Kuan-Rau Chiou

Diffusion Tensor Magnetic Resonance Imaging Mapping the Fiber Architecture Remodeling in Human Myocardium After Infarction Correlation With Viability and Wall Motion

Background— Diffusion tensor magnetic resonance imaging (DT-MRI) provides a means for nondestructive characterization of myocardial architecture. We used DT-MRI to investigate changes in direction-dependent water diffusivity to reflect alterations in tissue integrity (trace apparent diffusion coefficients [ADCs] and fractional anisotropy [FA]), as well as indicators of remodeling of fiber helix angles, in patients after myocardial infarction. Methods and Results— Thirty-seven patients (35 men, 2 women; median age, 59) after acute myocardial infarction (median interval from onset, 26 days) were enrolled. DT-MRI was performed at the midventricular level to measure trace ADC, FA, and helix angles of myofibers. Helix angles were grouped into left-handed helical fibers, circumferential fibers, and right-handed helical fibers. Measurements were correlated with viability and regional wall motion assessed by contrast-delay-enhancement and cine MRI, respectively. The infarct zone showed significantly increased trace ADC and decreased FA than the remote zone. The percentage of left-handed helical fibers increased from the remote zone (mean±SD, 13.3±5.8%) to the adjacent zone (19.2±9.7%) and infarct zone (25.8±18.4%) (MANOVA, P=0.004). The percentage of right-handed helical fibers decreased from the remote zone (35.0±9.0%) to the adjacent zone (25.5±11.5%) and infarct zone (15.9±9.2%) (P<0.001). Multiple linear regression showed that the percentage of left-handed helical fibers of the infarct zone was the strongest correlate of infarct size and predictor of ejection fraction. Conclusions— In vivo DT-MRI of postinfarct myocardium revealed a significant increase in trace ADC and a decrease in FA, indicating altered tissue integrity. The redistribution of fiber architecture correlated with infarct size and left ventricular function. This technique may help us understand structural correlates of functional remodeling after infarction.

Sequential Changes of Myocardial Microstructure in Patients Postmyocardial Infarction by Diffusion-Tensor Cardiac Mr Correlation with Left Ventricular Structure and Function

Background—We used diffusion-tensor cardiac MR to investigate myocardial microstructure changes, including tissue integrity (mean diffusivity [MD], fractional anisotropy) and fiber architecture (helix angles) in patients with recent myocardial infarction (MI). This study aimed to investigate the sequential changes of myocardial microstructure and its relationships with changes of macrostructure and function of the left ventricle post-MI. Methods and Results—Seventeen patients (age, 55.1±11.5 years; all men) participated in the follow-up study. Diffusion-tensor cardiac MR, cine gradient echo for left ventricle function, and late gadolinium enhancement for viability were measured from recent to chronic MI (median interval, 191 days). When compared with the remote zone, the infarct-adjacent zone showed overall increase of MD (2-way MANOVA, F1,16=36.3; P<0.001), decrease of fractional anisotropy (F1,16=5.8; P=0.029), and decrease of mean helix angles (F1,16=62.0; P<0.001). From recent to chronic MI, there was overall sequential decrease of MD (F1,16=22.6; P<0.001) and increase of fractional anisotropy (F1,16=7.8; P=0.013). Multiple linear regression showed that the improvement of wall thickening in the infarct-adjacent zone correlated with sequential decrease of MD in the infarct-adjacent zone (r=−0.70; P=0.002) and increase of mean helix angles (ie, more right-handed helical myofiber reorientation, predominantly subendocardial location) in the remote zone (r=0.60; P=0.011). Likewise, wall thickening in the remote zone correlated with MD in the remote zone (r=−0.72; P=0.001) and mean helix angles in the infarct-adjacent zone (r=0.72; P=0.001). Conclusion—Diffusion-tensor cardiac MR suggests that sequential zonal improvement of tissue integrity and fiber architecture remodeling both associate with sequential recovery of zonal wall thickening of the left ventricle from recent to chronic MI.

Intramural Blood Pools Accompanying Aortic Intramural Hematoma: CT Appearance and Natural Course

PURPOSE To evaluate multidetector computed tomographic (CT) images to investigate the prevalence, morphology, natural course, and prognostic effect of intramural blood pools (IBPs) in patients with acute intramural hematoma (IMH). MATERIALS AND METHODS Institutional review board approval and written informed consent were obtained. Sixty-five patients (41 men; mean age, 65.9 years ± 11.3 [standard deviation]) with acute IMH undergoing three or more multidetector CT examinations during follow-up for 12 months or longer (median = 18 months), except for those undergoing surgery (n = 16), were enrolled. Associated factors of developing and resorption of IBP in IMH were analyzed by using logistic regression. RESULTS There were 40 IBPs in 10 patients at initial multidetector CT, and 15 new IBPs developed in 11 patients during follow-up. IBPs occurred most in the descending thoracic (55% [31 of 56]) and abdominal (41% [23 of 56]) aorta in 28% (18 of 65) of patients. During 33.8 months (range, 2.8-50 months) of follow-up in these 18 patients, 57% (32 of 56) of IBPs showed complete resorption in 15 patients, 29% (16 of 56) of IBPs showed incomplete resorption in eight patients, and 14% (eight of 56) of IBPs had interrupted follow-up because of surgery or death in three patients. Logistic regression showed that age younger than 70 years (odds ratio [OR], 8.74; 95% confidence interval [CI]: 1.03, 76.9) and IMH wall thickness greater than 10 mm (OR, 4.93; 95% CI: 1.04, 23.0) were associated with developing IBP at initial multidetector CT, while IBP with larger transmural diameter (OR, 1.16; 95% CI: 1.02, 1.31) and multidetector CT-demonstrated connection with intercostal or lumbar artery (63% [35 of 56]) (OR, 5.44; 95% CI: 1.43, 20.9) were associated with incomplete resorption. CONCLUSION IBPs are frequently observed at multidetector CT in patients with IMH. They may resolve over time or appear during follow-up. These findings are not associated with a poor prognosis, and IBPs should be distinguished from ulcerlike projections.

Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is commonly caused by mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 genes. The study aim was to investigate patients with FH in Taiwan, using molecular diagnostic methods, and compare the abnormalities in the small mutation and large DNA rearrangement subgroups. In total, 102 unrelated probands with FH were tested for mutations by exon-by-exon sequence analysis (EBESA) and multiple ligation-dependent probe amplification (MLPA). EBESA identified gene apolipoprotein B R3500W in 8 probands and 25 mis-sense, 5 nonsense, and 6 frameshift LDLR mutations in 52 probands; 11 were novel mutations. Of the 42 probands with mutations undetected by EBESA, 8 had abnormal MLPA patterns, including 2 with exon 6 to 18 deletions, 2 with exon 9 deletion, 1 with exon 6 to 8 deletions, 1 with exon 11 deletion, 1 with exon 3 to 5 duplications, and 1 with exon 7 to 12 duplications. Pedigree analysis showed mutation cosegregation with hypercholesterolemia in affected family members. Mean lipid profiles and rate of failure to lower LDL cholesterol <100 mg/dl in response to rosuvastatin/ezetimibe treatment were similar in groups with abnormal MLPA patterns and groups carrying nonsense or frameshift mutations. In conclusion, frequency of large LDLR rearrangement was approximately 8% in Taiwanese patients with FH. The response to statin drugs differed between probands with abnormal MLPA patterns and probands carrying mis-sense or undetected mutations.

Identification and viability assessment of infarcted myocardium with late enhancement multidetector computed tomography: Comparison with thallium single photon emission computed tomography and echocardiography

BACKGROUND Recent studies revealed that multidetector computed tomography late enhancement (MDCT-LE) is a reliable technique for detecting necrotic and scarred myocardial tissue. The aims of the study were to identify infarcted myocardium using MDCT-LE protocol in patients after myocardial infarction (MI) and assess viability in resting wall motion abnormalities. METHODS One hundred one patients with previous MI (62 +/- 13 years, 1-6 months after MI) underwent MDCT-LE (15 minutes after contrast medium administration), rest-redistribution thallium single photon emission computed tomography (Tl-SPECT), and dobutamine echocardiography (DbE). In a 17-segment model, infarcted myocardium detected by MDCT-LE was categorized as none, 1%-25%, 26%-50%, 51%-75%, or >75% segmental extent and was compared with decreased uptake of Tl-SPECT and contractile function by DbE on per patient and segmental basis in a blinded fashion. RESULTS By per patient analysis, MDCT-LE identified the presence of infarcted myocardium in 97 patients (96%), and Tl-SPECT decreased uptake in 88 patients (87%), (P = .02). By per segment analysis, the concordance for detecting infarcted myocardium was good (kappa value = 0.792). In segments with resting wall motion abnormalities (N = 486), there was moderate concordance in assessing viability (kappa value between MDCT and Tl-SPECT = 0.555, MDCT and DbE = 0.498, Tl-SPECT and DbE = 0.478) with predefined MDCT-LE threshold of 50% segmental extent. Among segments with MDCT-LE >75% segmental extent, the proportion designated nonviable by Tl-SPECT and DbE reached 87.8% and 92.2%, respectively. CONCLUSIONS Multidetector computed tomography late enhancement is accurate in identifying the presence and extent of infarcted myocardium. Its segmental extent has good correlation with the magnitude of thallium decreased uptake and can predict contractile reserve. Multidetector computed tomography late enhancement can be an alternative to assess viability.

Vascular stiffness in familial hypercholesterolaemia is associated with C-reactive protein and cholesterol burden

Background  Familial hypercholesterolaemia (FH) is characterized by very high serum cholesterol and premature coronary atherosclerosis. Arterial stiffness and atherosclerosis are two major underlying pathophysiologies of arterial disease that are predictive of future cardiovascular events. The aims of this study were to quantify atherosclerosis and arterial stiffness and to evaluate their relationship with high sensitive C‐reactive protein (hs‐CRP) and the level of exposure to high serum cholesterol in FH patients.

Comparison of left atrial volume parameters in detecting left ventricular diastolic dysfunction versus tissue Doppler recordings.

Because of diastolic coupling between the left atrium and left ventricle, we hypothesized that left atrial (LA) function mirrors the diastolic function of left ventricle. The aims of this study were to assess whether LA volume parameters can be good indexes of left ventricular diastolic dysfunction. Six hundred fifty-nine patients underwent cardiac catheterization and measurements of left ventricular filling pressure (LVFP). Echocardiographic examinations including tissue Doppler and LA volumes were also assessed. Ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity and LVFP tended to increase after progression of diastolic dysfunction. The inverse phenomenon existed in LA ejection and LA distensibility. LA distensibility was superior to LA ejection fraction and early diastolic mitral inflow velocity/early diastolic mitral annular velocity for identifying LVFP >15 mm Hg (areas under receiver operating characteristic curve 0.868, 0.834, and 0.759, respectively) and for differentiating pseudonormal from normal diastolic filling (areas under receiver operating characteristic curve 0.962, 0.907, and 0.741, respectively). Multivariate logistic regression showed that LA ejection fraction and LA distensibility were associated significantly with the presence of pseudonormal/restrictive ventricular filling. In conclusion, LA volume parameters can identify LVFP >15 mm Hg and differentiate among patterns of ventricular diastolic dysfunction. For assessing diastolic function LA parameters offer better performance than even tissue Doppler.

Left Atrial Expansion Index for Predicting Atrial Fibrillation and In-Hospital Mortality After Coronary Artery Bypass Graft Surgery

BACKGROUND Atrial fibrillation (AF), a common complication after coronary artery bypass graft surgery (CABG), is associated with prolonged hospital stay. This prospective study assessed the accuracy of left atrial parameters and additional preoperative characteristics for predicting post-CABG AF and in-hospital mortality. METHODS A total of 197 patients without hemodynamic-significant valvular problems, who received isolated CABG, were enrolled. Echocardiography was performed before CABG. RESULTS Compared with patients without post-CABG AF, those with post-CABG AF were older (71 vs 64 years, p<0.0001), had a higher incidence of CABG during index hospitalization of acute myocardial infarction and preoperative respiratory failure requiring ventilator support, lower left ventricular ejection fraction (0.41 vs 0.48, p<0.0001), lower left atrial expansion index (52.2% vs 93.3%, p<0.0001), and higher left ventricular filling pressure (24.2 vs 19.1 mm Hg, p<0.0001). Multivariate analysis of preoperative variables showed that independent predictors of AF included age (odds ratio [OR], 1.064; 95% confidence interval [CI], 1.022 to 1.107 per 1-year increase; p 0.002), maximal indexed left atrial volume (OR, 1.026; 95% CI, 1.002 to 1.051 per 1 mL/m2 increase; p 0.037) and left atrial expansion index (OR, 0.981; 95% CI, 0.962 to 0.998 per 1% increase; p 0.029). The left atrial expansion index was also significantly associated with in-hospital mortality (OR, 0.982; 95% CI, 0.951 to 0.996 per 1% increase; p 0.042). Incidence of post-CABG AF in patients with left atrial expansion index less than 120% progressively increased as left atrial expansion index decreased. CONCLUSIONS Left atrial expansion index independently predicts post-CABG AF and in-hospital mortality.

Array-based resequencing for mutations causing familial hypercholesterolemia

BACKGROUND Familial hypercholesterolemia (FH) is a heterogeneous autosomal dominant disease with a prevalence of 1 in 500. To date, over 1200 unique pathogenic mutations have been identified in at least 3 genes. The large allelic and genetic heterogeneity of FH requires high-throughput, rapid, and affordable mutation detection technology to efficiently integrate molecular screening into clinical practice. We developed an array-based resequencing assay to facilitate genetic testing in FH patients. METHODS AND RESULTS We designed a custom DNA resequencing array to detect mutations on all 3 FH-causing genes - LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 gene (PCSK9) - and 290 known insertion/deletion mutations on LDLR. We verified FH array performance by analyzing 35 previously sequenced subjects (21 with point mutations, 2 insertions, 7 deletions, and 5 healthy controls) and blindly screening 125 FH patients. The average microarray call rate was 98.45% and the agreement between microarray and capillary sequencing was 99.99%. The FH array detected mutations by using automated software analysis, followed by manual review in 28 of the 30 subjects (pickup rate, 93.3%). In the blinded study, the FH array detected at least 1 mutation in 77.5% of patients clinically diagnosed with definite FH according to Simon Broome FH criteria and in 52.9% with probable FH diagnosis. CONCLUSIONS The high-throughput FH resequencing array detects LDLR, APOB, and PCSK9 with high efficiency and accuracy and identifies disease-causing mutations. Thus, it facilitates large-scale screening of the heterogeneous FH populations.

Common mutations of familial hypercholesterolemia patients in Taiwan: characteristics and implications of migrations from southeast China.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. This study investigated FH patients carrying common mutations in Taiwan and compared them to FH southeastern Asians. Causal FH mutations were identified by exon-by-exon sequencing with/without multiplex ligation-dependent probe amplification among 208 Taiwanese with clinically diagnosed FH. Haplotype analyses among probands and family members were undertaken using TaqMan® Assays. Totally, LDLR mutations were found in 118 probands, consisting of 61 different loci, and APOB 10579C>T mutations in 12 probands. Three mutations (64delG, 1661C>T, and 2099A>G) were novel. LDLR 986G>A (13.1%), 1747C>T (10.8%), and APOB 10579C>T (9.2%) were common mutations with no differences in phenotypes. LDLR 1747C>T associated with one haplotype (CAAGCCCCATGG/(dTA)n-112nt); LDLR 986G>A with two. APOB 10579C>T associated with the same LDLR binding-domain pattern in Taiwanese and southeastern Asians. We concluded that LDLR 986G>A, 1747C>T and APOB 10579C>T are common mutations, with combined frequency of approximately 33%. The presence of different haplotypes associated with FH common mutations in Taiwan indicates multiple historical migrations, probable multiple recurrent origins from southern China, and haplotype homologies reflect the presence of common ancestors in southern China.