertebrates. Beyond genes the system describes other genetic elements, including repeated elements and cis-regulatory modules. Gene expression profiles for several thousand genes are formalized in both wild-type and experimentally-manipulated conditions, using formal anatomical ontologies. These data can be explored through three complementary types of browsers, each offering a different view-point. A developmental browser summarizes the information in a gene- or territory-centric manner. Advanced genomic browsers integrate the genetic features surrounding genes or gene sets within a species. A Genomicus synteny browser explores the conservation of local gene order across deuterostome. This new release covers an extended taxonomic range of 14 species, including for the first time a non-ascidian species, the appendicularian Oikopleura dioica. Functional annotations, provided for each species, were enhanced through a combination of manual curation of gene models and the development of an improved orthology detection pipeline. Finally, gene expression profiles and anatomical territories can be explored in 4D online through the newly developed Morphonet morphogenetic browser.

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.

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.

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.

DNA-dependent formation of transcription factor pairs alters their binding specificity.

Gene expression is regulated by transcription factors (TFs), proteins that recognize short DNA sequence motifs. Such sequences are very common in the human genome, and an important determinant of the specificity of gene expression is the cooperative binding of multiple TFs to closely located motifs. However, interactions between DNA-bound TFs have not been systematically characterized. To identify TF pairs that bind cooperatively to DNA, and to characterize their spacing and orientation preferences, we have performed consecutive affinity-purification systematic evolution of ligands by exponential enrichment (CAP-SELEX) analysis of 9,400 TF-TF-DNA interactions. This analysis revealed 315 TF-TF interactions recognizing 618 heterodimeric motifs, most of which have not been previously described. The observed cooperativity occurred promiscuously between TFs from diverse structural families. Structural analysis of the TF pairs, including a novel crystal structure of MEIS1 and DLX3 bound to their identified recognition site, revealed that the interactions between the TFs were predominantly mediated by DNA. Most TF pair sites identified involved a large overlap between individual TF recognition motifs, and resulted in recognition of composite sites that were markedly different from the individual TF's motifs. Together, our results indicate that the DNA molecule commonly plays an active role in cooperative interactions that define the gene regulatory lexicon.

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.

A homozygous variant in NDUFA8 is associated with developmental delay, microcephaly, and epilepsy due to mitochondrial complex I deficiency.

Mitochondrial complex I deficiency is caused by pathogenic variants in mitochondrial and nuclear genes associated with complex I structure and assembly. We report the case of a patient with　NDUFA8-related mitochondrial disease. The patient presented with developmental delay, microcephaly, and epilepsy. His fibroblasts showed apparent biochemical defects in mitochondrial complex I. Whole-exome sequencing revealed that the patient carried a homozygous variant in NDUFA8. His fibroblasts showed a reduction in the protein expression level of not only NDUFA8, but also the other complex I subunits, consistent with assembly defects. The enzyme activity of complex I and oxygen consumption rate were restored by reintroducing wild-typeNDUFA8 cDNA into patient fibroblasts. The functional properties of the variant in NDUFA8 were also investigated using NDUFA8 knockout cells expressing wild-type or mutated NDUFA8 cDNA. These experiments further supported the pathogenicity of the variant in complex I assembly. This is the first report describing that the loss of NDUFA8, which has not previously been associated with mitochondrial disease, causes severe defect in the assembly of mitochondrial complex I, leading to progressive neurological and developmental abnormalities.

Non-Invasive Central Venous Pressure Measurement Using Enclosed-Zone Central Venous Pressure (ezCVPTM).

BACKGROUND: Central venous pressure (CVP) is measured to assess intravascular fluid status. Although the clinical gold standard for evaluating CVP is invasive measurement using catheterization, the use of catheterization is limited in a clinical setting because of its invasiveness. We developed novel non-invasive technique, enclosed-zone (ezCVPTM) measurement for estimating CVP. The purpose of this study was to assess the feasibility of ezCVP and the relationship between ezCVP and CVP measured by a catheter.Methods and Results:We conducted 291 measurements in 97 patients. Linear regression analysis revealed that ezCVP was significantly correlated with CVP (r=0.65, P<0.0001). The Bland-Altman analysis showed that ezCVP had an underestimation bias of -2.5 mmHg with 95% limits of agreement of -14.1 mmHg and 9.6 mmHg for CVP (P<0.0001). The areas under the curves of receiver operating curve with ezCVP to detect the CVP ≥12 cmH2O (8.8 mmHg) and CVP >10 mmHg were 0.81 or 0.88, respectively. The sensitivity, specificity and positive likelihood ratio of ezCVP for the CVP ≥8.8 mmHg and CVP >10 mmHg were 0.59, 0.96 and 14.8 with a cut-off value of 11.9 and 0.79, 0.97 and 26.3 with a cut-off value of 12.7. CONCLUSIONS: These findings suggest that ezCVP measurement is feasible and useful for assessing CVP.

Frontal QRS-T angle and left ventricular diastolic function assessed by ECG-gated SPECT in the absence of significant perfusion abnormality.

The frontal QRS-T angle, defined as the angle between QRS and T-wave axes, has recently become an area of research interest. We tested the hypothesis that the frontal QRS-T angle is associated with left ventricular (LV) diastolic function in the absence of significant perfusion abnormality using ECG-gated SPECT. One hundred twenty eight patients with no significant perfusion abnormality and preserved LV ejection fraction were enrolled. The peak filling rate (PFR) and the one-third mean filling rate (1/3 MFR) were obtained as LV diastolic parameters on ECG-gated SPECT. There were 115 male and 13 female patients with a mean age of 70 ± 9 years. The PFR and 1/3 MFR were 2.1 ± 0.4/s and 1.2 ± 0.3/s, respectively. The frontal QRS-T angle was 33° ± 31°, ranging from 0° to 151°. There were significant associations of frontal QRS-T angle with PFR (r = - 0.29, p = 0.001) and 1/3 MFR (r = - 0.30, p < 0.001). Multivariate linear regression analysis showed that age (ß = - 0.25, p = 0.003), heart rate (ß = 0.26, p = 0.002), LV ejection fraction (ß = 0.43, p < 0.001) and frontal QRS-T angle (ß = - 0.16, p = 0.03) were significant factors associated with PFR. Also, heart rate (ß = - 0.32, p < 0.001), LV mass index (ß = - 0.19, p = 0.03), LV ejection fraction (ß = 0.30, p < 0.001) and frontal QRS-T angle (ß = - 0.26, p = 0.002) were significant factors associated with 1/3 MFR. Our data suggested that the frontal QRS-T angle was associated with LV diastolic function in the absence of significant perfusion abnormality.

Associations of left ventricular shape with left ventricular volumes and functions assessed by ECG-gated SPECT in patients without significant perfusion abnormality.

Left ventricular (LV) remodeling often results from conditions with an elevated LV hemodynamic load or after myocardial infarction. The present study was undertaken to investigate the associations of LV shape with LV volumes and functions in patients without significant perfusion abnormality. One hundred and sixty-seven patients without significant perfusion abnormality on ECG-gated SPECT were enrolled. LV ejection fraction (LVEF) was obtained for assessing LV systolic function. Peak filling rate (PFR) and one-third mean filling rate (1/3 MFR) were obtained for assessing LV diastolic function. LV shape index (LVSI) was defined as the ratio of the maximum three-dimensional short- and long-axis LV dimension, and varies from 0 (line) to 1 (sphere). There were 125 male and 42 female patients with a mean age of 70 ± 8 years. End-systolic LVSI was 0.49 ± 0.07 (0.34-0.65). End-systolic LVSI was associated with LV end-diastolic volume (r = 0.51, p < 0.001) and LV end-systolic volume (LVESV) (r = 0.64, p < 0.001), and was inversely associated with LVEF (r = - 0.69, p < 0.001), PFR (r = - 0.45, p < 0.001) and 1/3 MFR (r = - 0.26, p = 0.008). End-systolic LVSI was increased with increased LVESV, and was not any more with LVESV of > 40 ml. Multivariate liner regression analysis showed that age (ß = 0.16, p = 0.01), LVESV (ß = 0.20, p = 0.03) and LVEF (ß = - 0.53, p < 0.001) were significantly associated with end-systolic LVSI. Our data suggest that end-systolic LVSI, a measurement of LV shape, has close correlations with LV volumes and functions in patients without significant perfusion abnormality.

Effects of aging on coronary flow reserve in patients with no evidence of myocardial perfusion abnormality.

Coronary flow reserve (CFR) reflects the functional capacity of microcirculation to adapt to blood demand during increased cardiac work. We tested the hypothesis that aging had impacts on coronary flow velocities and CFR in patients with no evidence of myocardial perfusion abnormality on single photon emission computed tomography (SPECT). Seventy-six patients undergoing transthoracic Doppler echocardiography with no evidence of myocardial perfusion abnormality on SPECT were enrolled in this study. CFR was defined as the ratio of hyperemic to resting peak diastolic coronary flow velocity. Patients were divided into the three groups based on age: 17 patients aged less than 70 years (Group I), 38 patients aged 70-79 years (Group II), and 21 patients aged 80 years or more (Group III). Compared with Group I, CFR was significantly lower in Group II (p < 0.01) and Group III (p < 0.01). Multivariate linear regression analysis showed that female (ß = - 0.26, p = 0.03), cigarette smoking (ß = - 0.32, p = 0.004), hemoglobin level (ß = - 0.40, p = 0.001) and LV mass index (ß = 0.24, p = 0.03) were determinants for resting coronary flow velocity. On the other hand, age (ß = -0.30, p = 0.008), hemoglobin level (ß = -0.47, p < 0.001) and LV mass index (ß = 0.24, p = 0.04) were determinants for hyperemic coronary flow velocity. Age was only determinant for CFR (ß = -0.48, p < 0.001). Our data suggested that that aging had a decreased effect on hyperemic coronary flow velocity rather than resting coronary flow velocity, and was further associated with impaired CFR in patients with no evidence of myocardial perfusion abnormality.